Bachmann-Bupp Syndrome

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Classifications

Harrison's Part

ICIMD (Inherited Metabolic Disorders)

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Inheritance

2

Autosomal dominant HP:0000006

Heterozygous ODC1 variants are sufficient; reported cases have been de novo, so recurrence risk to siblings is presumed low.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:36007106 SUPPORT Human Clinical

"BABS is expressed in an autosomal dominant manner and typically caused by a de novo ODC1 pathogenic variant."

GeneReviews states the autosomal dominant mode and the de novo origin of the causative variant.

PMID:36443247 SUPPORT Human Clinical

"Bachmann-Bupp syndrome (OMIM #619075) is a novel autosomal dominant disorder caused by variants in the c-terminus of the ornithine decarboxylase 1 gene, resulting in increased levels of ornithine decarboxylase."

Independent confirmation of autosomal dominant transmission and of the C-terminal location of the causative variants.

De novo occurrence HP:0003745

Reported causative variants have generally arisen de novo; the founding four-patient cohort documented de novo heterozygous alleles in all four individuals. Parental testing is needed to establish origin in an individual family.

Sporadic

Show evidence (1 reference)

PMID:30475435 SUPPORT Human Clinical

"In this report, we present four patients with a distinct neurometabolic disorder associated with de novo heterozygous, gain-of-function variants in the ODC1 gene."

A four-patient cohort in which every causative allele arose de novo.

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Discussions and Knowledge Gaps

2

The K6/ODC mouse reproduces the alopecia and follicular cysts of BABS and predicted the DFMO response, but it also develops skin tumours and is skin-restricted. Does whole-body expression of stabilised ODC in BABS patients carry a tumour risk, and does the absence of a whole-body model mean the neurodevelopmental arm of the disease has never been modelled?

HUMAN MODEL MISMATCH OPEN babs_k6odc_model_scope_and_cancer_risk

Attached to

pathophysiology#Dysregulated Neural Progenitor Proliferation

The only well-characterised animal model of this exact lesion targets the transgene to hair follicle keratinocytes. Its tumour phenotype has been interpreted as evidence that polyamine excess promotes tumorigenesis, and the index human cohort report raised cancer surveillance as a consideration on that basis. But no BABS patient tumour series exists, GeneReviews does not recommend tumour surveillance, and there is no whole-body C-terminally-truncated-ODC model in which the neurodevelopmental phenotype could be studied. The mismatch matters in both directions: it risks over-calling a cancer risk that has not been observed in patients, and it leaves the central neurodevelopmental mechanism without an in vivo model.

Proposed experiments

Whole-body or CNS-conditional Odc1 C-terminal truncation knock-in

exp_babs_whole_body_truncation_knockin

Generate a mouse carrying a knock-in of a human-equivalent C-terminally truncated Odc1 allele expressed ubiquitously or conditionally in neural lineages, rather than under a keratin 6 promoter, and characterise cortical progenitor proliferation, brain growth, white matter development and response to eflornithine started at different postnatal ages.

Prospective tumour-surveillance registry across the BABS cohort

exp_babs_tumour_surveillance_registry

Assemble a prospective, standardised tumour-surveillance registry across the international BABS cohort to establish whether the mouse skin-tumour phenotype has any human counterpart, and whether long-term eflornithine exposure modifies it.

Show evidence (2 references)

PMID:30475435 SUPPORT Human Clinical

"As the ODC1 gene has been implicated in neoplasia, cancer surveillance may be important in this disorder."

The index cohort raises cancer surveillance as a hypothesis, phrased as a possibility rather than a recommendation.

PMID:41925768 SUPPORT REVIEW SYNTHESIS Human Clinical

"However, unlike the K6/ODC mouse where this mutation was directed to the skin, the ODC mutation is expressed in all tissues of BABS patients resulting in macrosomia, macrocephaly, neurodevelopmental delay, spasticity, hypotonia, delayed visual maturation, and sensorineural hearing loss"

States the exact scope difference between the model and the human disease.

Does earlier initiation of eflornithine, for example in a neonate diagnosed before neurological damage accrues, change the neurodevelopmental trajectory of BABS?

KNOWLEDGE GAP OPEN babs_treatment_window_neonatal_initiation

Attached to

pathophysiology#Abnormal Brain Development

The index patient began eflornithine at 4 years 8 months. A later treatment review reports diagnosis and treatment across ages from the neonatal period to adulthood, so a blanket absence of neonatal treatment is outdated. Whether earlier initiation changes neurodevelopmental outcomes remains unresolved without comparable longitudinal assessments.

Proposed experiments

Natural-history cohort comparing early versus late eflornithine initiation

exp_babs_early_versus_late_initiation_cohort

Establish a prospective international natural-history cohort with standardised developmental assessment at fixed ages, then compare developmental trajectories, MRI findings and N-acetylputrescine normalisation between patients started on eflornithine before and after 12 months of age.

Show evidence (2 references)

PMID:34282722 SUPPORT Human Clinical

"This could be especially consequential if we could initiate therapy in a neonate diagnosed early before neurological damage occurs."

The treating team states the open question directly.

PMID:40167220 SUPPORT Human Clinical

"The age of diagnosis and the onset of treatment has also varied from the neonatal period to adulthood."

The later review qualifies the original early-treatment question; it does not supply a controlled comparison of treatment windows.

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Pathophysiology

11

ODC1 C-Terminal Truncating Variant

Heterozygous nonsense, frameshift, and splice-site variants affecting the ODC1 C-terminal region produce shortened ODC proteins. The index c.1342A>T (p.Lys448Ter) allele removes the final 14 amino acids; other alleles truncate different portions of the C-terminal region.

ODC1 hgnc:8109 ⚠ ABNORMAL

Genetic context ODC1 hgnc:8109 variant_origin: DE_NOVO zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION

Reported de novo heterozygous nonsense, frameshift, and splice-site alleles converge on C-terminal truncation and increased enzyme abundance. Splice consequences are predicted for some alleles rather than directly assayed.

Downstream

Escape from Antizyme-Mediated Proteasomal Degradation Loss of the C-terminal degron removes the signal that normally targets ODC for ubiquitin-independent proteasomal turnover.

Show evidence (5 references)

PMID:37469105 SUPPORT Human Clinical

"The condition is caused by 3'-end mutations of the ornithine decarboxylase 1 (ODC1) gene, which produce carboxy (C)-terminally truncated variants of ODC, a pyridoxal 5'-phosphate-dependent enzyme."

Names the location of the causative variants and the protein consequence that defines this node.

PMID:30239107 SUPPORT Human Clinical

"Here, we report an 32-month-old Caucasian female with a heterozygous de novo nonsense mutation in the ODC1 gene that leads to a premature abrogation of 14-aa residues at the ODC protein c-terminus."

The index case defines the specific lesion: a de novo nonsense variant truncating the last 14 residues.

PMID:34477286 SUPPORT Human Clinical

"Variants continue to cluster, providing support to a universal biochemical mechanism related to elevated ODC protein, enzyme activity, and abnormalities in polyamine levels."

Establishes that the reported variants cluster in one region and converge on a single biochemical mechanism.

+ 2 more references

Escape from Antizyme-Mediated Proteasomal Degradation

Wild-type ODC is one of the shortest-lived mammalian proteins because its C-terminus acts as a degron for ubiquitin-independent, antizyme-dependent proteasomal degradation. The truncated BABS enzyme cannot be cleared by this route, so it escapes normal turnover. This is a stability defect, not a catalytic defect.

proteasomal ubiquitin-independent protein catabolic process GO:0010499 ↓ DECREASED

Experimental models

Engineered murine ODC C-terminal truncation in mammalian cells OTHER Engineered tail deletion increases intracellular stability; the quoted experiment does not isolate antizyme binding as the affected step.

Downstream

ODC Protein Accumulation A protein that cannot be degraded accumulates in the cell.

Show evidence (7 references)

PMID:40382142 SUPPORT Human Clinical

"These shortened ODC proteins remain enzymatically active and are not cleared by the proteasome, therefore leading to ODC protein accumulation in cells."

States both halves of this node: preserved catalysis and failed proteasomal clearance.

PMID:31249027 SUPPORT In Vitro

"We hypothesized that this new mutation (c.1342 A>T) leads to a C-terminal truncation variant of the ODC protein that is resistant to normal proteasomal degradation, leading to putrescine accumulation in cells."

States the degradation-resistance hypothesis that the same study then tested in patient-derived cells.

PMID:41925768 SUPPORT Model Organism

"a premature stop codon at position 427 in the mouse ODC cDNA was placed downstream of the K6 promoter resulting in a carboxyl-truncated ODC protein with a much longer in vivo half-life than the full-length ODC protein"

The engineered mouse allele demonstrates that C-terminal truncation alone extends the half-life of the ODC protein.

+ 4 more references

ODC Protein Accumulation

Stabilised ODC protein accumulates to large excess in patient cells, demonstrated in primary dermal fibroblasts and in red blood cells.

fibroblast CL:0000057 erythrocyte CL:0000232

Experimental models

Index-patient dermal fibroblasts and DFMO rescue PRIMARY CELL CULTURE Patient fibroblasts contain elevated ODC protein.

Downstream

Elevated ODC Enzyme Activity The accumulated truncated protein remains catalytically active; elevated protein and ODC activity were measured in cells from the index patient.

Show evidence (2 references)

PMID:31249027 SUPPORT In Vitro

"In this study, we show that primary dermal fibroblasts derived from a skin biopsy of a 3-year-old patient contain large amounts of ODC protein and putrescine compared with primary dermal (neonatal and adult) fibroblast control cells."

Direct measurement of accumulated ODC protein in patient-derived fibroblasts.

PMID:30239107 SUPPORT Human Clinical

"Red blood cells obtained from our patient showed elevated ODC protein and polyamine levels compared to healthy controls."

Confirms ODC protein accumulation in a second, circulating patient cell type.

Elevated ODC Enzyme Activity

In the index patient, ODC activity was 12-17-fold above controls in cultured dermal fibroblasts and 125-137-fold in red blood cells. These are preparation-specific measurements from one patient, not established ranges for all BABS alleles. ODC catalyzes the rate-limiting conversion of ornithine to putrescine.

polyamine biosynthetic process GO:0006596 ↑ INCREASED

ornithine decarboxylase activity GO:0004586 ↑ INCREASED

Experimental models

Index-patient dermal fibroblasts and DFMO rescue PRIMARY CELL CULTURE Radiolabeled ornithine assay detected elevated catalytic activity.

Downstream

Putrescine Accumulation ODC converts ornithine to putrescine; excess enzyme activity drives putrescine accumulation.

Ornithine Substrate Depletion Excess ornithine consumption by ODC is a proposed explanation for low plasma ornithine and its rise during treatment; flux was not directly measured.

Show evidence (3 references)

PMID:31249027 SUPPORT In Vitro

"Importantly, the accumulated ODC protein variant remained functionally active as we detected exceptionally high ODC enzyme activity in both primary dermal fibroblasts (12-17-fold of controls) and red blood cells (RBCs) (125-137-fold of controls), using a specific 14C radioactive ODC activity assay."

Quantifies the magnitude of the enzyme-activity gain in patient material.

PMID:41410504 SUPPORT Human Clinical

"Bachmann-Bupp syndrome results from heterozygous gain-of-function variants in the ornithine decarboxylase 1 (ODC1) gene, resulting in increased ornithine decarboxylase enzyme activity."

The polyaminopathy review states increased enzyme activity as the defining biochemical consequence.

PMID:30475435 SUPPORT Human Clinical

"Ornithine decarboxylase 1 (ODC1) is the rate-limiting enzyme in endogenous polyamine synthesis."

Establishes why a change in ODC activity controls flux through the whole polyamine pathway.

Putrescine Accumulation

Putrescine, the immediate product of ODC, accumulates in patient cells. It is the proximate biochemical lesion of BABS and the target of eflornithine therapy.

Experimental models

Index-patient dermal fibroblasts and DFMO rescue PRIMARY CELL CULTURE DFMO reduced the elevated putrescine pool to control levels in culture.

Downstream

Elevated N-Acetylputrescine Excess putrescine is acetylated, and it is the acetylated species that is measurable on clinical metabolomic profiling.

Hair Follicle Dysfunction Sustained ODC activity and elevated polyamine biosynthesis perturb follicular function in the skin-restricted transgenic model; the intermediate steps producing human alopecia are unresolved.

Dysregulated Neural Progenitor Proliferation ODC1 expression tracks neural progenitor proliferation in fetal brain and cerebral organoids; gain of function is proposed to drive over-proliferation. The steps between the raised polyamine pool and the progenitor phenotype are not established.

Show evidence (4 references)

PMID:31249027 SUPPORT In Vitro

"In this study, we show that primary dermal fibroblasts derived from a skin biopsy of a 3-year-old patient contain large amounts of ODC protein and putrescine compared with primary dermal (neonatal and adult) fibroblast control cells."

Direct measurement of putrescine accumulation in patient-derived cells.

PMID:40382142 SUPPORT Human Clinical

"ODC is a key enzyme of polyamine biosynthesis by converting ornithine to putrescine, and if accumulated, can lead to high putrescine levels in human cells including red blood cells (RBCs) and primary dermal fibroblasts."

States that accumulated ODC leads to high putrescine in patient cell types.

PMID:30475435 SUPPORT Human Clinical

"Plasma clinical metabolomics analysis demonstrates elevation of N-acetylputrescine, the acetylated form of putrescine, with otherwise normal polyamine levels."

The four-patient study reports elevated N-acetylputrescine with otherwise normal plasma polyamines. This plasma result does not exclude changes in spermidine or spermine in other cell types or preparations.

+ 1 more reference

Ornithine Substrate Depletion

Plasma ornithine sat below the 2.5th percentile of a paediatric reference cohort before treatment in the first treated patient and normalised on eflornithine, consistent with excess consumption by the overactive enzyme.

Show evidence (2 references)

PMID:34282722 SUPPORT Human Clinical

"Ornithine andN-acetylarginine were below the 2.5th percentile at start of therapy and normalized to the larger pediatric values over the course of therapy."

Documents the pre-treatment ornithine deficit and its correction on ODC inhibition, which is what makes substrate drawdown by the overactive enzyme the most parsimonious explanation. The snippet reproduces a missing-space text-extraction artefact present in the cached source ("andN-acetylarginine") and is quoted byte-exactly rather than tidied.

PMID:34282722 SUPPORT Human Clinical

"Urea cycle components citrulline and arginine, along with other metabolites, remained at 1 to -1 standard deviation throughout the study period"

Citrulline and arginine remained within the reported reference range during this patient’s treatment. This does not prove that every urea-cycle process or metabolite is unaffected.

Elevated N-Acetylputrescine

N-acetylputrescine is the clinically measurable signature of the accumulated putrescine pool and is the metabolite that makes metabolomic profiling diagnostically suggestive of BABS. Other polyamine levels may be normal.

Show evidence (2 references)

PMID:30475435 SUPPORT Human Clinical

"Plasma clinical metabolomics analysis demonstrates elevation of N-acetylputrescine, the acetylated form of putrescine, with otherwise normal polyamine levels."

Establishes the elevation and its selectivity within the polyamine panel.

PMID:36007106 SUPPORT Human Clinical

"The finding of abnormal polyamine pathway metabolites (including increased N-acetylputrescine) on metabolomic profiling is suggestive of a diagnosis of BABS."

GeneReviews makes this metabolite the biochemical entry point to the diagnosis.

Hair Follicle Dysfunction

Constitutive expression of truncated ODC in outer root sheath keratinocytes disrupts hair cycling in K6/ODC mice. Hair loss after the first cycle resembles the postnatal alopecia in BABS. A separate inducible ODC-ER model recruits bulge stem cells while retaining a normal skin phenotype, so recruitment is not established as the cause of BABS alopecia.

outer root sheath cell CL:0002561

Animal models

Skin-restricted K6/ODC transgenic mouse Mus musculus partially recapitulates Postnatal hair loss and DFMO-induced regrowth reproduce the ectodermal phenotype.

Downstream

Follicular Cyst Formation Follicular cyst formation accompanies constitutive ODC overexpression and abnormal hair cycling in the transgenic model. The tissue intermediates have not been fully resolved.

Alopecia Follicular dysfunction is linked to alopecia by the transgenic skin phenotype and DFMO response; direct human follicle measurements are limited.

Absent eyebrow Eyebrow and eyelash involvement extend the observed follicular phenotype; the mechanism of regional hair loss remains incompletely defined.

Sparse eyebrow Eyebrow and eyelash involvement extend the observed follicular phenotype; the mechanism of regional hair loss remains incompletely defined.

Sparse or absent eyelashes Eyebrow and eyelash involvement extend the observed follicular phenotype; the mechanism of regional hair loss remains incompletely defined.

Show evidence (2 references)

PMID:8618048 SUPPORT Model Organism

"These transgenic mice have a normal first hair cycle, but lose their hair completely beginning 2-3 wk after birth."

Establishes the hair-cycle-specific timing of the defect in the model that carries the same class of lesion.

PMID:8618048 SUPPORT Model Organism

"Mice that overexpress a mutated ornithine decarboxylase (ODC) transgene in outer root sheath keratinocytes of the hair follicle were used to study the role of this enzyme in regulating hair follicle structure and function."

Identifies the outer root sheath keratinocyte as the cell type in which excess ODC produces the follicular phenotype.

Follicular Cyst Formation

Recurrent follicular cysts form on the scalp, neck and back, beginning as small maculopapular pustules and enlarging to several centimetres, sometimes requiring surgical removal.

Downstream

Cutaneous cyst Follicular cyst formation produces the recurrent cutaneous cyst phenotype.

Show evidence (2 references)

PMID:34282722 SUPPORT Human Clinical

"Multiple lesions located on the posterior scalp and back that first were small maculopapular pustules slowly increased in size to approximately 6-7 cm in diameter"

Describes the natural history and size of the cysts in a genotyped patient.

PMID:7671221 SUPPORT Model Organism

"Effects observed include development of dermal follicular cysts, excessive skin wrinkling, enhanced nail growth, alopecia, and spontaneous tumor development."

The original transgenic report lists dermal follicular cysts alongside alopecia and accelerated nail growth, the ectodermal cluster later recognised in BABS patients.

Dysregulated Neural Progenitor Proliferation

Mechanism confidence: Provisional

ODC1 expression during fetal brain development and in cerebral organoids associates with neural progenitor cell proliferation, and gain-of-function variants are proposed to produce neural over-proliferation. This node is the weakest link in the chain: the human neurodevelopmental phenotype is not yet mechanistically connected to a measured progenitor abnormality in BABS patient tissue.

neural progenitor cell CL:0011020

neural precursor cell proliferation GO:0061351 ⚠ ABNORMAL

Experimental models

Reference-line cerebral organoids for ODC1 expression ORGANOID Measures expression associations underlying the proposed neural mechanism, not the putative proliferation defect itself.

Downstream

Abnormal Brain Development Disturbed progenitor proliferation is the proposed route to the structural and functional brain abnormalities, but the intermediates are unknown.

Show evidence (1 reference)

PMID:33806076 SUPPORT Computational

"The linkage from the expression data of ODC1 in early neural progenitor proliferation to phenotypes of neurodevelopmental delay and to the connection of polyamine metabolites in brain function establish ODC1 as a bona fide neurodevelopmental disorder gene."

States the inferential chain from progenitor proliferation to neurodevelopmental delay on which this node rests.

Abnormal Brain Development

Structural neuroimaging findings are variable and inconsistent across patients, and include white matter abnormalities, prominent Virchow-Robin spaces, periventricular and subependymal cysts, and corpus callosum abnormalities. Absolute or relative macrocephaly is common.

Downstream

Abnormal cerebral white matter morphology White matter abnormalities are an observed imaging component of the variable brain phenotype.

Abnormal corpus callosum morphology Variable callosal abnormalities are an imaging component of the reported developmental brain phenotype.

Dilation of Virchow-Robin spaces This observed imaging finding is a component of the variable structural brain phenotype.

Subependymal cysts This observed imaging finding is a component of the variable structural brain phenotype.

Show evidence (2 references)

PMID:30475435 SUPPORT Human Clinical

"Neuroimaging variably demonstrates white matter abnormalities, prominent Virchow-Robin spaces, periventricular cysts, and abnormalities of the corpus callosum."

Enumerates the structural findings that define this node.

PMID:34477286 SUPPORT Human Clinical

"Neuroimaging abnormalities continue to be an inconsistent feature of the syndrome."

This evidence is limited because it qualifies the finding as inconsistent rather than obligate, which is why no frequency band is assigned.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

52

Cardiovascular 5

Vascular skin abnormality HP:0011276

Show evidence (1 reference)

PMID:30239107 SUPPORT Human Clinical

"Phenotypic manifestations include macrosomia, macrocephaly, developmental delay, alopecia, spasticity, hypotonia, cutaneous vascular malformation, delayed visual maturation, and sensorineural hearing loss."

The source reports a cutaneous vascular malformation without identifying the vessel type; the binding preserves that scope.

Abnormal heart morphology HP:0001627

Show evidence (1 reference)

PMID:36007106 SUPPORT Human Clinical

"Feeding therapy with a low threshold for a clinical feeding evaluation and/or gastrostomy tube placement; nutritional intervention for those with obesity; stool softeners, prokinetics, osmotic agents or laxatives for constipation; standard treatment for epilepsy, developmental delay /..."

Congenital heart defects are named among the manifestations requiring standard treatment.

Dilation of Virchow-Robin spaces HP:0012520

Show evidence (1 reference)

PMID:30475435 SUPPORT Human Clinical

"Neuroimaging variably demonstrates white matter abnormalities, prominent Virchow-Robin spaces, periventricular cysts, and abnormalities of the corpus callosum."

Names prominent Virchow-Robin spaces among the neuroimaging findings.

Ventricular septal defect HP:0001629

Show evidence (1 reference)

PMID:37092498 SUPPORT Human Clinical

"Concerning prenatal findings included cerebral ventricular enlargement, cerebral cysts, polyhydramnios, and a ventricular septal defect."

A clinical case with a confirmed ODC1 variant documents a prenatal ventricular septal defect.

Valvular pulmonary stenosis HP:0034350

Show evidence (1 reference)

PMID:37469105 SUPPORT Human Clinical

"Additionally, one individual has unilateral congenital sensorineural hearing loss, two individuals have congenital heart disease (one with mild pulmonary valve stenosis, the other with spontaneously resolved ventricular septal defect), three individuals have nail differences, and one individual..."

The review specifies a valvular pulmonary lesion; it does not establish a high frequency of this particular defect.

Digestive 2

Feeding difficulties HP:0011968

Show evidence (2 references)

PMID:36007106 SUPPORT Human Clinical

"Bachmann-Bupp syndrome (BABS) is characterized by a distinctive type of alopecia, global developmental delay in the moderate to severe range, hypotonia, nonspecific dysmorphic features, behavioral abnormalities (autism spectrum disorder, attention-deficit/hyperactivity disorder) and feeding difficulties."

GeneReviews lists feeding difficulties among the defining characteristics.

PMID:36007106 SUPPORT Human Clinical

"Feeding therapy with a low threshold for a clinical feeding evaluation and/or gastrostomy tube placement; nutritional intervention for those with obesity; stool softeners, prokinetics, osmotic agents or laxatives for constipation; standard treatment for epilepsy, developmental delay /..."

The management recommendation reflects the clinical weight of the feeding problem.

Constipation FREQUENT HP:0002019

Show evidence (2 references)

PMID:36007106 SUPPORT Human Clinical

"Feeding therapy with a low threshold for a clinical feeding evaluation and/or gastrostomy tube placement; nutritional intervention for those with obesity; stool softeners, prokinetics, osmotic agents or laxatives for constipation; standard treatment for epilepsy, developmental delay /..."

GeneReviews management lists a full constipation treatment ladder, indicating this is an expected manifestation.

PMID:34477286 SUPPORT Human Clinical

"Constipation, a common ailment and even more common in general with patients with developmental delay, is present in three of seven patients (Table 1)."

The narrative reports 3/7 (43%), mapping to FREQUENT. Other summaries use different assessed denominators; this is a small-series estimate.

Ear 2

Conductive hearing impairment VERY_RARE HP:0000405

Show evidence (1 reference)

PMID:36007106 SUPPORT Human Clinical

"Rare findings may include seizures with onset in later childhood and conductive hearing loss."

GeneReviews explicitly classifies conductive hearing loss as a rare finding, mapping to VERY_RARE.

Sensorineural hearing impairment HP:0000407

Show evidence (2 references)

PMID:30239107 SUPPORT Human Clinical

"Phenotypic manifestations include macrosomia, macrocephaly, developmental delay, alopecia, spasticity, hypotonia, cutaneous vascular malformation, delayed visual maturation, and sensorineural hearing loss."

The index case report documents sensorineural, not conductive, hearing loss.

PMID:41925768 SUPPORT REVIEW SYNTHESIS Human Clinical

"the ODC mutation is expressed in all tissues of BABS patients resulting in macrosomia, macrocephaly, neurodevelopmental delay, spasticity, hypotonia, delayed visual maturation, and sensorineural hearing loss"

A review restates sensorineural hearing loss among the multisystem consequences of ubiquitous expression of the mutant enzyme.

Eye 5

Strabismus HP:0000486

Show evidence (1 reference)

PMID:36007106 SUPPORT Human Clinical

"Feeding therapy with a low threshold for a clinical feeding evaluation and/or gastrostomy tube placement; nutritional intervention for those with obesity; stool softeners, prokinetics, osmotic agents or laxatives for constipation; standard treatment for epilepsy, developmental delay /..."

Strabismus is named among the manifestations requiring standard treatment.

Abnormality of refraction HP:0000539

Show evidence (1 reference)

PMID:36007106 SUPPORT Human Clinical

"Feeding therapy with a low threshold for a clinical feeding evaluation and/or gastrostomy tube placement; nutritional intervention for those with obesity; stool softeners, prokinetics, osmotic agents or laxatives for constipation; standard treatment for epilepsy, developmental delay /..."

Refractive error is named among the manifestations requiring standard treatment.

Hypertelorism FREQUENT HP:0000316

Show evidence (1 reference)

PMID:37092498 SUPPORT Human Clinical

"8/11 forehead differences 6/11 hypertelorism"

Table 1 reports hypertelorism in 6/11 (55%), mapping to FREQUENT; the broader forehead-difference count is not substituted for this specific feature.

Ptosis HP:0000508

Show evidence (1 reference)

PMID:34477286 SUPPORT Human Clinical

"High forehead, hypertelorism, mild ptosis, down‐slanting palpebral fissures, cryptorchidism"

The comparative clinical table records mild ptosis in one founding case and ptosis in another.

Deeply set eye HP:0000490

Show evidence (1 reference)

PMID:34477286 SUPPORT Human Clinical

"High and broad forehead, hypertelorism, deep‐set eyes, blepharophimosis, tapering of the arms and legs"

Table 1 documents deeply set eyes in this founding case and one other; no population frequency is inferred.

Genitourinary 1

Cryptorchidism FREQUENT HP:0000028

Show evidence (1 reference)

PMID:34477286 SUPPORT Human Clinical

"Cryptorchidism is present in three of six males."

3/6 is 50%, mapping to FREQUENT among males in that series; female individuals are excluded from the denominator.

Head and Neck 9

Absent eyebrow HP:0002223

Show evidence (2 references)

PMID:34282722 SUPPORT Human Clinical

"One month into treatment, hair growth was noted, with eyebrows appearing first"

Eyebrow regrowth on treatment implies the pre-treatment absence of eyebrows in this genotyped patient.

PMID:36443247 SUPPORT Human Clinical

"In both patients, treatment with difluoromethylornithine has resulted in improved dermatologic signs, including regrowth of eyebrow and scalp hair and cessation of recurrent follicular cyst development."

Two treated individuals had eyebrow/scalp hair regrowth and cessation of recurrent follicular cysts. They should not be assumed to be additional independent cases beyond other publications.

Macrocephaly FREQUENT HP:0000256

Show evidence (3 references)

PMID:30475435 SUPPORT Human Clinical

"This disorder presents with global developmental delay, ectodermal abnormalities including alopecia, absolute or relative macrocephaly, and characteristic facial dysmorphisms."

Establishes that macrocephaly may be absolute or only relative to body size.

PMID:34477286 SUPPORT Human Clinical

"BABS is characterized by developmental delay, macrocephaly, macrosomia, and an unusual pattern of non-congenital alopecia."

Independent cohort listing macrocephaly among the defining features.

PMID:41410504 SUPPORT REVIEW SYNTHESIS Human Clinical

"The majority of patients (9/12, 75%) also presented with macrocephaly, which would be considered a distinctive feature of BABS, as this was not reported in any patients with DHPS deficiency, FABAS, or DOHH disorder, and was only reported in 3/33 (9%) of patients with SRS."

The review reports 9/12 (75%), mapping to FREQUENT in that small published cohort.

Dysmorphic facial features Abnormal facial shape HP:0001999

Show evidence (2 references)

PMID:36007106 SUPPORT Human Clinical

"Bachmann-Bupp syndrome (BABS) is characterized by a distinctive type of alopecia, global developmental delay in the moderate to severe range, hypotonia, nonspecific dysmorphic features, behavioral abnormalities (autism spectrum disorder, attention-deficit/hyperactivity disorder) and feeding difficulties."

GeneReviews lists nonspecific dysmorphic features among the defining characteristics.

PMID:30475435 SUPPORT Human Clinical

"This disorder presents with global developmental delay, ectodermal abnormalities including alopecia, absolute or relative macrocephaly, and characteristic facial dysmorphisms."

This evidence is limited because this cohort calls the dysmorphisms characteristic whereas GeneReviews calls them nonspecific; the two sources disagree on specificity.

Sparse eyebrow HP:0045075

Show evidence (1 reference)

PMID:34477286 SUPPORT Human Clinical

"Sparse hair is now present throughout the scalp with very little eyebrow hair and eyelashes."

The clinical narrative explicitly documents reduced rather than absent eyebrow hair.

Sparse or absent eyelashes HP:0200102

Show evidence (1 reference)

PMID:37092498 SUPPORT Human Clinical

"Some individuals have regrowth of scalp hair that typically remains sparse, with congenital absence of the eyebrows and eyelashes."

The expanded clinical series describes congenital eyelash absence. Its individual cases and earlier tables also include sparse eyelashes.

Broad forehead HP:0000337

Show evidence (1 reference)

PMID:34477286 SUPPORT Human Clinical

"Dysmorphic features include a long face, broad forehead, sagittal craniosynostosis, cryptorchidism, and choanal atresia."

This patient narrative directly documents the broad forehead; the comparative table reports it in several additional individuals.

Long face HP:0000276

Show evidence (1 reference)

PMID:34477286 SUPPORT Human Clinical

"Dysmorphic features include a long face, broad forehead, sagittal craniosynostosis, cryptorchidism, and choanal atresia."

The patient narrative records a long face; Table 1 separately records an elongated face in another individual.

High palate HP:0000218

Show evidence (1 reference)

PMID:34477286 SUPPORT Human Clinical

"Dysmorphic facial features noted include bilateral epicanthal folds, high palate, slight facial asymmetry with drooping of the left mouth corner, frontal bossing, dolichocephaly, and kyphosis (Figure 1)."

The older patient narrative supports this finding; the comparative table also reports a high arched palate in the index case.

High forehead HP:0000348

Show evidence (1 reference)

PMID:34477286 SUPPORT Human Clinical

"High forehead, hypertelorism, mild ptosis, down‐slanting palpebral fissures, cryptorchidism"

The full-text clinical narrative or comparative table documents this specific finding; no population frequency is inferred.

Integument 7

Alopecia OBLIGATE HP:0001596

Show evidence (5 references)

PMID:36007106 SUPPORT Human Clinical

"Bachmann-Bupp syndrome (BABS) is characterized by a distinctive type of alopecia, global developmental delay in the moderate to severe range, hypotonia, nonspecific dysmorphic features, behavioral abnormalities (autism spectrum disorder, attention-deficit/hyperactivity disorder) and feeding difficulties."

GeneReviews establishes the association; the quantitative review below supplies the observed cohort frequency.

PMID:36007106 SUPPORT Human Clinical

"Hair is typically present at birth but may be sparse and of an unexpected color with subsequent loss of hair in large clumps within the first few weeks of life."

Gives the natural history that distinguishes this alopecia from congenital atrichia.

PMID:37469105 SUPPORT Human Clinical

"Bachmann-Bupp syndrome (BABS) is a neurodevelopmental disorder characterized by developmental delay, hypotonia, and varying forms of non-congenital alopecia."

Independent review confirming the non-congenital character and variable form of the alopecia.

+ 2 more references

Abnormal nail growth HP:0030807

Show evidence (2 references)

PMID:41925768 SUPPORT REVIEW SYNTHESIS Human Clinical

"Similar to the phenotypic abnormalities observed in K6/ODC transgenic mice, human patients with this ODC mutation also displayed alopecia, accelerated nail growth and skin cysts"

A review states that BABS patients, like the transgenic mice, show accelerated nail growth.

PMID:7671221 SUPPORT Model Organism

"Effects observed include development of dermal follicular cysts, excessive skin wrinkling, enhanced nail growth, alopecia, and spontaneous tumor development."

The corresponding mouse observation, recorded separately so the human and model evidence are not conflated.

Cutaneous cyst HP:0025245

Show evidence (3 references)

PMID:36007106 SUPPORT Human Clinical

"Complete skin evaluation for follicular cysts at least annually."

GeneReviews makes annual follicular cyst surveillance a standing recommendation.

PMID:34282722 SUPPORT Human Clinical

"She had a history of recurring follicular cyst formation and enlargement."

Patient-level documentation of recurrent follicular cyst formation.

PMID:36443247 SUPPORT Human Clinical

"In both patients, treatment with difluoromethylornithine has resulted in improved dermatologic signs, including regrowth of eyebrow and scalp hair and cessation of recurrent follicular cyst development."

Two treated individuals had eyebrow/scalp hair regrowth and cessation of recurrent follicular cysts. They should not be assumed to be additional independent cases beyond other publications.

Keratosis pilaris HP:0032152

Show evidence (1 reference)

PMID:34477286 SUPPORT Human Clinical

"Past medical history also includes hypotonia, ataxia, significant constipation, keratosis pilaris on the upper and lower limbs and cheeks, significantly reduced sweating, and reduced sensitivity to pain."

The case narrative documents keratosis pilaris and its distribution. Table 1 also reports it in a previously published individual.

Hypohidrosis HP:0000966

Show evidence (2 references)

PMID:34477286 SUPPORT Human Clinical

"Past medical history also includes hypotonia, ataxia, significant constipation, keratosis pilaris on the upper and lower limbs and cheeks, significantly reduced sweating, and reduced sensitivity to pain."

Reduced sweating is explicitly described in this individual.

PMID:37092498 SUPPORT Human Clinical

"Her past medical history also includes hyperlaxity and anhidrosis with hyperthermia episodes."

A second individual had absent sweating and hyperthermia, expanding the severity of the sweating phenotype.

Fragile nails HP:0001808

Show evidence (1 reference)

PMID:37469105 SUPPORT Human Clinical

"Before DFMO treatment, two patients with BABS had a history of recurring follicular cysts, also observed in the transgenic mouse model,87, 89 and brittle fingernails."

The clinical review documents brittle fingernails in two patients. This finding is distinct from accelerated nail growth.

Hypoplastic toenails HP:0001800

Show evidence (1 reference)

PMID:34477286 SUPPORT Human Clinical

"ESES on EEG, myringotomy, celiac disease, hypoplastic toenails"

Table 1 explicitly specifies toenail hypoplasia in this individual; another patient’s unspecified hypoplastic nails are not assumed to be toenails.

Musculoskeletal 4

Hypotonia VERY_FREQUENT HP:0001252

Show evidence (3 references)

PMID:36007106 SUPPORT Human Clinical

"Bachmann-Bupp syndrome (BABS) is characterized by a distinctive type of alopecia, global developmental delay in the moderate to severe range, hypotonia, nonspecific dysmorphic features, behavioral abnormalities (autism spectrum disorder, attention-deficit/hyperactivity disorder) and feeding difficulties."

GeneReviews lists hypotonia among the defining characteristics, mapping to VERY_FREQUENT.

PMID:40167220 SUPPORT Human Clinical

"First described in 2018, Bachmann-Bupp Syndrome (BABS) is a rare neurodevelopmental disorder that is caused by gain-of-function variants in the ornithine decarboxylase (ODC1) gene and is characterized by developmental delay, hypotonia, and alopecia."

Independent confirmation of hypotonia as one of the three core clinical features.

PMID:41410504 SUPPORT Human Clinical

"| Hypotonia | 21/33 (64.3%) | 11/12 (91.7%) | 4/5 (80%) | 3/7 (42.9%) | 5/5 (100%) | 44/62 (71%) |"

The second disease column of Table 1 is BABS: 11/12 (91.7%) maps to VERY_FREQUENT. These are overlapping published cases, not an independent cohort.

Spasticity HP:0001257

Show evidence (1 reference)

PMID:30239107 SUPPORT Human Clinical

"Phenotypic manifestations include macrosomia, macrocephaly, developmental delay, alopecia, spasticity, hypotonia, cutaneous vascular malformation, delayed visual maturation, and sensorineural hearing loss."

The index case report documents spasticity alongside hypotonia.

Joint hypermobility HP:0001382

Show evidence (1 reference)

PMID:37092498 SUPPORT Human Clinical

"Her past medical history also includes hypotonia, feeding difficulties, food aspiration, marked joint hypermobility, and hepatic calcifications."

The younger patient had marked hypermobility; the older patient is separately described as having hyperlaxity.

Myopathy HP:0003198

Show evidence (1 reference)

PMID:37092498 SUPPORT Human Clinical

"She has had an increase in hypotonia over time and has developed proximal myopathy identified by electromyogram EMG, bilateral medius lameness, and bilateral heel defects leading to walking degradation and the need of a wheelchair for long distances along with difficulty climbing stairs."

The case documents progressive proximal myopathy and walking impairment; no general frequency or inevitable progression is inferred.

Nervous System 13

Global developmental delay OBLIGATE HP:0001263

Show evidence (4 references)

PMID:36007106 SUPPORT Human Clinical

"Bachmann-Bupp syndrome (BABS) is characterized by a distinctive type of alopecia, global developmental delay in the moderate to severe range, hypotonia, nonspecific dysmorphic features, behavioral abnormalities (autism spectrum disorder, attention-deficit/hyperactivity disorder) and feeding difficulties."

GeneReviews supports the association and severity range; the 2021 liveborn series supplies the frequency statement.

PMID:34282722 SUPPORT Human Clinical

"Prior to therapy, she had delayed development which manifested with no standing, cruising, or sitting, and limited fine motor skills."

Patient-level description of the functional severity of the delay before treatment.

PMID:30475435 SUPPORT Human Clinical

"This disorder presents with global developmental delay, ectodermal abnormalities including alopecia, absolute or relative macrocephaly, and characteristic facial dysmorphisms."

Independent four-patient cohort with global developmental delay as the leading feature.

+ 1 more reference

Autistic behavior HP:0000729

Show evidence (2 references)

PMID:36007106 SUPPORT Human Clinical

"Bachmann-Bupp syndrome (BABS) is characterized by a distinctive type of alopecia, global developmental delay in the moderate to severe range, hypotonia, nonspecific dysmorphic features, behavioral abnormalities (autism spectrum disorder, attention-deficit/hyperactivity disorder) and feeding difficulties."

GeneReviews names autism spectrum disorder explicitly among the behavioural abnormalities.

PMID:36007106 SUPPORT Human Clinical

"Behavioral assessment for signs of autism spectrum disorder, attention, and aggressive or self-injurious behaviors annually."

Annual behavioral screening is recommended; the recommendation alone does not supply a frequency estimate.

Attention deficit hyperactivity disorder HP:0007018

Show evidence (1 reference)

PMID:36007106 SUPPORT Human Clinical

"Bachmann-Bupp syndrome (BABS) is characterized by a distinctive type of alopecia, global developmental delay in the moderate to severe range, hypotonia, nonspecific dysmorphic features, behavioral abnormalities (autism spectrum disorder, attention-deficit/hyperactivity disorder) and feeding difficulties."

GeneReviews names attention-deficit/hyperactivity disorder explicitly.

Seizure OCCASIONAL HP:0001250

Show evidence (5 references)

PMID:36007106 SUPPORT Human Clinical

"Rare findings may include seizures with onset in later childhood and conductive hearing loss."

GeneReviews describes seizures qualitatively as rare. The quantitative series supersedes that wording for frequency assignment.

PMID:34477286 SUPPORT Human Clinical

"Recent diagnosis of four more BABS patients provides further characterization of the phenotype of this syndrome including late-onset seizures in the oldest reported patient at 23 years of age, representing the first report for this phenotype in BABS."

Documents the single index observation of late-onset seizures in the published series.

PMID:34477286 SUPPORT Human Clinical

"Novel findings in these newly reported patients include the first report of seizures, with onset at age 14 years. These seizures have been resistant to treatment."

The full text distinguishes age at onset (14 years) from age at reporting (23 years).

+ 2 more references

Abnormal cerebral white matter morphology HP:0002500

Show evidence (2 references)

PMID:30475435 SUPPORT Human Clinical

"Neuroimaging variably demonstrates white matter abnormalities, prominent Virchow-Robin spaces, periventricular cysts, and abnormalities of the corpus callosum."

Lists white matter abnormalities first among the neuroimaging findings.

PMID:34282722 SUPPORT Human Clinical

"A neonatal brain MRI showed abnormal cerebral white matter and subependymal cysts"

Patient-level neonatal MRI documentation of the white matter abnormality.

Subependymal cysts HP:0002416

Show evidence (2 references)

PMID:34282722 SUPPORT Human Clinical

"A neonatal brain MRI showed abnormal cerebral white matter and subependymal cysts"

Documents subependymal cysts on the neonatal MRI of a genotyped patient.

PMID:30475435 SUPPORT Human Clinical

"Neuroimaging variably demonstrates white matter abnormalities, prominent Virchow-Robin spaces, periventricular cysts, and abnormalities of the corpus callosum."

This evidence is limited because this cohort describes the cysts as periventricular rather than specifically subependymal.

Abnormal corpus callosum morphology HP:0001273

Show evidence (1 reference)

PMID:30475435 SUPPORT Human Clinical

"Neuroimaging variably demonstrates white matter abnormalities, prominent Virchow-Robin spaces, periventricular cysts, and abnormalities of the corpus callosum."

Names corpus callosum abnormalities among the neuroimaging findings.

Intellectual disability HP:0001249

Show evidence (1 reference)

PMID:37092498 SUPPORT Human Clinical

"At 12 years of age, she has moderate developmental delay and intellectual disability, with the ability to read and write."

Direct clinical documentation supports intellectual disability without treating all developmental delay as a formal cognitive diagnosis.

Delayed speech and language development HP:0000750

Show evidence (1 reference)

PMID:34477286 SUPPORT Human Clinical

"Speech appears limited with first words at 2–3 years and some patients remain nonverbal."

The series summarizes speech delay and variable acquisition rather than implying that all patients eventually develop speech.

Ventriculomegaly HP:0002119

Show evidence (1 reference)

PMID:37092498 SUPPORT Human Clinical

"Concerning prenatal findings included cerebral ventricular enlargement, cerebral cysts, polyhydramnios, and a ventricular septal defect."

The prenatal findings explicitly include cerebral ventricular enlargement.

Hypoplasia of the corpus callosum HP:0002079

Show evidence (1 reference)

PMID:37092498 SUPPORT Human Clinical

"A brain MRI identified myelination impairment with dilated Virchow–Robin spaces, bilateral paraventricular cysts, enlargement of subarachnoid spaces associated with ventricular dilatation, and hypoplasia of the middle part of the corpus callosum."

The imaging description supports the specific callosal hypoplasia finding in this patient.

Aggressive behavior HP:0000718

Show evidence (1 reference)

PMID:34477286 SUPPORT Human Clinical

"At age 19, he had a psychological evaluation that diagnosed him with anxiety, disruptive behavior, mild aggression, poor social and coping skills, difficulties in academic performance, and self‐injurious behaviors."

The full-text clinical narrative or comparative table documents this specific finding; no population frequency is inferred.

Self-injurious behavior HP:0100716

Show evidence (1 reference)

PMID:34477286 SUPPORT Human Clinical

"At age 19, he had a psychological evaluation that diagnosed him with anxiety, disruptive behavior, mild aggression, poor social and coping skills, difficulties in academic performance, and self‐injurious behaviors."

The full-text clinical narrative or comparative table documents this specific finding; no population frequency is inferred.

Prenatal and Birth 1

Polyhydramnios FREQUENT HP:0001561

Show evidence (1 reference)

PMID:37092498 SUPPORT Human Clinical

"Additionally, though non-specifically, 7/10 patients so far have had polyhydramnios prenatally."

7/10 is 70%, mapping to FREQUENT in the reported series. The denominator includes pregnancies with available prenatal data, not population prevalence.

Growth 2

Macrosomia Overgrowth HP:0001548

Show evidence (3 references)

PMID:34477286 SUPPORT Human Clinical

"BABS is characterized by developmental delay, macrocephaly, macrosomia, and an unusual pattern of non-congenital alopecia."

Names macrosomia among the four defining features of the syndrome.

PMID:30239107 SUPPORT Human Clinical

"Phenotypic manifestations include macrosomia, macrocephaly, developmental delay, alopecia, spasticity, hypotonia, cutaneous vascular malformation, delayed visual maturation, and sensorineural hearing loss."

The index case report lists macrosomia first among the phenotypic manifestations.

PMID:34477286 SUPPORT Human Clinical

"Macrocephaly continues to be a consistent finding in most cases; however, macrosomia now does not."

The expanded cohort explicitly qualifies macrosomia as an inconsistent feature.

Obesity HP:0001513

Show evidence (1 reference)

PMID:36007106 SUPPORT Human Clinical

"Feeding therapy with a low threshold for a clinical feeding evaluation and/or gastrostomy tube placement; nutritional intervention for those with obesity; stool softeners, prokinetics, osmotic agents or laxatives for constipation; standard treatment for epilepsy, developmental delay /..."

GeneReviews management explicitly provides for nutritional intervention in those with obesity.

Other 1

Delayed visual maturation

Needs a specific HPO term. Searches `runoak -i sqlite:obo:hp search 't~visual maturation'` and `runoak -i ols:hp search 'visual maturation'` returned no match. HP:0000505 Visual impairment includes additional severity and uncorrectability criteria not established by this report, so it is not substituted.

Show evidence (1 reference)

PMID:30239107 SUPPORT Human Clinical

"Phenotypic manifestations include macrosomia, macrocephaly, developmental delay, alopecia, spasticity, hypotonia, cutaneous vascular malformation, delayed visual maturation, and sensorineural hearing loss."

The index case report explicitly lists delayed visual maturation; no frequency or specific visual-pathway lesion is inferred.

🧬

Genetic Associations

1

ODC1 (Causative)

Gene: ODC1 hgnc:8109 relationship_type: CAUSATIVE variant_origin: DE_NOVO

Autosomal dominant

Show evidence (7 references)

PMID:30239107 SUPPORT Human Clinical

"The ODC1 gene mutation (c.1342 A>T) was identified by whole-exome sequencing and confirmed by Sanger sequencing."

Names the index allele and the method by which it was identified and confirmed.

PMID:30475435 SUPPORT Human Clinical

"In this report, we present four patients with a distinct neurometabolic disorder associated with de novo heterozygous, gain-of-function variants in the ODC1 gene."

Independent replication establishing the gene-disease relationship in four further patients with de novo gain-of-function alleles.

PMID:36007106 SUPPORT Human Clinical

"Heterozygous pathogenic variants in ODC1 that cause BABS are typically gain-of-function variants."

GeneReviews states the direction of effect explicitly, which is the single most important fact to preserve when reading ODC1 literature.

+ 4 more references

🔬

Variants

5

NM_002539.3:c.1342A>T (p.Lys448Ter) Pathogenic

Gene: ODC1 hgnc:8109 single nucleotide variant

Variant detail: Nonsense

Index de novo allele removing the final 14 amino acids. ClinVar RCV001263232 reports pathogenic from one OMIM literature-only submission with no assertion criteria, not expert-panel review. The 2021 table printed A>G; the published correction confirms A>T.

Show evidence (3 references)

PMID:30239107 SUPPORT Human Clinical

"The ODC1 gene mutation (c.1342 A>T) was identified by whole-exome sequencing and confirmed by Sanger sequencing."

Primary report establishes the nucleotide substitution.

url:https://www.ncbi.nlm.nih.gov/clinvar/RCV001263232/ SUPPORT Human Clinical

"Germline classification: ... Pathogenic (1 submission) ... no assertion criteria provided"

ClinVar classification is represented with its single-submitter, no-criteria limitations in the description.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC10479987/ SUPPORT Human Clinical

"In the originally published article, Table 1 contained the variant c.1342A>G. This variant should have been 1342A>T."

The published erratum resolves the nucleotide discrepancy as A>T. HTML entity spelling in the snippet follows the generated cache.

ODC1 c.1242-2A>G

Gene: ODC1 hgnc:8109 single nucleotide variant

Variant detail: Splice acceptor

Recurrent de novo intron-11 splice acceptor variant reported in three individuals. The predicted splice consequence is not represented as an experimentally demonstrated transcript change. No formal ACMG class is assigned from the case narrative alone.

Show evidence (2 references)

PMID:37092498 SUPPORT Human Clinical

"After trio exome sequencing, she was diagnosed as having a de novo heterozygous variant in the ODC1 gene, c.1242-2A > G, (IVS11-2A > G), which is predicted to destroy a canonical splice acceptor site in intron 11."

The paper describes a predicted acceptor disruption and de novo origin.

PMID:41410504 SUPPORT Human Clinical

"One variant, c.1242–2A>G (p.IVS11–2A>G), has been reported in 3 individuals (Michael et al., 2023; VanSickle et al., 2021)."

A recurrent allele is not proof of a mutational hotspot or shared founder.

ODC1 c.1252C>T (p.Gln418Ter)

Gene: ODC1 hgnc:8109 single nucleotide variant

Variant detail: Nonsense

De novo premature-termination variant reported in patient 9 of the 2021 cohort. The table uses NM_001287190.1. No formal ACMG class is inferred solely from inclusion in this case series.

Show evidence (1 reference)

PMID:34477286 SUPPORT Human Clinical

"Trio WES demonstrated a de novo heterozygous variant in the ODC1 gene, c.1252C>T (p.Gln418*), which causes premature termination of the protein."

Patient-level molecular result establishes the variant and predicted protein consequence.

ODC1 c.1307_1311delinsT (p.Thr436IlefsTer11)

Gene: ODC1 hgnc:8109 Deletion-insertion causing frameshift

De novo frameshift from the 2023 patient narrative. The table contains c.1307_3111delinsT, whereas the narrative gives c.1307_1311delinsT, consistent with the reported protein effect. The narrative spelling is retained; no formal ACMG class is inferred.

Show evidence (1 reference)

PMID:37092498 SUPPORT Human Clinical

"After trio whole genome sequencing, she was diagnosed as having a de novo heterozygous variant in the ODC1 gene, c.1307_1311delinsT (p.Thr436IlefsX11), which is predicted to shift the reading frame, resulting in premature truncation of the protein on genome sequencing."

The narrative provides the allele; its predicted reading-frame effect is distinguished from a directly assayed transcript or protein.

NM_001287189.1:c.1217A>T (p.Tyr406Phe) Uncertain Significance

Gene: ODC1 hgnc:8109 single nucleotide variant

Variant detail: Missense

Reported in an individual with an atypical phenotype, without elevated erythrocyte ODC activity. This remains an uncertain variant and is not counted as a confirmed BABS allele or as evidence of DFMO responsiveness. The paper contradicts itself about population presence; no frequency assertion is imported.

Show evidence (3 references)

PMID:40167220 SUPPORT Human Clinical

"She was originally connected to our team at the age of 5 months, when exome sequencing identified a de novo heterozygous variant in the ODC1 gene, c.1217A > T (NM_001287189.1), which is predicted to result in the amino acid substitution (p.Tyr406Phe)."

The molecular result is a de novo missense finding, not an established diagnosis.

PMID:40167220 SUPPORT Human Clinical

"was classified as a variant of uncertain significance."

The source explicitly assigns uncertain significance; no population-frequency assertion is adopted.

PMID:40167220 SUPPORT Human Clinical

"Unlike other patients with BABS who demonstrated elevated baseline ODC activity, the patient’s ODC activity levels were not greater than unaffected control patients’ samples (Figure 1)."

The negative biochemical result limits the BABS interpretation; it does not alone establish a benign ACMG class.

💊

Medical Actions

7

Eflornithine (difluoromethylornithine, DFMO)

Action: Pharmacotherapy NCIT:C15986

Agent: eflornithine CHEBI:41948

Platform: Small molecule

Eflornithine is an irreversible ODC inhibitor used experimentally for BABS. The index compassionate-use regimen began at 500 mg/m2 per dose twice daily by gastrostomy, escalating to 750 and then 1000 mg/m2 per dose twice daily with a concurrent low-polyamine diet. Hair regrowth, cessation of follicular cysts, biochemical normalization, and developmental gains were reported. The 2025 series described six treated individuals, five under US single-patient IND protocols and one outside the US. These uncontrolled observations do not establish efficacy for all manifestations or comparative benefit at different ages.

Mechanism Target:

INHIBITS Elevated ODC Enzyme Activity — Eflornithine irreversibly inhibits ODC, so it suppresses the catalytic activity of the accumulated truncated enzyme rather than restoring its degradation.

Show evidence (1 reference)

PMID:31249027 SUPPORT In Vitro

"Exposure of primary dermal fibroblasts to ODC inhibitor α-difluoromethylornithine (DFMO) reduced the ODC activity and putrescine to levels observed in controls without adversely affecting cell morphology or inducing cell death."

Demonstrates in the patient's own cells that DFMO normalises the raised enzyme activity without cytotoxicity.

INHIBITS Putrescine Accumulation — Inhibiting the enzyme lowers the putrescine pool and its measurable acetylated derivative back toward the reference range.

Show evidence (1 reference)

PMID:34282722 SUPPORT Human Clinical

"Eflornithine normalized polyamine levels without disrupting other pathways."

In-patient confirmation that the drug corrects the polyamine disturbance selectively.

INHIBITS Hair Follicle Dysfunction — Suppressing follicular ODC activity restores hair growth, an effect first shown in the truncated-ODC mouse and then reproduced in patients.

Show evidence (1 reference)

PMID:8618048 SUPPORT Model Organism

"2-Difluoromethylornithine could also reactivate hair growth in animals with complete hair loss."

The model result that motivated trying the drug in patients with established alopecia.

Show evidence (11 references)

PMID:34282722 SUPPORT Human Clinical

"Eflornithine normalized polyamine levels without disrupting other pathways. She demonstrated remarkable improvement in both neurological symptoms and cortical architecture. She gained fine motor skills with the capacity to feed herself and sit with support."

The primary treated-patient report, giving biochemical, neurological and functional outcomes in the first patient treated.

PMID:34282722 SUPPORT Human Clinical

"At age 4 years and 8 months, we started eflornithine (Sanofi Aventis) treatment with 500 mg/m2/dose bid twice daily via a gastrostomy tube along with a low polyamine diet on November 14, 2019, for 3 months, increasing to 750 mg/m2/dose twice daily, and a final increase to 1000 mg/m2/dose twice..."

Documents the actual regimen, route and escalation schedule used in the index treated case.

PMID:34282722 SUPPORT Human Clinical

"Dosing was based on what had been demonstrated to be safe in pediatric patients in maintenance therapy for neuroblastoma treated with eflornithine (Saulnier Sholler et al., 2015)."

Records that the paediatric dose and safety basis was borrowed from the neuroblastoma maintenance literature, not generated in BABS.

+ 8 more references

Low-polyamine diet

Action: Dietary Intervention NCIT:C15447

Platform: Behavioral / lifestyle

Dietary restriction of polyamines was given alongside eflornithine in the index treated patient. It has never been tested as monotherapy in BABS, and the review literature raises dietary intervention and gut-flora-directed antibiotics only as candidate approaches to lowering putrescine.

Mechanism Target:

INHIBITS Putrescine Accumulation — Reducing dietary and gut-derived polyamine input is intended to lower the systemic putrescine burden.

Show evidence (1 reference)

PMID:30475435 SUPPORT Human Clinical

"Therapies aimed at reducing putrescine levels, including ODC1 inhibitors, dietary interventions, and antibiotics to reduce polyamine production by gastrointestinal flora could be considered as disease-modifying therapies."

This evidence is limited because this is a proposal for what could be considered, not a report of a tested dietary intervention.

Show evidence (1 reference)

PMID:34282722 SUPPORT Human Clinical

"At age 4 years and 8 months, we started eflornithine (Sanofi Aventis) treatment with 500 mg/m2/dose bid twice daily via a gastrostomy tube along with a low polyamine diet on November 14, 2019, for 3 months, increasing to 750 mg/m2/dose twice daily, and a final increase to 1000 mg/m2/dose twice..."

This evidence is limited because the diet was co-administered with eflornithine, so no independent effect can be attributed to it.

Supportive and symptom-directed management

Action: Supportive Care NCIT:C15747

Platform: Other

Standard multidisciplinary care for the individual manifestations: feeding therapy with a low threshold for gastrostomy placement, nutritional intervention for obesity, a constipation ladder of stool softeners, prokinetics, osmotic agents and laxatives, and standard treatment for epilepsy, developmental delay and intellectual disability, refractive error, strabismus, hearing loss, follicular cysts and congenital heart defects. At each visit, GeneReviews recommends monitoring growth, feeding safety, constipation, mobility, development, and new neurological manifestations; skin and behavioral assessments are at least annual.

Show evidence (5 references)

PMID:36007106 SUPPORT Human Clinical

"Feeding therapy with a low threshold for a clinical feeding evaluation and/or gastrostomy tube placement; nutritional intervention for those with obesity; stool softeners, prokinetics, osmotic agents or laxatives for constipation; standard treatment for epilepsy, developmental delay /..."

The GeneReviews management paragraph is the source for every element of this supportive-care package.

PMID:36007106 SUPPORT Human Clinical

"Ophthalmology and audiology evaluations annually or as clinically indicated."

Specifies the recommended sensory surveillance cadence.

PMID:36007106 SUPPORT Human Clinical

"Measurement of growth parameters, evaluation of nutritional status and safety of oral intake, monitoring for signs and symptoms of constipation, assessment of mobility and self-help skills, monitoring of developmental progress and educational needs, and assessment for new manifestations..."

GeneReviews specifies clinical surveillance beyond annual ophthalmology and audiology.

+ 2 more references

Genetic counseling

Action: Genetic Counseling NCIT:C15240

Platform: Other

BABS is autosomal dominant and typically de novo, so the recurrence risk to other family members is presumed low. Once the familial ODC1 variant is known, prenatal and preimplantation genetic testing are possible.

Show evidence (1 reference)

PMID:36007106 SUPPORT Human Clinical

"Therefore, the risk to other family members is presumed to be low. Once an ODC1 pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic testing are possible."

GeneReviews states the recurrence-risk counselling message and the reproductive testing options.

Physical Therapy

Action: Physical Therapy NCIT:C15302

Platform: Behavioral / lifestyle

Physical therapy addresses motor development and functional mobility; the clinical series recommends individualized developmental intervention.

Show evidence (1 reference)

PMID:34477286 SUPPORT Human Clinical

"Developmental assessment and intervention, such as physical and speech therapy are recommended; particularly as developmental milestones vary in patients."

The clinical report documents the recommendation or use of this service without a controlled efficacy estimate.

Speech Language Therapy

Action: Speech Language Therapy NCIT:C159273

Platform: Behavioral / lifestyle

Speech and language intervention supports communication in individuals with variable expressive language development.

Show evidence (1 reference)

PMID:34477286 SUPPORT Human Clinical

"Developmental assessment and intervention, such as physical and speech therapy are recommended; particularly as developmental milestones vary in patients."

The clinical report documents the recommendation or use of this service without a controlled efficacy estimate.

Occupational Therapy

Action: Occupational Therapy NCIT:C121351

Platform: Behavioral / lifestyle

Occupational therapy was used alongside other rehabilitation services in a reported patient; independent treatment efficacy was not measured.

Show evidence (1 reference)

PMID:37092498 SUPPORT Human Clinical

"At the time of reporting, the patient is receiving physical, occupational, and speech therapy services."

The clinical report documents the recommendation or use of this service without a controlled efficacy estimate.

🔬

Biochemical Markers

4

Elevated plasma N-acetylputrescine (INCREASED)

Show evidence (3 references)

PMID:30475435 SUPPORT Human Clinical

"Plasma clinical metabolomics analysis demonstrates elevation of N-acetylputrescine, the acetylated form of putrescine, with otherwise normal polyamine levels."

Establishes the elevation in plasma and its selectivity within the polyamine panel.

PMID:34282722 SUPPORT Human Clinical

"N-acetylputrescine, the only polyamine that meets CAP/CLIA standards in this analysis, served as the primary indicator of putrescine levels."

Explains why this metabolite, rather than putrescine itself, is the clinical readout.

PMID:36007106 SUPPORT Human Clinical

"The finding of abnormal polyamine pathway metabolites (including increased N-acetylputrescine) on metabolomic profiling is suggestive of a diagnosis of BABS."

GeneReviews uses this metabolite as the biochemical trigger for genetic confirmation.

Elevated erythrocyte and fibroblast ODC enzyme activity (INCREASED)

Show evidence (2 references)

PMID:31249027 SUPPORT In Vitro

"Importantly, the accumulated ODC protein variant remained functionally active as we detected exceptionally high ODC enzyme activity in both primary dermal fibroblasts (12-17-fold of controls) and red blood cells (RBCs) (125-137-fold of controls), using a specific 14C radioactive ODC activity assay."

Supplies the quantitative fold-change and the assay used.

PMID:40382142 SUPPORT Human Clinical

"Here we describe how to quantitatively measure ODC enzymatic activity and the polyamines by a radiolabeled 14C-ornithine assay and by reverse phase (RP)-HPLC, respectively."

Documents the standardised protocol for measuring the enzyme activity and polyamines in BABS patient samples.

Elevated erythrocyte polyamines (INCREASED)

Show evidence (1 reference)

PMID:30239107 SUPPORT Human Clinical

"Red blood cells obtained from our patient showed elevated ODC protein and polyamine levels compared to healthy controls."

Direct measurement of raised polyamines in a patient's circulating cells.

Elevated plasma acisoga (INCREASED)

Show evidence (1 reference)

PMID:34282722 SUPPORT Human Clinical

"The initial elevation of bothN-acetylputrescine as well as the polyamine metaboliteN-(3-acetamidopropyl) pyrrolidin-2-one (acisoga), which were above the 97.5th percentile, decreased at initiation of therapy and remained reduced at all time points"

The serial metabolomic study documents acisoga as a second treatment-responsive metabolite; the finding is from a single treated patient.

🔬

Diagnosis

3

ODC1 molecular genetic testing (PRESENT)

The diagnosis is established by identifying a heterozygous pathogenic ODC1 variant in a proband with suggestive findings. Exome sequencing identified the index allele, confirmed by Sanger sequencing.

Show evidence (2 references)

PMID:36007106 SUPPORT Human Clinical

"The diagnosis is established in a proband with suggestive findings and a heterozygous pathogenic variant in ODC1 identified by molecular genetic testing."

GeneReviews defines the diagnostic standard.

PMID:30239107 SUPPORT Human Clinical

"The ODC1 gene mutation (c.1342 A>T) was identified by whole-exome sequencing and confirmed by Sanger sequencing."

Illustrates the two-step molecular workflow used in the index case.

Plasma metabolomic profiling for polyamine metabolites (PRESENT)

Elevated N-acetylputrescine on plasma metabolomic profiling can support suspicion of BABS or characterize a molecular finding. Published diagnoses were made through broad sequencing; metabolomics is not an obligatory preceding step.

Show evidence (3 references)

PMID:36007106 SUPPORT Human Clinical

"The finding of abnormal polyamine pathway metabolites (including increased N-acetylputrescine) on metabolomic profiling is suggestive of a diagnosis of BABS."

GeneReviews positions metabolomic profiling as the suggestive biochemical test.

PMID:30475435 SUPPORT Human Clinical

"Plasma clinical metabolomics analysis demonstrates elevation of N-acetylputrescine, the acetylated form of putrescine, with otherwise normal polyamine levels."

Documents the specific plasma metabolomic pattern in a genotyped cohort.

PMID:34477286 SUPPORT Human Clinical

"All diagnoses to date have been made using broad sequencing, such as WES or WGS."

The 2021 series establishes the diagnostic sequence actually used, rather than assuming that biochemical testing usually comes first.

Erythrocyte ODC enzyme activity assay (PRESENT)

A 14C-ornithine radiolabelled assay on red blood cells, with polyamines measured by reverse-phase HPLC, quantifies the enzymatic gain of function and is used to monitor response to eflornithine.

Show evidence (1 reference)

PMID:40382142 SUPPORT Human Clinical

"The detailed protocols of this chapter provide step-by-step guidance detailing how to measure ODC activity and polyamines in human RBCs."

Establishes the red blood cell assay as the standardised BABS monitoring method.

📊

Prevalence

1

Worldwide, published cases

Cases In Literature Ultra Rare

Population prevalence is unknown. The 2026 narrative review identified 12 published clinical cases, including a conference abstract, and reported 18 cases known to its authors worldwide. These are overlapping literature and investigator counts rather than a population-based rate.

Show evidence (4 references)

PMID:37469105 SUPPORT Human Clinical

"BABS is an ultra-rare condition with few reported cases, but it serves as a convincing example for drug repurposing therapy."

The disease-specific review characterises BABS as ultra-rare with few reported cases.

PMID:34282722 SUPPORT Human Clinical

"The novel treatment of this ultra-rare (less than 10 known cases) genetic syndrome presented unique challenges for monitoring efficacy over time."

Supplies the explicit published denominator underpinning the ultra-rare tier at the time of the first treated case.

PMID:37092498 SUPPORT Human Clinical

"This case study provides insights from two new patients diagnosed with Bachmann-Bupp syndrome, further expanding our understanding of this ultra-rare condition, as well as a general discussion about other known polyaminopathies."

An incremental two-patient addition to the published series, again described as ultra-rare.

+ 1 more reference

🔀

Differential Diagnoses

6

Conditions with similar clinical presentations that must be differentiated from Bachmann-Bupp Syndrome:

Alopecia-intellectual disability syndrome 4 (LSS-related) MONDO:0030009

Overlapping Features LSS-related alopecia-intellectual disability is a recessive neuroectodermal syndrome affecting cholesterol biosynthesis. The cited cohort had congenital alopecia, intellectual disability or developmental delay, frequent early-onset epilepsy, and additional skin findings. Timing of scalp hair loss can help distinguish it from the typical postnatal shedding in BABS, but molecular testing establishes the diagnosis.

Distinguishing Features

Biallelic LSS variants and autosomal recessive inheritance, compared with heterozygous ODC1 gain-of-function variants in BABS.
Congenital alopecia in the cited LSS cohort, compared with typically postnatal scalp hair shedding in BABS.
Early-onset epilepsy and ichthyosis or erythroderma were common in the LSS cohort.
LSS affects cholesterol biosynthesis; the study does not establish a universal negative polyamine profile or a clinical contraindication to ODC inhibition.

Show evidence (3 references)

PMID:30723320 SUPPORT Human Clinical

"It is a rare autosomal recessive condition characterized by hypotrichosis and intellectual disability (ID) or developmental delay (DD), frequently associated with early-onset epilepsy and other dermatological features."

Gives the inheritance mode and the alopecia-plus-developmental-delay core that make this the closest non-polyaminopathy mimic of BABS.

PMID:30723320 SUPPORT Human Clinical

"Total alopecia with sparse eyelashes and eyebrows was noted at birth in all affected individuals."

Establishes the congenital timing of the alopecia, the discriminator against the non-congenital clump shedding of BABS.

PMID:36007106 SUPPORT Human Clinical

"Hair is typically present at birth but may be sparse and of an unexpected color with subsequent loss of hair in large clumps within the first few weeks of life."

The BABS side of the same discriminator, stated by GeneReviews: hair is present at birth and lost afterwards.

Snyder-Robinson syndrome MONDO:0010664

Overlapping Features The first-described and best-known polyaminopathy, and the disorder whose prior research the BABS team explicitly credits with accelerating BABS from discovery to treatment. It shares intellectual disability and hypotonia with BABS, and its literature uses the same polyamine-pathway vocabulary, so mechanism sentences are easily misattributed between the two. It is separated from BABS by the affected enzyme (spermine synthase, several steps downstream of ODC), by the direction of effect (loss of function, not gain), and by X-linked hemizygous rather than autosomal dominant transmission. Alopecia is not its presenting feature.

Distinguishing Features

Caused by SMS (spermine synthase), not ODC1
Loss-of-function with decreased or absent enzyme activity, the opposite direction of effect to the ODC1 gain of function in BABS
X-linked, affecting hemizygous males, rather than de novo autosomal dominant
Osteoporosis, kyphoscoliosis, unsteady gait and facial asymmetry dominate; the non-congenital clump alopecia and macrocephaly/macrosomia of BABS are not its core

Show evidence (3 references)

PMID:41410504 SUPPORT Human Clinical

"Snyder-Robinson syndrome results from hemizygous loss-of-function variants in the spermine synthase (SMS) gene, resulting in decreased or complete loss of spermine synthase enzyme activity."

Gives the gene, the zygosity and the direction of effect that separate Snyder-Robinson syndrome from BABS.

PMID:37092498 SUPPORT Human Clinical

"Recent identification of four additional polyaminopathies, including Bachmann-Bupp syndrome, have benefited from previous research on Snyder-Robinson syndrome in order to advance from research to treatment more quickly."

Documents the direct research lineage between the two disorders, which is precisely why their literatures are intertwined and confusable.

PMID:40167220 SUPPORT REVIEW SYNTHESIS Human Clinical

"DFMO usage in SRS has been considered and further study is ongoing (Gilmour, 2023; Stewart, 2023)."

ODC inhibition is under investigation in SRS; biochemical differences do not justify a blanket contraindication.

Faundes-Banka syndrome Not Yet Curated MONDO:0859163

Overlapping Features Faundes-Banka syndrome is a neurodevelopmental polyaminopathy caused by heterozygous EIF5A variants that impair eIF5A function. The eIF5A protein is the substrate for DHPS- and DOHH-mediated hypusination; it is not itself the hypusination enzyme. Gene, molecular consequence, and phenotype distinguish it from ODC1 gain-of-function BABS.

Distinguishing Features

Heterozygous EIF5A variants impair eIF5A translation-factor function.
The affected protein requires spermidine-dependent hypusination, distinct from ODC-mediated putrescine synthesis.
Micrognathia and microcephaly are characteristic in the reviewed FABAS cohort.

Show evidence (2 references)

PMID:41410504 SUPPORT Human Clinical

"Faundes-Banka syndrome results from heterozygous loss-of-function variants in the eukaryotic translation initiation factor 5A (EIF5A) gene, impairing eIF5A protein function."

Gives the gene and the direction of effect that separate Faundes-Banka syndrome from BABS.

PMID:41410504 SUPPORT Human Clinical

"The five known syndromes associated with the polyamine pathway share many similar clinical phenotypes, and yet patients with each syndrome present with distinctive syndromic features."

Establishes that the five polyaminopathies overlap clinically, which is the condition under which their evidence gets mixed up.

Deoxyhypusine synthase (DHPS) deficiency MONDO:0032775

Overlapping Features An autosomal recessive polyaminopathy caused by bi-allelic hypomorphic DHPS variants. It sits on the same hypusination branch as Faundes-Banka syndrome and, like BABS, presents as a Mendelian neurodevelopmental disorder with seizures and developmental impairment, so it appears in the same polyaminopathy tables. It is separated from BABS by the gene, by recessive rather than dominant inheritance, and by reduced rather than increased enzyme activity.

Distinguishing Features

Caused by DHPS (deoxyhypusine synthase), not ODC1
Autosomal recessive with bi-allelic hypomorphic variants, not de novo heterozygous
Reduced enzyme activity, the opposite direction of effect to BABS
Acts on the spermidine-dependent hypusination of eIF5A rather than on polyamine synthesis, so putrescine and N-acetylputrescine are not the diagnostic signature
Seizures and speech and walking impairment define the phenotype; the BABS alopecia and macrocephaly/macrosomia combination is not its core

Show evidence (1 reference)

PMID:41410504 SUPPORT Human Clinical

"DHPS (deoxyhypusine synthase) deficiency is an autosomal recessive disease and results from bi-allelic hypomorphic variants in the deoxyhypusine synthase (DHPS) gene, which results in reduced deoxyhypusine synthase enzyme activity."

Gives the gene, the inheritance mode and the direction of effect that separate DHPS deficiency from BABS.

Deoxyhypusine hydroxylase (DOHH) disorder Not Yet Curated MONDO:0859293

Overlapping Features The fifth recognised polyaminopathy, caused by bi-allelic loss-of-function DOHH variants, and the second step of the hypusination branch. It is the newest member of the family and is grouped with BABS in every polyaminopathy review, which is the setting in which its findings can be misattributed. It is separated from BABS by the gene, by autosomal recessive inheritance, by decreased rather than increased enzyme activity, and by a microcephaly-with-cerebral-atrophy brain phenotype that is close to the inverse of the BABS macrocephaly.

Distinguishing Features

Caused by DOHH (deoxyhypusine hydroxylase), not ODC1
Autosomal recessive bi-allelic loss of function, not de novo heterozygous gain of function
Decreased enzyme activity, the opposite direction of effect to BABS
Microcephaly with cerebral atrophy and visual impairment, the inverse of the absolute or relative macrocephaly and macrosomia of BABS

Show evidence (1 reference)

PMID:41410504 SUPPORT Human Clinical

"Finally, DOHH (deoxyhypusine hydroxylase) disorder is an autosomal recessive disorder caused by bi-allelic loss-of-function variants in the deoxyhypusine hydroxylase (DOHH) gene, which causes decreased deoxyhypusine hydroxylase enzyme activity."

Gives the gene, the inheritance mode and the direction of effect that separate DOHH disorder from BABS.

ODC1 G84R hypomorphic variant association

Overlapping Features G84R is a population missense variant with reduced activity of purified recombinant enzyme and exploratory neurological phenotype associations. It is not an established BABS allele or a validated separate Mendelian diagnosis. The study calls for co-segregation and in-vivo experiments to establish causality.

Distinguishing Features

C-terminal truncation and increased enzyme abundance define the established BABS mechanism; purified G84R enzyme instead showed reduced catalytic activity.
Association and functional evidence for G84R do not establish Mendelian pathogenicity or a clinical treatment recommendation.

Show evidence (2 references)

PMID:33806076 SUPPORT In Vitro

"A functional enzyme assay for recombinant ODC WT or ODC G84R showed a 2.5-fold reduction of enzyme activity because of the variant, confirming alteration of enzymatic function due to the variant (Figure 1I)."

Purified recombinant enzyme assay demonstrates hypomorphic activity; this experiment is in vitro rather than solely computational.

PMID:33806076 SUPPORT Computational

"However, future in vivo analyses and co-segregation strategies should be performed to establish the causal roles of ODC G84R into phenotypic changes."

The authors explicitly distinguish association from established causality.

📊

Related Datasets

1

Multi-transcriptomic analysis of diesel particulate matter exposed cerebral organoids bioproject:PRJNA640661

Broader cerebral-organoid project cited for the ODC1 developmental-expression analysis. The repository title describes a diesel-particle exposure experiment; this is not a BABS patient or ODC1-mutant dataset, and the cited ODC1 paper does not identify the exact subset reused.

SINGLE CELL RNA SEQ

PMID:33806076

The accession resolves in NCBI BioProject. No sample count, disease-control contrast, or exposure effect is assigned to the ODC1 analysis without subset-level provenance.

Show evidence (2 references)

PMID:33806076 SUPPORT Computational

"Data are available within BioProject PRJNA640661."

The paper names this project as the data location; the project’s broader scope limits disease-specific interpretation.

url:https://www.ncbi.nlm.nih.gov/bioproject/PRJNA640661 SUPPORT In Vitro

"We used multiple RNAseq platforms (ribosomal reduced, single-cell, and direct nanopore) to examine the toxicogenomic effects of diesel particulate matter(DPM) on human cerebral organoids."

The BioProject describes a broader multi-platform exposure experiment. Its relationship to the ODC1 expression analysis is reuse of a referenced project, not a BABS disease cohort.

🧫

Experimental Models

3

Index-patient dermal fibroblasts and DFMO rescue PRIMARY_CELL_CULTURE

Patient fibroblasts accumulated ODC and putrescine and had elevated ODC activity. DFMO reduced activity and putrescine to control levels. This is a non-neural, single-patient model; controls were not described as isogenic.

Cell source

Primary dermal fibroblasts from the index patient with ODC1 c.1342A>T (p.Lys448Ter); neonatal and adult control fibroblasts

Publication

PMID:31249027

Pathograph links

ODC Protein Accumulation recapitulates Patient fibroblasts contain elevated ODC protein.

Show evidence (1 reference)

PMID:31249027 SUPPORT In Vitro

"In this study, we show that primary dermal fibroblasts derived from a skin biopsy of a 3-year-old patient contain large amounts of ODC protein and putrescine compared with primary dermal (neonatal and adult) fibroblast control cells."

Patient-derived fibroblasts provide direct cellular evidence from the index p.Lys448Ter case.

Elevated ODC Enzyme Activity recapitulates Radiolabeled ornithine assay detected elevated catalytic activity.

Show evidence (1 reference)

PMID:31249027 SUPPORT In Vitro

"Importantly, the accumulated ODC protein variant remained functionally active as we detected exceptionally high ODC enzyme activity in both primary dermal fibroblasts (12-17-fold of controls) and red blood cells (RBCs) (125-137-fold of controls), using a specific 14C radioactive ODC activity assay."

Assay results are from one patient, with separate fibroblast and erythrocyte preparations.

Putrescine Accumulation rescues DFMO reduced the elevated putrescine pool to control levels in culture.

Limitations: Biochemical rescue in fibroblasts does not establish neural or whole-patient efficacy.

Show evidence (1 reference)

PMID:31249027 SUPPORT In Vitro

"Exposure of primary dermal fibroblasts to ODC inhibitor α-difluoromethylornithine (DFMO) reduced the ODC activity and putrescine to levels observed in controls without adversely affecting cell morphology or inducing cell death."

Drug exposure normalized these measured biochemical readouts; absence of reported morphological change or cell death is not a comprehensive safety assay.

Show evidence (3 references)

PMID:31249027 SUPPORT In Vitro

"In this study, we show that primary dermal fibroblasts derived from a skin biopsy of a 3-year-old patient contain large amounts of ODC protein and putrescine compared with primary dermal (neonatal and adult) fibroblast control cells."

Patient-derived fibroblasts provide direct cellular evidence from the index p.Lys448Ter case.

PMID:31249027 SUPPORT In Vitro

"Importantly, the accumulated ODC protein variant remained functionally active as we detected exceptionally high ODC enzyme activity in both primary dermal fibroblasts (12-17-fold of controls) and red blood cells (RBCs) (125-137-fold of controls), using a specific 14C radioactive ODC activity assay."

Assay results are from one patient, with separate fibroblast and erythrocyte preparations.

PMID:31249027 SUPPORT In Vitro

"Exposure of primary dermal fibroblasts to ODC inhibitor α-difluoromethylornithine (DFMO) reduced the ODC activity and putrescine to levels observed in controls without adversely affecting cell morphology or inducing cell death."

Drug exposure normalized these measured biochemical readouts; absence of reported morphological change or cell death is not a comprehensive safety assay.

Reference-line cerebral organoids for ODC1 expression ORGANOID

Reference-line cerebral organoids were profiled to relate ODC1 expression to immature SOX-expressing cells. These are observational expression data; no disease allele was introduced and neural over-proliferation was not experimentally demonstrated.

Cell source

Human iPSC line AICS-0011; not a BABS patient line

Culture

STEMdiff cerebral organoid differentiation with single-cell RNA sequencing

Publication

PMID:33806076

Pathograph links

Dysregulated Neural Progenitor Proliferation measures Measures expression associations underlying the proposed neural mechanism, not the putative proliferation defect itself.

Limitations: Unperturbed reference line; expression is not a proliferation assay or proof of disease causation.

Show evidence (1 reference)

PMID:33806076 SUPPORT Computational

"There was also a higher expression of ODC1 in cells expressing pluripotent SOX gene markers, with both the number of cells and total expression levels of ODC1 lower in cells that did not have SOX gene expression (Figure 2D)."

Single-cell expression associations support a developmental hypothesis; no BABS perturbation was tested.

Show evidence (1 reference)

PMID:33806076 SUPPORT In Vitro

"To test the hypothesis that ODC1 expression correlates with the maturity of neurons, we developed induced pluripotent stem cells (iPSCs) differentiated into cerebral organoids followed by single cell RNA-Seq."

The study generated organoids; it was not solely a reanalysis of published organoid data.

Engineered murine ODC C-terminal truncation in mammalian cells OTHER

Deletion of the final 37 residues stabilized ODC in a classical cellular experiment. This demonstrates the function of the C-terminal degradation region, but is not a patient-derived BABS model and is not the same truncation length as p.Lys448Ter.

Cell source

Mammalian cells expressing engineered murine ODC

Publication

PMID:2928784

Pathograph links

Escape from Antizyme-Mediated Proteasomal Degradation perturbs Engineered tail deletion increases intracellular stability; the quoted experiment does not isolate antizyme binding as the affected step.

Show evidence (1 reference)

PMID:2928784 SUPPORT In Vitro

"Ornithine decarboxylase (ODC) was converted from a protein with a short intracellular half-life in mammalian cells to a stable protein by truncating 37 residues at its carboxyl terminus."

An engineered truncation establishes the contribution of the C terminus to ODC turnover.

Show evidence (1 reference)

PMID:2928784 SUPPORT In Vitro

"Thus, a carboxyl-terminal domain is responsible for the rapid intracellular degradation of murine ODC."

Cellular turnover experiment; human tissue consequences are not assessed.

🐁

Animal Models

2

Skin-restricted K6/ODC transgenic mouse Transgenic

The K6/ODC mouse expresses a mouse ODC cDNA carrying a premature stop codon at position 427, driven by a bovine keratin 6 promoter, in outer root sheath keratinocytes of the hair follicle. The lesion is the same class as the human BABS allele - carboxyl truncation producing a stabilised, catalytically active enzyme - which is why this 1995-1996 model predicted the human syndrome. Mice have a normal first hair cycle, lose their hair completely from 2-3 weeks of age, and develop dermal follicular cysts. DFMO both prevents the hair loss and reactivates hair growth after complete loss. The model is skin-restricted, so it does not model the neurodevelopmental, growth or sensory features of BABS, and it also develops skin tumours, which has no established human BABS counterpart.

Species

Mus musculus

Genotype

K6/ODC transgenic

Pathograph links

Hair Follicle Dysfunction partially recapitulates Postnatal hair loss and DFMO-induced regrowth reproduce the ectodermal phenotype.

Limitations: Skin-restricted transgene expression does not model the neural or systemic human phenotype.

Show evidence (1 reference)

PMID:8618048 SUPPORT Model Organism

"Mice that overexpress a mutated ornithine decarboxylase (ODC) transgene in outer root sheath keratinocytes of the hair follicle were used to study the role of this enzyme in regulating hair follicle structure and function."

The promoter targets follicular keratinocytes.

Show evidence (6 references)

PMID:8618048 SUPPORT Model Organism

"The ODC inhibitor 2-difluoromethylornithine could prevent hair loss and partially normalize skin histology if administered before the onset of ODC overexpression."

Establishes the preventive arm of the DFMO effect in the model that motivated human treatment.

PMID:41925768 SUPPORT Model Organism

"Ornithine decarboxylase (ODC), a key regulating enzyme of polyamine biosynthesis, was constitutively expressed in the outer root sheath cells of hair follicles near the bulge stem cell niche using a keratin 6 promoter in K6/ODC mice."

Defines the transgene construct and the targeted cell population.

PMID:41925768 SUPPORT REVIEW SYNTHESIS Human Clinical

"Remarkably, the heterozygous de novo mutation in the ODC gene of this patient and others subsequently identified as having the Bachmann-Bupp syndrome (BABS) introduces a stop codon in the ODC gene, leading to premature abrogation and deletion of the c-terminal 14 amino acids of the ODC protein,..."

The review draws a mechanistic analogy between C-terminal truncations. The mouse p.427 stop and human p.Lys448Ter allele remove different lengths and are not identical variants.

+ 3 more references

Constitutive Odc1-null mouse as a loss-of-function contrast Knockout

Constitutive Odc1 knockout is a mechanistic contrast to BABS gain of function. Homozygous embryos failed to develop after implantation; heterozygotes were described as viable, normal, and fertile in the original study. This experiment neither models the BABS allele nor establishes a human pharmacological safety threshold. In cultured null blastocysts the inner cell mass degenerated despite initially preserved mitotic-cell counts; this loss-of-function observation is not a demonstrated neural-proliferation defect in BABS.

Species

Mus musculus

Genotype

Odc1 knockout

Show evidence (3 references)

PMID:11533243 SUPPORT Model Organism

"ODC-heterozygous mice were viable, normal, and fertile."

Loss-of-function mouse evidence provides biological context; it is not evidence that a human BABS allele causes this phenotype or that a particular inhibitor dose is safe.

PMID:11533243 SUPPORT Model Organism

"Embryonic day E3.5 ODC-deficient embryos were capable of uterine implantation and induced maternal decidualization yet failed to develop substantially thereafter."

Loss-of-function mouse evidence provides biological context; it is not evidence that a human BABS allele causes this phenotype or that a particular inhibitor dose is safe.

PMID:11533243 SUPPORT In Vitro

"No striking differences were observed in any of the embryos analyzed, and ODC-deficient blastocysts (n = 3) contained similar numbers of mitotic cells as their wild-type littermates (Fig. 5A)."

Cultured/isolated blastocyst evidence distinguishes initial mitotic-cell counts from subsequent inner-cell-mass survival; it does not model BABS gain of function.

{ }

Source YAML

click to show

name: Bachmann-Bupp Syndrome
creation_date: '2026-08-01T00:00:00Z'
category: Mendelian
synonyms:
- BABS
- NEDABA
- neurodevelopmental disorder with alopecia and brain abnormalities
- global developmental delay-alopecia-macrocephaly-facial dysmorphism-structural brain anomalies syndrome
description: Bachmann-Bupp syndrome (BABS) is an ultra-rare autosomal dominant neurodevelopmental disorder caused by heterozygous ODC1 gain-of-function variants, typically arising de novo. Reported variants truncate the carboxy terminus of ornithine decarboxylase, impairing its proteasomal turnover while preserving catalytic activity and causing ODC and putrescine accumulation. The phenotype includes non-congenital alopecia, developmental delay, hypotonia, macrocephaly, variable dysmorphism, feeding and behavioral difficulties, and nonspecific brain imaging abnormalities. Macrosomia is variable. Eflornithine inhibits ODC and has been used experimentally in affected individuals, with reported biochemical correction, hair regrowth, cessation of follicular cysts, and developmental gains. The clinical evidence remains uncontrolled and does not establish the magnitude of developmental benefit or an optimal treatment window.
disease_term:
preferred_term: Bachmann-Bupp syndrome
term:
id: MONDO:0033642
label: neurodevelopmental disorder with alopecia and brain abnormalities
parents:
- Disorder of polyamine metabolism
- Mendelian neurodevelopmental disorder
classifications:
harrisons_chapter:
- classification_value: GENETICS_ENVIRONMENT_DISEASE
evidence:
- reference: PMID:36007106
reference_title: Bachmann-Bupp Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The diagnosis is established in a proband with suggestive findings and a heterozygous pathogenic variant in ODC1 identified by molecular genetic testing.
explanation: A monogenic disorder established by molecular genetic testing of a single gene belongs to the genetics chapter.
- classification_value: NEUROLOGIC
evidence:
- reference: PMID:37469105
reference_title: Bachmann-Bupp syndrome and treatment.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Bachmann-Bupp syndrome (BABS) is a neurodevelopmental disorder characterized by developmental delay, hypotonia, and varying forms of non-congenital alopecia.
explanation: The disease-specific review classifies BABS as a neurodevelopmental disorder with developmental delay and hypotonia as core features.
- classification_value: DERMATOLOGY
evidence:
- reference: PMID:36443247
reference_title: Improvement of dermatological symptoms in patients with Bachmann-Bupp syndrome using difluoromethylornithine treatment.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: In both patients, treatment with difluoromethylornithine has resulted in improved dermatologic signs, including regrowth of eyebrow and scalp hair and cessation of recurrent follicular cyst development.
explanation: Alopecia and recurrent follicular cysts are defining, often presenting manifestations that are managed dermatologically.
- classification_value: ENDOCRINOLOGY_METABOLISM
evidence:
- reference: PMID:30475435
reference_title: Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: In this report, we present four patients with a distinct neurometabolic disorder associated with de novo heterozygous, gain-of-function variants in the ODC1 gene.
explanation: The index cohort report characterises BABS as a neurometabolic disorder of endogenous polyamine synthesis.
icimd_category:
- classification_value: polyamine_metabolism
evidence:
- reference: PMID:41410504
reference_title: 'Genetic and Phenotypic Features of the Five Known Polyaminopathies: A Critical Narrative Review.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Bachmann-Bupp syndrome results from heterozygous gain-of-function variants in the ornithine decarboxylase 1 (ODC1) gene, resulting in increased ornithine decarboxylase enzyme activity.
explanation: The polyaminopathy review places BABS within the family of disorders of polyamine metabolism.
notes: Reported cohorts are very small, overlap across publications, and include a stillborn fetus. Frequencies describe the cited series and are not population estimates. Clinical and biochemical effects of ODC1 variants require allele-specific interpretation; an ODC1 finding alone does not establish BABS. The skin-restricted K6/ODC model supports the ectodermal mechanism but does not establish the neural mechanism or cancer risk in affected humans.
inheritance:
- name: Autosomal dominant
description: Heterozygous ODC1 variants are sufficient; reported cases have been de novo, so recurrence risk to siblings is presumed low.
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
evidence:
- reference: PMID:36007106
reference_title: Bachmann-Bupp Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: BABS is expressed in an autosomal dominant manner and typically caused by a de novo ODC1 pathogenic variant.
explanation: GeneReviews states the autosomal dominant mode and the de novo origin of the causative variant.
- reference: PMID:36443247
reference_title: Improvement of dermatological symptoms in patients with Bachmann-Bupp syndrome using difluoromethylornithine treatment.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'Bachmann-Bupp syndrome (OMIM #619075) is a novel autosomal dominant disorder caused by variants in the c-terminus of the ornithine decarboxylase 1 gene, resulting in increased levels of ornithine decarboxylase.'
explanation: Independent confirmation of autosomal dominant transmission and of the C-terminal location of the causative variants.
- name: De novo occurrence
description: Reported causative variants have generally arisen de novo; the founding four-patient cohort documented de novo heterozygous alleles in all four individuals. Parental testing is needed to establish origin in an individual family.
inheritance_term:
preferred_term: Sporadic
term:
id: HP:0003745
label: Sporadic
evidence:
- reference: PMID:30475435
reference_title: Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: In this report, we present four patients with a distinct neurometabolic disorder associated with de novo heterozygous, gain-of-function variants in the ODC1 gene.
explanation: A four-patient cohort in which every causative allele arose de novo.
prevalence:
- population: Worldwide, published cases
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: Population prevalence is unknown. The 2026 narrative review identified 12 published clinical cases, including a conference abstract, and reported 18 cases known to its authors worldwide. These are overlapping literature and investigator counts rather than a population-based rate.
evidence:
- reference: PMID:37469105
reference_title: Bachmann-Bupp syndrome and treatment.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: BABS is an ultra-rare condition with few reported cases, but it serves as a convincing example for drug repurposing therapy.
explanation: The disease-specific review characterises BABS as ultra-rare with few reported cases.
- reference: PMID:34282722
reference_title: Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The novel treatment of this ultra-rare (less than 10 known cases) genetic syndrome presented unique challenges for monitoring efficacy over time.
explanation: Supplies the explicit published denominator underpinning the ultra-rare tier at the time of the first treated case.
- reference: PMID:37092498
reference_title: Two New Cases of Bachmann-Bupp Syndrome Identified through the International Center for Polyamine Disorders.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: This case study provides insights from two new patients diagnosed with Bachmann-Bupp syndrome, further expanding our understanding of this ultra-rare condition, as well as a general discussion about other known polyaminopathies.
explanation: An incremental two-patient addition to the published series, again described as ultra-rare.
- reference: PMID:41410504
reference_title: 'Genetic and Phenotypic Features of the Five Known Polyaminopathies: A Critical Narrative Review.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: While there are 18 cases of BABS known worldwide (authors’ personal knowledge), spanning eight countries, 12 clinical cases have been reported in the literature (Bupp et al., 2018; Halleb et al., 2023; Michael et al., 2023; Rodan et al., 2018; VanSickle et al., 2021).
explanation: Dated 2026 synthesis distinguishes published cases from additional cases known personally to the authors.
quote_role: REVIEW_SYNTHESIS
pathophysiology:
- name: ODC1 C-Terminal Truncating Variant
biological_scale: MOLECULAR
description: Heterozygous nonsense, frameshift, and splice-site variants affecting the ODC1 C-terminal region produce shortened ODC proteins. The index c.1342A>T (p.Lys448Ter) allele removes the final 14 amino acids; other alleles truncate different portions of the C-terminal region.
genes:
- preferred_term: ODC1
term:
id: hgnc:8109
label: ODC1
modifier: ABNORMAL
genetic_context:
gene:
preferred_term: ODC1
term:
id: hgnc:8109
label: ODC1
variant_origin: DE_NOVO
zygosity: HETEROZYGOUS
functional_impact_category: GAIN_OF_FUNCTION
description: Reported de novo heterozygous nonsense, frameshift, and splice-site alleles converge on C-terminal truncation and increased enzyme abundance. Splice consequences are predicted for some alleles rather than directly assayed.
evidence:
- reference: PMID:37469105
reference_title: Bachmann-Bupp syndrome and treatment.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The condition is caused by 3'-end mutations of the ornithine decarboxylase 1 (ODC1) gene, which produce carboxy (C)-terminally truncated variants of ODC, a pyridoxal 5'-phosphate-dependent enzyme.
explanation: Names the location of the causative variants and the protein consequence that defines this node.
- reference: PMID:30239107
reference_title: Novel de novo pathogenic variant in the ODC1 gene in a girl with developmental delay, alopecia, and dysmorphic features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Here, we report an 32-month-old Caucasian female with a heterozygous de novo nonsense mutation in the ODC1 gene that leads to a premature abrogation of 14-aa residues at the ODC protein c-terminus.
explanation: 'The index case defines the specific lesion: a de novo nonsense variant truncating the last 14 residues.'
- reference: PMID:34477286
reference_title: 'Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Variants continue to cluster, providing support to a universal biochemical mechanism related to elevated ODC protein, enzyme activity, and abnormalities in polyamine levels.
explanation: Establishes that the reported variants cluster in one region and converge on a single biochemical mechanism.
- reference: PMID:40382142
reference_title: Monitoring ODC activity and polyamines in Bachmann-Bupp syndrome patient biological samples.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: ODC1 gene mutations that are linked to BABS always produce C-terminally truncated versions of the enzyme ornithine decarboxylase (ODC).
explanation: States that C-terminal truncation is an invariant feature of the BABS allele spectrum.
- reference: PMID:30475435
reference_title: Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: In this report, we present four patients with a distinct neurometabolic disorder associated with de novo heterozygous, gain-of-function variants in the ODC1 gene.
explanation: The founding case series classifies the causal ODC1 alleles as de novo, heterozygous and gain-of-function, which is the functional impact recorded here.
downstream:
- target: Escape from Antizyme-Mediated Proteasomal Degradation
description: Loss of the C-terminal degron removes the signal that normally targets ODC for ubiquitin-independent proteasomal turnover.
causal_link_type: DIRECT
evidence:
- reference: PMID:37469105
reference_title: Bachmann-Bupp syndrome and treatment.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: C-terminal truncation of ODC prevents its ubiquitin-independent proteasomal degradation and leads to cellular accumulation of ODC enzyme that remains catalytically active.
explanation: Directly links the C-terminal truncation to failure of the degradation route.
- name: Escape from Antizyme-Mediated Proteasomal Degradation
biological_scale: MOLECULAR
description: Wild-type ODC is one of the shortest-lived mammalian proteins because its C-terminus acts as a degron for ubiquitin-independent, antizyme-dependent proteasomal degradation. The truncated BABS enzyme cannot be cleared by this route, so it escapes normal turnover. This is a stability defect, not a catalytic defect.
biological_processes:
- preferred_term: proteasomal ubiquitin-independent protein catabolic process
term:
id: GO:0010499
label: proteasomal ubiquitin-independent protein catabolic process
modifier: DECREASED
evidence:
- reference: PMID:40382142
reference_title: Monitoring ODC activity and polyamines in Bachmann-Bupp syndrome patient biological samples.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: These shortened ODC proteins remain enzymatically active and are not cleared by the proteasome, therefore leading to ODC protein accumulation in cells.
explanation: 'States both halves of this node: preserved catalysis and failed proteasomal clearance.'
- reference: PMID:31249027
reference_title: Biochemical features of primary cells from a pediatric patient with a gain-of-function ODC1 genetic mutation.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: We hypothesized that this new mutation (c.1342 A>T) leads to a C-terminal truncation variant of the ODC protein that is resistant to normal proteasomal degradation, leading to putrescine accumulation in cells.
explanation: States the degradation-resistance hypothesis that the same study then tested in patient-derived cells.
- reference: PMID:41925768
reference_title: 'The remarkable legacy of the K6/ODC mouse: mechanisms of polyamine-promoted tumorigenesis revealed.'
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: a premature stop codon at position 427 in the mouse ODC cDNA was placed downstream of the K6 promoter resulting in a carboxyl-truncated ODC protein with a much longer in vivo half-life than the full-length ODC protein
explanation: The engineered mouse allele demonstrates that C-terminal truncation alone extends the half-life of the ODC protein.
- reference: PMID:2928784
reference_title: Prevention of rapid intracellular degradation of ODC by a carboxyl-terminal truncation.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Ornithine decarboxylase (ODC) was converted from a protein with a short intracellular half-life in mammalian cells to a stable protein by truncating 37 residues at its carboxyl terminus.
explanation: 'The founding experiment: removing the C-terminal 37 residues converts ODC from a short-lived to a stable protein. This is, three decades early, an in vitro pre-enactment of the human BABS lesion.'
- reference: PMID:2928784
reference_title: Prevention of rapid intracellular degradation of ODC by a carboxyl-terminal truncation.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Thus, a carboxyl-terminal domain is responsible for the rapid intracellular degradation of murine ODC.
explanation: Localises the degradation signal to the carboxyl-terminal domain, the domain that BABS variants delete.
- reference: PMID:1334232
reference_title: Ornithine decarboxylase is degraded by the 26S proteasome without ubiquitination.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: In addition, purified 26S proteasome complex, but not the 20S proteasome, catalyses ODC degradation in the absence of ubiquitin.
explanation: 'Identifies the specific proteolytic route that the truncation escapes: 26S-proteasomal degradation without ubiquitination.'
- reference: PMID:1334232
reference_title: Ornithine decarboxylase is degraded by the 26S proteasome without ubiquitination.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: We have shown that its degradation is accelerated by ODC antizyme, an inhibitory protein induced by polyamines.
explanation: Establishes antizyme as the accelerator of ODC turnover, the regulatory arm that a C-terminally truncated enzyme is insensitive to.
downstream:
- target: ODC Protein Accumulation
description: A protein that cannot be degraded accumulates in the cell.
causal_link_type: DIRECT
evidence:
- reference: PMID:40382142
reference_title: Monitoring ODC activity and polyamines in Bachmann-Bupp syndrome patient biological samples.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: These shortened ODC proteins remain enzymatically active and are not cleared by the proteasome, therefore leading to ODC protein accumulation in cells.
explanation: Names failed proteasomal clearance as the direct cause of ODC protein accumulation.
- name: ODC Protein Accumulation
biological_scale: CELLULAR
description: Stabilised ODC protein accumulates to large excess in patient cells, demonstrated in primary dermal fibroblasts and in red blood cells.
cell_types:
- preferred_term: fibroblast
term:
id: CL:0000057
label: fibroblast
- preferred_term: erythrocyte
term:
id: CL:0000232
label: erythrocyte
evidence:
- reference: PMID:31249027
reference_title: Biochemical features of primary cells from a pediatric patient with a gain-of-function ODC1 genetic mutation.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: In this study, we show that primary dermal fibroblasts derived from a skin biopsy of a 3-year-old patient contain large amounts of ODC protein and putrescine compared with primary dermal (neonatal and adult) fibroblast control cells.
explanation: Direct measurement of accumulated ODC protein in patient-derived fibroblasts.
- reference: PMID:30239107
reference_title: Novel de novo pathogenic variant in the ODC1 gene in a girl with developmental delay, alopecia, and dysmorphic features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Red blood cells obtained from our patient showed elevated ODC protein and polyamine levels compared to healthy controls.
explanation: Confirms ODC protein accumulation in a second, circulating patient cell type.
downstream:
- target: Elevated ODC Enzyme Activity
description: The accumulated truncated protein remains catalytically active; elevated protein and ODC activity were measured in cells from the index patient.
causal_link_type: DIRECT
evidence:
- reference: PMID:31249027
reference_title: Biochemical features of primary cells from a pediatric patient with a gain-of-function ODC1 genetic mutation.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Importantly, the accumulated ODC protein variant remained functionally active as we detected exceptionally high ODC enzyme activity in both primary dermal fibroblasts (12-17-fold of controls) and red blood cells (RBCs) (125-137-fold of controls), using a specific 14C radioactive ODC activity assay.
explanation: Quantifies the step from accumulated protein to elevated catalytic activity in two patient cell types.
- name: Elevated ODC Enzyme Activity
biological_scale: MOLECULAR
description: In the index patient, ODC activity was 12-17-fold above controls in cultured dermal fibroblasts and 125-137-fold in red blood cells. These are preparation-specific measurements from one patient, not established ranges for all BABS alleles. ODC catalyzes the rate-limiting conversion of ornithine to putrescine.
molecular_functions:
- preferred_term: ornithine decarboxylase activity
term:
id: GO:0004586
label: ornithine decarboxylase activity
modifier: INCREASED
biological_processes:
- preferred_term: polyamine biosynthetic process
term:
id: GO:0006596
label: polyamine biosynthetic process
modifier: INCREASED
evidence:
- reference: PMID:31249027
reference_title: Biochemical features of primary cells from a pediatric patient with a gain-of-function ODC1 genetic mutation.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Importantly, the accumulated ODC protein variant remained functionally active as we detected exceptionally high ODC enzyme activity in both primary dermal fibroblasts (12-17-fold of controls) and red blood cells (RBCs) (125-137-fold of controls), using a specific 14C radioactive ODC activity assay.
explanation: Quantifies the magnitude of the enzyme-activity gain in patient material.
- reference: PMID:41410504
reference_title: 'Genetic and Phenotypic Features of the Five Known Polyaminopathies: A Critical Narrative Review.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Bachmann-Bupp syndrome results from heterozygous gain-of-function variants in the ornithine decarboxylase 1 (ODC1) gene, resulting in increased ornithine decarboxylase enzyme activity.
explanation: The polyaminopathy review states increased enzyme activity as the defining biochemical consequence.
- reference: PMID:30475435
reference_title: Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Ornithine decarboxylase 1 (ODC1) is the rate-limiting enzyme in endogenous polyamine synthesis.
explanation: Establishes why a change in ODC activity controls flux through the whole polyamine pathway.
downstream:
- target: Putrescine Accumulation
description: ODC converts ornithine to putrescine; excess enzyme activity drives putrescine accumulation.
causal_link_type: DIRECT
evidence:
- reference: PMID:40382142
reference_title: Monitoring ODC activity and polyamines in Bachmann-Bupp syndrome patient biological samples.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: ODC is a key enzyme of polyamine biosynthesis by converting ornithine to putrescine, and if accumulated, can lead to high putrescine levels in human cells including red blood cells (RBCs) and primary dermal fibroblasts.
explanation: Names the reaction and the direct consequence of enzyme accumulation.
- target: Ornithine Substrate Depletion
description: Excess ornithine consumption by ODC is a proposed explanation for low plasma ornithine and its rise during treatment; flux was not directly measured.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:34282722
reference_title: Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Ornithine andN-acetylarginine were below the 2.5th percentile at start of therapy and normalized to the larger pediatric values over the course of therapy.
explanation: The observation supports low plasma ornithine and treatment-associated normalization. It does not directly establish increased substrate consumption as the cause.
- name: Putrescine Accumulation
biological_scale: MOLECULAR
description: Putrescine, the immediate product of ODC, accumulates in patient cells. It is the proximate biochemical lesion of BABS and the target of eflornithine therapy.
chemical_entities:
- preferred_term: putrescine
term:
id: CHEBI:17148
label: putrescine
modifier: INCREASED
evidence:
- reference: PMID:31249027
reference_title: Biochemical features of primary cells from a pediatric patient with a gain-of-function ODC1 genetic mutation.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: In this study, we show that primary dermal fibroblasts derived from a skin biopsy of a 3-year-old patient contain large amounts of ODC protein and putrescine compared with primary dermal (neonatal and adult) fibroblast control cells.
explanation: Direct measurement of putrescine accumulation in patient-derived cells.
- reference: PMID:40382142
reference_title: Monitoring ODC activity and polyamines in Bachmann-Bupp syndrome patient biological samples.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: ODC is a key enzyme of polyamine biosynthesis by converting ornithine to putrescine, and if accumulated, can lead to high putrescine levels in human cells including red blood cells (RBCs) and primary dermal fibroblasts.
explanation: States that accumulated ODC leads to high putrescine in patient cell types.
- reference: PMID:30475435
reference_title: Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Plasma clinical metabolomics analysis demonstrates elevation of N-acetylputrescine, the acetylated form of putrescine, with otherwise normal polyamine levels.
explanation: The four-patient study reports elevated N-acetylputrescine with otherwise normal plasma polyamines. This plasma result does not exclude changes in spermidine or spermine in other cell types or preparations.
- reference: PMID:9563478
reference_title: Polyamines regulate expression of the neoplastic phenotype in mouse skin.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: The regulatory polyamine in this model appears to be putrescine, the immediate product of ornithine decarboxylase.
explanation: The mouse skin study implicates putrescine in its neoplastic phenotype; this is model evidence rather than proof of which polyamine causes every human manifestation.
downstream:
- target: Elevated N-Acetylputrescine
description: Excess putrescine is acetylated, and it is the acetylated species that is measurable on clinical metabolomic profiling.
causal_link_type: DIRECT
evidence:
- reference: PMID:30475435
reference_title: Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Plasma clinical metabolomics analysis demonstrates elevation of N-acetylputrescine, the acetylated form of putrescine, with otherwise normal polyamine levels.
explanation: Identifies N-acetylputrescine as the acetylated derivative of the accumulated putrescine pool.
- target: Hair Follicle Dysfunction
description: Sustained ODC activity and elevated polyamine biosynthesis perturb follicular function in the skin-restricted transgenic model; the intermediate steps producing human alopecia are unresolved.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:8618048
reference_title: Modulation of murine hair follicle function by alterations in ornithine decarboxylase activity.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: These transgenic mice have a normal first hair cycle, but lose their hair completely beginning 2-3 wk after birth.
explanation: The skin-targeted model connects increased ODC activity with hair-cycle disruption, without proving bulge recruitment mediates alopecia.
- target: Dysregulated Neural Progenitor Proliferation
description: ODC1 expression tracks neural progenitor proliferation in fetal brain and cerebral organoids; gain of function is proposed to drive over-proliferation. The steps between the raised polyamine pool and the progenitor phenotype are not established.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:33806076
reference_title: Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development.
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: Further dissection of RNA-Seq during fetal brain development and within cerebral organoids showed an association of ODC1 expression with cell proliferation of neural progenitor cells, suggesting gain-of-function variants with neural over-proliferation and loss-of-function variants with neural depletion.
explanation: Transcriptomic analysis links ODC1 level to neural progenitor proliferation and explicitly separates the gain-of-function from the loss-of-function direction.
- name: Ornithine Substrate Depletion
biological_scale: MOLECULAR
description: Plasma ornithine sat below the 2.5th percentile of a paediatric reference cohort before treatment in the first treated patient and normalised on eflornithine, consistent with excess consumption by the overactive enzyme.
chemical_entities:
- preferred_term: L-ornithine
term:
id: CHEBI:15729
label: L-ornithine
modifier: DECREASED
evidence:
- reference: PMID:34282722
reference_title: Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Ornithine andN-acetylarginine were below the 2.5th percentile at start of therapy and normalized to the larger pediatric values over the course of therapy.
explanation: Documents the pre-treatment ornithine deficit and its correction on ODC inhibition, which is what makes substrate drawdown by the overactive enzyme the most parsimonious explanation. The snippet reproduces a missing-space text-extraction artefact present in the cached source ("andN-acetylarginine") and is quoted byte-exactly rather than tidied.
- reference: PMID:34282722
reference_title: Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Urea cycle components citrulline and arginine, along with other metabolites, remained at 1 to -1 standard deviation throughout the study period
explanation: Citrulline and arginine remained within the reported reference range during this patient’s treatment. This does not prove that every urea-cycle process or metabolite is unaffected.
- name: Elevated N-Acetylputrescine
biological_scale: MOLECULAR
description: N-acetylputrescine is the clinically measurable signature of the accumulated putrescine pool and is the metabolite that makes metabolomic profiling diagnostically suggestive of BABS. Other polyamine levels may be normal.
chemical_entities:
- preferred_term: N-acetylputrescine
term:
id: CHEBI:17768
label: N-acetylputrescine
modifier: INCREASED
evidence:
- reference: PMID:30475435
reference_title: Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Plasma clinical metabolomics analysis demonstrates elevation of N-acetylputrescine, the acetylated form of putrescine, with otherwise normal polyamine levels.
explanation: Establishes the elevation and its selectivity within the polyamine panel.
- reference: PMID:36007106
reference_title: Bachmann-Bupp Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The finding of abnormal polyamine pathway metabolites (including increased N-acetylputrescine) on metabolomic profiling is suggestive of a diagnosis of BABS.
explanation: GeneReviews makes this metabolite the biochemical entry point to the diagnosis.
- name: Hair Follicle Dysfunction
biological_scale: TISSUE
description: Constitutive expression of truncated ODC in outer root sheath keratinocytes disrupts hair cycling in K6/ODC mice. Hair loss after the first cycle resembles the postnatal alopecia in BABS. A separate inducible ODC-ER model recruits bulge stem cells while retaining a normal skin phenotype, so recruitment is not established as the cause of BABS alopecia.
cell_types:
- preferred_term: outer root sheath cell
term:
id: CL:0002561
label: outer root sheath cell
evidence:
- reference: PMID:8618048
reference_title: Modulation of murine hair follicle function by alterations in ornithine decarboxylase activity.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: These transgenic mice have a normal first hair cycle, but lose their hair completely beginning 2-3 wk after birth.
explanation: Establishes the hair-cycle-specific timing of the defect in the model that carries the same class of lesion.
- reference: PMID:8618048
reference_title: Modulation of murine hair follicle function by alterations in ornithine decarboxylase activity.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Mice that overexpress a mutated ornithine decarboxylase (ODC) transgene in outer root sheath keratinocytes of the hair follicle were used to study the role of this enzyme in regulating hair follicle structure and function.
explanation: Identifies the outer root sheath keratinocyte as the cell type in which excess ODC produces the follicular phenotype.
downstream:
- target: Follicular Cyst Formation
description: Follicular cyst formation accompanies constitutive ODC overexpression and abnormal hair cycling in the transgenic model. The tissue intermediates have not been fully resolved.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:8618048
reference_title: Modulation of murine hair follicle function by alterations in ornithine decarboxylase activity.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Transgene overexpression in follicular keratinocytes is first detected at day 12 after birth, coincident with the development of follicular cysts in the upper portion of the dermis.
explanation: Ties the onset of follicular ODC overexpression to the appearance of dermal follicular cysts.
- reference: PMID:41925768
reference_title: 'The remarkable legacy of the K6/ODC mouse: mechanisms of polyamine-promoted tumorigenesis revealed.'
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: These sustained high levels of polyamine biosynthesis in K6/ODC mouse skin lead to hair loss beginning at 3 weeks of age when the second cycle of hair growth begins followed by the subsequent development of follicular dermal cysts
explanation: Places hair loss and follicular cyst formation in sequence downstream of sustained polyamine excess.
- target: Alopecia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Follicular dysfunction is linked to alopecia by the transgenic skin phenotype and DFMO response; direct human follicle measurements are limited.
evidence:
- reference: PMID:8618048
reference_title: Modulation of murine hair follicle function by alterations in ornithine decarboxylase activity.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: 2-Difluoromethylornithine could also reactivate hair growth in animals with complete hair loss.
explanation: Reactivation of hair growth after ODC inhibition supports the follicular route in the mouse model.
- target: Absent eyebrow
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Eyebrow and eyelash involvement extend the observed follicular phenotype; the mechanism of regional hair loss remains incompletely defined.
evidence:
- reference: PMID:36443247
reference_title: Improvement of dermatological symptoms in patients with Bachmann-Bupp syndrome using difluoromethylornithine treatment.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: In both patients, treatment with difluoromethylornithine has resulted in improved dermatologic signs, including regrowth of eyebrow and scalp hair and cessation of recurrent follicular cyst development.
explanation: The clinical hair phenotype is consistent with follicular dysfunction; the tissue intermediates are not directly measured in these patients.
- target: Sparse eyebrow
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Eyebrow and eyelash involvement extend the observed follicular phenotype; the mechanism of regional hair loss remains incompletely defined.
evidence:
- reference: PMID:34477286
reference_title: 'Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Sparse hair is now present throughout the scalp with very little eyebrow hair and eyelashes.
explanation: The clinical hair phenotype is consistent with follicular dysfunction; the tissue intermediates are not directly measured in these patients.
- target: Sparse or absent eyelashes
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Eyebrow and eyelash involvement extend the observed follicular phenotype; the mechanism of regional hair loss remains incompletely defined.
evidence:
- reference: PMID:37092498
reference_title: Two New Cases of Bachmann-Bupp Syndrome Identified through the International Center for Polyamine Disorders.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Some individuals have regrowth of scalp hair that typically remains sparse, with congenital absence of the eyebrows and eyelashes.
explanation: The clinical hair phenotype is consistent with follicular dysfunction; the tissue intermediates are not directly measured in these patients.
- name: Follicular Cyst Formation
biological_scale: TISSUE
description: Recurrent follicular cysts form on the scalp, neck and back, beginning as small maculopapular pustules and enlarging to several centimetres, sometimes requiring surgical removal.
evidence:
- reference: PMID:34282722
reference_title: Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Multiple lesions located on the posterior scalp and back that first were small maculopapular pustules slowly increased in size to approximately 6-7 cm in diameter
explanation: Describes the natural history and size of the cysts in a genotyped patient.
- reference: PMID:7671221
reference_title: Increased frequency of spontaneous skin tumors in transgenic mice which overexpress ornithine decarboxylase.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Effects observed include development of dermal follicular cysts, excessive skin wrinkling, enhanced nail growth, alopecia, and spontaneous tumor development.
explanation: The original transgenic report lists dermal follicular cysts alongside alopecia and accelerated nail growth, the ectodermal cluster later recognised in BABS patients.
downstream:
- target: Cutaneous cyst
causal_link_type: DIRECT
description: Follicular cyst formation produces the recurrent cutaneous cyst phenotype.
evidence:
- reference: PMID:34282722
reference_title: Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: She had a history of recurring follicular cyst formation and enlargement.
explanation: The human case documents the corresponding clinical manifestation.
- name: Dysregulated Neural Progenitor Proliferation
biological_scale: CELLULAR
description: 'ODC1 expression during fetal brain development and in cerebral organoids associates with neural progenitor cell proliferation, and gain-of-function variants are proposed to produce neural over-proliferation. This node is the weakest link in the chain: the human neurodevelopmental phenotype is not yet mechanistically connected to a measured progenitor abnormality in BABS patient tissue.'
cell_types:
- preferred_term: neural progenitor cell
term:
id: CL:0011020
label: neural progenitor cell
biological_processes:
- preferred_term: neural precursor cell proliferation
term:
id: GO:0061351
label: neural precursor cell proliferation
modifier: ABNORMAL
evidence:
- reference: PMID:33806076
reference_title: Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development.
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: The linkage from the expression data of ODC1 in early neural progenitor proliferation to phenotypes of neurodevelopmental delay and to the connection of polyamine metabolites in brain function establish ODC1 as a bona fide neurodevelopmental disorder gene.
explanation: States the inferential chain from progenitor proliferation to neurodevelopmental delay on which this node rests.
downstream:
- target: Abnormal Brain Development
description: Disturbed progenitor proliferation is the proposed route to the structural and functional brain abnormalities, but the intermediates are unknown.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:33806076
reference_title: Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development.
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: Further dissection of RNA-Seq during fetal brain development and within cerebral organoids showed an association of ODC1 expression with cell proliferation of neural progenitor cells, suggesting gain-of-function variants with neural over-proliferation and loss-of-function variants with neural depletion.
explanation: Expression associations motivate a hypothesis about progenitor proliferation. Neither patient neural tissue nor a BABS-variant organoid perturbation establishes this causal link.
mechanism_confidence: PROVISIONAL
- name: Abnormal Brain Development
biological_scale: TISSUE
description: Structural neuroimaging findings are variable and inconsistent across patients, and include white matter abnormalities, prominent Virchow-Robin spaces, periventricular and subependymal cysts, and corpus callosum abnormalities. Absolute or relative macrocephaly is common.
evidence:
- reference: PMID:30475435
reference_title: Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Neuroimaging variably demonstrates white matter abnormalities, prominent Virchow-Robin spaces, periventricular cysts, and abnormalities of the corpus callosum.
explanation: Enumerates the structural findings that define this node.
- reference: PMID:34477286
reference_title: 'Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Neuroimaging abnormalities continue to be an inconsistent feature of the syndrome.
explanation: This evidence is limited because it qualifies the finding as inconsistent rather than obligate, which is why no frequency band is assigned.
downstream:
- target: Abnormal cerebral white matter morphology
causal_link_type: DIRECT
description: White matter abnormalities are an observed imaging component of the variable brain phenotype.
evidence:
- reference: PMID:30475435
reference_title: Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Neuroimaging variably demonstrates white matter abnormalities, prominent Virchow-Robin spaces, periventricular cysts, and abnormalities of the corpus callosum.
explanation: The clinical series supplies the structural brain readout; it does not identify the upstream cellular cause.
- target: Abnormal corpus callosum morphology
causal_link_type: DIRECT
description: Variable callosal abnormalities are an imaging component of the reported developmental brain phenotype.
evidence:
- reference: PMID:30475435
reference_title: Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Neuroimaging variably demonstrates white matter abnormalities, prominent Virchow-Robin spaces, periventricular cysts, and abnormalities of the corpus callosum.
explanation: The series reports a spectrum of callosal anomalies without assigning all cases to hypoplasia.
- target: Dilation of Virchow-Robin spaces
causal_link_type: DIRECT
description: This observed imaging finding is a component of the variable structural brain phenotype.
evidence:
- reference: PMID:30475435
reference_title: Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Neuroimaging variably demonstrates white matter abnormalities, prominent Virchow-Robin spaces, periventricular cysts, and abnormalities of the corpus callosum.
explanation: The imaging report establishes this component of the variable structural brain phenotype without identifying its upstream cellular cause.
- target: Subependymal cysts
causal_link_type: DIRECT
description: This observed imaging finding is a component of the variable structural brain phenotype.
evidence:
- reference: PMID:34282722
reference_title: Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: A neonatal brain MRI showed abnormal cerebral white matter and subependymal cysts
explanation: The imaging report establishes this component of the variable structural brain phenotype without identifying its upstream cellular cause.
phenotypes:
- name: Alopecia
category: Dermatologic
description: The distinctive BABS alopecia is non-congenital. Hair is typically present at birth, may be sparse and of an unexpected colour, and is then lost in large clumps within the first few weeks of life. The index patient was born with a full head of silver-blond hair and became essentially hairless. Reported severity ranges up to alopecia universalis.
phenotype_term:
preferred_term: Alopecia
term:
id: HP:0001596
label: Alopecia
frequency: OBLIGATE
evidence:
- reference: PMID:36007106
reference_title: Bachmann-Bupp Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Bachmann-Bupp syndrome (BABS) is characterized by a distinctive type of alopecia, global developmental delay in the moderate to severe range, hypotonia, nonspecific dysmorphic features, behavioral abnormalities (autism spectrum disorder, attention-deficit/hyperactivity disorder) and feeding difficulties.
explanation: GeneReviews establishes the association; the quantitative review below supplies the observed cohort frequency.
- reference: PMID:36007106
reference_title: Bachmann-Bupp Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Hair is typically present at birth but may be sparse and of an unexpected color with subsequent loss of hair in large clumps within the first few weeks of life.
explanation: Gives the natural history that distinguishes this alopecia from congenital atrichia.
- reference: PMID:37469105
reference_title: Bachmann-Bupp syndrome and treatment.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Bachmann-Bupp syndrome (BABS) is a neurodevelopmental disorder characterized by developmental delay, hypotonia, and varying forms of non-congenital alopecia.
explanation: Independent review confirming the non-congenital character and variable form of the alopecia.
- reference: PMID:34282722
reference_title: Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The patient was born with a full head of silver-blond hair similar to a previously described murine phenotype ... which fell out in early months and she remained hairless other than a few scattered, long hairs on the scalp.
explanation: Patient-level description of the birth hair, its unusual colour and the subsequent loss.
- reference: PMID:41410504
reference_title: 'Genetic and Phenotypic Features of the Five Known Polyaminopathies: A Critical Narrative Review.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: All 12 patients with BABS described in the literature presented with varying forms of non-congenital alopecia.
explanation: Observed in all 12 reported cases, mapping to OBLIGATE for this literature cohort. This is not proof of complete population penetrance or lifelong absence of every type of hair.
- name: Absent eyebrow
category: Dermatologic
description: Absent eyebrows are documented in several individuals. Others have sparse eyebrows, a distinct finding. Eyebrow regrowth has been observed after eflornithine.
phenotype_term:
preferred_term: Absent eyebrow
term:
id: HP:0002223
label: Absent eyebrow
evidence:
- reference: PMID:34282722
reference_title: Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: One month into treatment, hair growth was noted, with eyebrows appearing first
explanation: Eyebrow regrowth on treatment implies the pre-treatment absence of eyebrows in this genotyped patient.
- reference: PMID:36443247
reference_title: Improvement of dermatological symptoms in patients with Bachmann-Bupp syndrome using difluoromethylornithine treatment.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: In both patients, treatment with difluoromethylornithine has resulted in improved dermatologic signs, including regrowth of eyebrow and scalp hair and cessation of recurrent follicular cyst development.
explanation: Two treated individuals had eyebrow/scalp hair regrowth and cessation of recurrent follicular cysts. They should not be assumed to be additional independent cases beyond other publications.
- name: Abnormal nail growth
category: Dermatologic
description: Accelerated nail growth has been reported in BABS patients, mirroring the enhanced nail growth of the truncated-ODC transgenic mouse. HPO has no accelerated-nail-growth term, so the general abnormal-nail-growth term is used.
phenotype_term:
preferred_term: Accelerated nail growth
term:
id: HP:0030807
label: Abnormal nail growth
evidence:
- reference: PMID:41925768
reference_title: 'The remarkable legacy of the K6/ODC mouse: mechanisms of polyamine-promoted tumorigenesis revealed.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Similar to the phenotypic abnormalities observed in K6/ODC transgenic mice, human patients with this ODC mutation also displayed alopecia, accelerated nail growth and skin cysts
explanation: A review states that BABS patients, like the transgenic mice, show accelerated nail growth.
quote_role: REVIEW_SYNTHESIS
- reference: PMID:7671221
reference_title: Increased frequency of spontaneous skin tumors in transgenic mice which overexpress ornithine decarboxylase.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Effects observed include development of dermal follicular cysts, excessive skin wrinkling, enhanced nail growth, alopecia, and spontaneous tumor development.
explanation: The corresponding mouse observation, recorded separately so the human and model evidence are not conflated.
- name: Global developmental delay
category: Neurologic
description: Global developmental delay in the moderate to severe range is a defining feature. Before treatment the index patient could not stand, cruise or sit and had limited fine motor skills.
phenotype_term:
preferred_term: Global developmental delay
term:
id: HP:0001263
label: Global developmental delay
frequency: OBLIGATE
evidence:
- reference: PMID:36007106
reference_title: Bachmann-Bupp Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Bachmann-Bupp syndrome (BABS) is characterized by a distinctive type of alopecia, global developmental delay in the moderate to severe range, hypotonia, nonspecific dysmorphic features, behavioral abnormalities (autism spectrum disorder, attention-deficit/hyperactivity disorder) and feeding difficulties.
explanation: GeneReviews supports the association and severity range; the 2021 liveborn series supplies the frequency statement.
- reference: PMID:34282722
reference_title: Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Prior to therapy, she had delayed development which manifested with no standing, cruising, or sitting, and limited fine motor skills.
explanation: Patient-level description of the functional severity of the delay before treatment.
- reference: PMID:30475435
reference_title: Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: This disorder presents with global developmental delay, ectodermal abnormalities including alopecia, absolute or relative macrocephaly, and characteristic facial dysmorphisms.
explanation: Independent four-patient cohort with global developmental delay as the leading feature.
- reference: PMID:34477286
reference_title: 'Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Global developmental delay is uniform with this syndrome, typically in the more severe range with associated behavior concerns.
explanation: The 2021 series describes delay in all eight liveborn individuals (Table 1 excludes the stillborn fetus). OBLIGATE reflects that observed cohort, not independently measured penetrance.
- name: Hypotonia
category: Neurologic
description: Hypotonia is a core feature. Treatment-associated improvement has been reported in uncontrolled observations; progressive hypotonia and proximal myopathy were described in one older child.
phenotype_term:
preferred_term: Hypotonia
term:
id: HP:0001252
label: Hypotonia
frequency: VERY_FREQUENT
evidence:
- reference: PMID:36007106
reference_title: Bachmann-Bupp Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Bachmann-Bupp syndrome (BABS) is characterized by a distinctive type of alopecia, global developmental delay in the moderate to severe range, hypotonia, nonspecific dysmorphic features, behavioral abnormalities (autism spectrum disorder, attention-deficit/hyperactivity disorder) and feeding difficulties.
explanation: GeneReviews lists hypotonia among the defining characteristics, mapping to VERY_FREQUENT.
- reference: PMID:40167220
reference_title: 'Repurposing With Purpose: Treatment of Bachmann-Bupp Syndrome With Eflornithine and Implications for Other Polyaminopathies.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: First described in 2018, Bachmann-Bupp Syndrome (BABS) is a rare neurodevelopmental disorder that is caused by gain-of-function variants in the ornithine decarboxylase (ODC1) gene and is characterized by developmental delay, hypotonia, and alopecia.
explanation: Independent confirmation of hypotonia as one of the three core clinical features.
- reference: PMID:41410504
reference_title: 'Genetic and Phenotypic Features of the Five Known Polyaminopathies: A Critical Narrative Review.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| Hypotonia | 21/33 (64.3%) | 11/12 (91.7%) | 4/5 (80%) | 3/7 (42.9%) | 5/5 (100%) | 44/62 (71%) |'
explanation: 'The second disease column of Table 1 is BABS: 11/12 (91.7%) maps to VERY_FREQUENT. These are overlapping published cases, not an independent cohort.'
- name: Macrocephaly
category: Growth
description: Absolute or relative macrocephaly is commonly reported, although not universal.
phenotype_term:
preferred_term: Macrocephaly
term:
id: HP:0000256
label: Macrocephaly
evidence:
- reference: PMID:30475435
reference_title: Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: This disorder presents with global developmental delay, ectodermal abnormalities including alopecia, absolute or relative macrocephaly, and characteristic facial dysmorphisms.
explanation: Establishes that macrocephaly may be absolute or only relative to body size.
- reference: PMID:34477286
reference_title: 'Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: BABS is characterized by developmental delay, macrocephaly, macrosomia, and an unusual pattern of non-congenital alopecia.
explanation: Independent cohort listing macrocephaly among the defining features.
- reference: PMID:41410504
reference_title: 'Genetic and Phenotypic Features of the Five Known Polyaminopathies: A Critical Narrative Review.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The majority of patients (9/12, 75%) also presented with macrocephaly, which would be considered a distinctive feature of BABS, as this was not reported in any patients with DHPS deficiency, FABAS, or DOHH disorder, and was only reported in 3/33 (9%) of patients with SRS.
explanation: The review reports 9/12 (75%), mapping to FREQUENT in that small published cohort.
quote_role: REVIEW_SYNTHESIS
frequency: FREQUENT
- name: Macrosomia
category: Growth
description: Overgrowth is variable. The expanded cohort distinguished commonly reported macrocephaly from less consistently present macrosomia; prenatal and postnatal size must be interpreted separately.
phenotype_term:
preferred_term: Overgrowth
term:
id: HP:0001548
label: Overgrowth
evidence:
- reference: PMID:34477286
reference_title: 'Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: BABS is characterized by developmental delay, macrocephaly, macrosomia, and an unusual pattern of non-congenital alopecia.
explanation: Names macrosomia among the four defining features of the syndrome.
- reference: PMID:30239107
reference_title: Novel de novo pathogenic variant in the ODC1 gene in a girl with developmental delay, alopecia, and dysmorphic features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Phenotypic manifestations include macrosomia, macrocephaly, developmental delay, alopecia, spasticity, hypotonia, cutaneous vascular malformation, delayed visual maturation, and sensorineural hearing loss.
explanation: The index case report lists macrosomia first among the phenotypic manifestations.
- reference: PMID:34477286
reference_title: 'Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Macrocephaly continues to be a consistent finding in most cases; however, macrosomia now does not.
explanation: The expanded cohort explicitly qualifies macrosomia as an inconsistent feature.
- name: Dysmorphic facial features
category: Craniofacial
description: Facial dysmorphism is consistently reported but nonspecific; GeneReviews describes the features as nonspecific while the four-patient cohort called them characteristic.
phenotype_term:
preferred_term: Abnormal facial shape
term:
id: HP:0001999
label: Abnormal facial shape
evidence:
- reference: PMID:36007106
reference_title: Bachmann-Bupp Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Bachmann-Bupp syndrome (BABS) is characterized by a distinctive type of alopecia, global developmental delay in the moderate to severe range, hypotonia, nonspecific dysmorphic features, behavioral abnormalities (autism spectrum disorder, attention-deficit/hyperactivity disorder) and feeding difficulties.
explanation: GeneReviews lists nonspecific dysmorphic features among the defining characteristics.
- reference: PMID:30475435
reference_title: Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: This disorder presents with global developmental delay, ectodermal abnormalities including alopecia, absolute or relative macrocephaly, and characteristic facial dysmorphisms.
explanation: This evidence is limited because this cohort calls the dysmorphisms characteristic whereas GeneReviews calls them nonspecific; the two sources disagree on specificity.
- name: Autistic behavior
category: Behavioral
description: Autism spectrum disorder is one of the behavioural abnormalities named in the GeneReviews clinical characteristics and is a standing surveillance item.
phenotype_term:
preferred_term: Autistic behavior
term:
id: HP:0000729
label: Autistic behavior
evidence:
- reference: PMID:36007106
reference_title: Bachmann-Bupp Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Bachmann-Bupp syndrome (BABS) is characterized by a distinctive type of alopecia, global developmental delay in the moderate to severe range, hypotonia, nonspecific dysmorphic features, behavioral abnormalities (autism spectrum disorder, attention-deficit/hyperactivity disorder) and feeding difficulties.
explanation: GeneReviews names autism spectrum disorder explicitly among the behavioural abnormalities.
- reference: PMID:36007106
reference_title: Bachmann-Bupp Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Behavioral assessment for signs of autism spectrum disorder, attention, and aggressive or self-injurious behaviors annually.
explanation: Annual behavioral screening is recommended; the recommendation alone does not supply a frequency estimate.
- name: Attention deficit hyperactivity disorder
category: Behavioral
description: Attention-deficit/hyperactivity disorder is the second behavioural abnormality named in the GeneReviews clinical characteristics.
phenotype_term:
preferred_term: Attention deficit hyperactivity disorder
term:
id: HP:0007018
label: Attention deficit hyperactivity disorder
evidence:
- reference: PMID:36007106
reference_title: Bachmann-Bupp Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Bachmann-Bupp syndrome (BABS) is characterized by a distinctive type of alopecia, global developmental delay in the moderate to severe range, hypotonia, nonspecific dysmorphic features, behavioral abnormalities (autism spectrum disorder, attention-deficit/hyperactivity disorder) and feeding difficulties.
explanation: GeneReviews names attention-deficit/hyperactivity disorder explicitly.
- name: Feeding difficulties
category: Gastrointestinal
description: Feeding difficulties are a defining feature and warrant a low threshold for formal feeding evaluation or gastrostomy tube placement. The first treated patient received eflornithine via a gastrostomy tube.
phenotype_term:
preferred_term: Feeding difficulties
term:
id: HP:0011968
label: Feeding difficulties
evidence:
- reference: PMID:36007106
reference_title: Bachmann-Bupp Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Bachmann-Bupp syndrome (BABS) is characterized by a distinctive type of alopecia, global developmental delay in the moderate to severe range, hypotonia, nonspecific dysmorphic features, behavioral abnormalities (autism spectrum disorder, attention-deficit/hyperactivity disorder) and feeding difficulties.
explanation: GeneReviews lists feeding difficulties among the defining characteristics.
- reference: PMID:36007106
reference_title: Bachmann-Bupp Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Feeding therapy with a low threshold for a clinical feeding evaluation and/or gastrostomy tube placement; nutritional intervention for those with obesity; stool softeners, prokinetics, osmotic agents or laxatives for constipation; standard treatment for epilepsy, developmental delay / intellectual disability, refractive error, strabismus, hearing loss, follicular cysts, and congenital heart defects.
explanation: The management recommendation reflects the clinical weight of the feeding problem.
- name: Seizure
category: Neurologic
description: One individual in the initial eight liveborn cases developed seizures at age 14 and was described at age 23. Multiple seizure types became difficult to control. Younger individuals may not yet have reached the age of onset observed in that case. In that individual, vagus nerve stimulation worsened seizures and a ketogenic diet did not improve them.
phenotype_term:
preferred_term: Seizure
term:
id: HP:0001250
label: Seizure
frequency: OCCASIONAL
evidence:
- reference: PMID:36007106
reference_title: Bachmann-Bupp Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Rare findings may include seizures with onset in later childhood and conductive hearing loss.
explanation: GeneReviews describes seizures qualitatively as rare. The quantitative series supersedes that wording for frequency assignment.
- reference: PMID:34477286
reference_title: 'Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Recent diagnosis of four more BABS patients provides further characterization of the phenotype of this syndrome including late-onset seizures in the oldest reported patient at 23 years of age, representing the first report for this phenotype in BABS.
explanation: Documents the single index observation of late-onset seizures in the published series.
- reference: PMID:34477286
reference_title: 'Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Novel findings in these newly reported patients include the first report of seizures, with onset at age 14 years. These seizures have been resistant to treatment.
explanation: The full text distinguishes age at onset (14 years) from age at reporting (23 years).
- reference: PMID:41410504
reference_title: 'Genetic and Phenotypic Features of the Five Known Polyaminopathies: A Critical Narrative Review.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Epilepsy has also been reported in lesser frequencies in patients with SRS (21/33, 63.6%), BABS (1/12, 8.3%), and DOHH disorder (3/5, 60%).
explanation: The 2026 review reports 1/12 (8.3%), within OCCASIONAL; the earlier liveborn cohort had 1/8. Both denominators are small and age-dependent.
quote_role: REVIEW_SYNTHESIS
- reference: PMID:34477286
reference_title: 'Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: No controlling medication has since been identified, with vagal nerve stimulator implanted at age 20, which exacerbated the seizures and recent ketogenic diet that showed no improvement.
explanation: These are negative outcomes in one individual, not proof that these interventions are ineffective or contraindicated in every patient.
- name: Conductive hearing impairment
category: Otologic
description: Conductive hearing loss is listed by GeneReviews as a rare finding.
phenotype_term:
preferred_term: Conductive hearing impairment
term:
id: HP:0000405
label: Conductive hearing impairment
frequency: VERY_RARE
evidence:
- reference: PMID:36007106
reference_title: Bachmann-Bupp Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Rare findings may include seizures with onset in later childhood and conductive hearing loss.
explanation: GeneReviews explicitly classifies conductive hearing loss as a rare finding, mapping to VERY_RARE.
- name: Sensorineural hearing impairment
category: Otologic
description: Sensorineural hearing loss was reported in the index patient. GeneReviews names only conductive hearing loss among the rare findings, so the two mechanisms are curated separately.
phenotype_term:
preferred_term: Sensorineural hearing impairment
term:
id: HP:0000407
label: Sensorineural hearing impairment
evidence:
- reference: PMID:30239107
reference_title: Novel de novo pathogenic variant in the ODC1 gene in a girl with developmental delay, alopecia, and dysmorphic features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Phenotypic manifestations include macrosomia, macrocephaly, developmental delay, alopecia, spasticity, hypotonia, cutaneous vascular malformation, delayed visual maturation, and sensorineural hearing loss.
explanation: The index case report documents sensorineural, not conductive, hearing loss.
- reference: PMID:41925768
reference_title: 'The remarkable legacy of the K6/ODC mouse: mechanisms of polyamine-promoted tumorigenesis revealed.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: the ODC mutation is expressed in all tissues of BABS patients resulting in macrosomia, macrocephaly, neurodevelopmental delay, spasticity, hypotonia, delayed visual maturation, and sensorineural hearing loss
explanation: A review restates sensorineural hearing loss among the multisystem consequences of ubiquitous expression of the mutant enzyme.
quote_role: REVIEW_SYNTHESIS
- name: Spasticity
category: Neurologic
description: Spasticity was documented in the index patient and is restated in the review literature as part of the multisystem phenotype.
phenotype_term:
preferred_term: Spasticity
term:
id: HP:0001257
label: Spasticity
evidence:
- reference: PMID:30239107
reference_title: Novel de novo pathogenic variant in the ODC1 gene in a girl with developmental delay, alopecia, and dysmorphic features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Phenotypic manifestations include macrosomia, macrocephaly, developmental delay, alopecia, spasticity, hypotonia, cutaneous vascular malformation, delayed visual maturation, and sensorineural hearing loss.
explanation: The index case report documents spasticity alongside hypotonia.
- name: Vascular skin abnormality
category: Dermatologic
description: A cutaneous vascular malformation was reported in the index patient. The available description does not establish a capillary subtype.
phenotype_term:
preferred_term: Cutaneous vascular malformation
term:
id: HP:0011276
label: Vascular skin abnormality
evidence:
- reference: PMID:30239107
reference_title: Novel de novo pathogenic variant in the ODC1 gene in a girl with developmental delay, alopecia, and dysmorphic features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Phenotypic manifestations include macrosomia, macrocephaly, developmental delay, alopecia, spasticity, hypotonia, cutaneous vascular malformation, delayed visual maturation, and sensorineural hearing loss.
explanation: The source reports a cutaneous vascular malformation without identifying the vessel type; the binding preserves that scope.
- name: Obesity
category: Growth
description: Obesity is recognized in GeneReviews as a possible management issue. The index treatment report’s BMI increase to the 90th percentile, attributed to increased muscle bulk, is not itself evidence of obesity.
phenotype_term:
preferred_term: Obesity
term:
id: HP:0001513
label: Obesity
evidence:
- reference: PMID:36007106
reference_title: Bachmann-Bupp Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Feeding therapy with a low threshold for a clinical feeding evaluation and/or gastrostomy tube placement; nutritional intervention for those with obesity; stool softeners, prokinetics, osmotic agents or laxatives for constipation; standard treatment for epilepsy, developmental delay / intellectual disability, refractive error, strabismus, hearing loss, follicular cysts, and congenital heart defects.
explanation: GeneReviews management explicitly provides for nutritional intervention in those with obesity.
- name: Constipation
category: Gastrointestinal
description: Constipation is a recurrent management problem requiring stool softeners, prokinetics, osmotic agents or laxatives, and is a standing surveillance item at each visit.
phenotype_term:
preferred_term: Constipation
term:
id: HP:0002019
label: Constipation
evidence:
- reference: PMID:36007106
reference_title: Bachmann-Bupp Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Feeding therapy with a low threshold for a clinical feeding evaluation and/or gastrostomy tube placement; nutritional intervention for those with obesity; stool softeners, prokinetics, osmotic agents or laxatives for constipation; standard treatment for epilepsy, developmental delay / intellectual disability, refractive error, strabismus, hearing loss, follicular cysts, and congenital heart defects.
explanation: GeneReviews management lists a full constipation treatment ladder, indicating this is an expected manifestation.
- reference: PMID:34477286
reference_title: 'Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Constipation, a common ailment and even more common in general with patients with developmental delay, is present in three of seven patients (Table 1).
explanation: The narrative reports 3/7 (43%), mapping to FREQUENT. Other summaries use different assessed denominators; this is a small-series estimate.
frequency: FREQUENT
- name: Strabismus
category: Ophthalmologic
description: Strabismus is among the manifestations GeneReviews directs to standard treatment, with annual ophthalmology evaluation recommended.
phenotype_term:
preferred_term: Strabismus
term:
id: HP:0000486
label: Strabismus
evidence:
- reference: PMID:36007106
reference_title: Bachmann-Bupp Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Feeding therapy with a low threshold for a clinical feeding evaluation and/or gastrostomy tube placement; nutritional intervention for those with obesity; stool softeners, prokinetics, osmotic agents or laxatives for constipation; standard treatment for epilepsy, developmental delay / intellectual disability, refractive error, strabismus, hearing loss, follicular cysts, and congenital heart defects.
explanation: Strabismus is named among the manifestations requiring standard treatment.
- name: Abnormality of refraction
category: Ophthalmologic
description: Refractive error is among the manifestations GeneReviews directs to standard treatment, with annual ophthalmology evaluation recommended.
phenotype_term:
preferred_term: Abnormality of refraction
term:
id: HP:0000539
label: Abnormality of refraction
evidence:
- reference: PMID:36007106
reference_title: Bachmann-Bupp Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Feeding therapy with a low threshold for a clinical feeding evaluation and/or gastrostomy tube placement; nutritional intervention for those with obesity; stool softeners, prokinetics, osmotic agents or laxatives for constipation; standard treatment for epilepsy, developmental delay / intellectual disability, refractive error, strabismus, hearing loss, follicular cysts, and congenital heart defects.
explanation: Refractive error is named among the manifestations requiring standard treatment.
- name: Abnormal heart morphology
category: Cardiovascular
description: Congenital cardiac abnormalities are variable. Published patients include ventricular septal defect and mild pulmonary valve stenosis; these findings are not universal.
phenotype_term:
preferred_term: Abnormal heart morphology
term:
id: HP:0001627
label: Abnormal heart morphology
evidence:
- reference: PMID:36007106
reference_title: Bachmann-Bupp Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Feeding therapy with a low threshold for a clinical feeding evaluation and/or gastrostomy tube placement; nutritional intervention for those with obesity; stool softeners, prokinetics, osmotic agents or laxatives for constipation; standard treatment for epilepsy, developmental delay / intellectual disability, refractive error, strabismus, hearing loss, follicular cysts, and congenital heart defects.
explanation: Congenital heart defects are named among the manifestations requiring standard treatment.
- name: Cutaneous cyst
category: Dermatologic
description: Recurrent follicular cysts occur on the scalp, neck, back, and other sites. Some enlarge and require drainage or removal. A cutaneous-cyst binding does not infer epidermoid histology from the clinical term follicular cyst.
phenotype_term:
preferred_term: Follicular cyst
term:
id: HP:0025245
label: Cutaneous cyst
evidence:
- reference: PMID:36007106
reference_title: Bachmann-Bupp Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Complete skin evaluation for follicular cysts at least annually.
explanation: GeneReviews makes annual follicular cyst surveillance a standing recommendation.
- reference: PMID:34282722
reference_title: Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: She had a history of recurring follicular cyst formation and enlargement.
explanation: Patient-level documentation of recurrent follicular cyst formation.
- reference: PMID:36443247
reference_title: Improvement of dermatological symptoms in patients with Bachmann-Bupp syndrome using difluoromethylornithine treatment.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: In both patients, treatment with difluoromethylornithine has resulted in improved dermatologic signs, including regrowth of eyebrow and scalp hair and cessation of recurrent follicular cyst development.
explanation: Two treated individuals had eyebrow/scalp hair regrowth and cessation of recurrent follicular cysts. They should not be assumed to be additional independent cases beyond other publications.
- name: Abnormal cerebral white matter morphology
category: Neurologic
description: 'White matter abnormalities vary across patients. The index report compared neonatal MRI with a scan after nine months of eflornithine: signal normalized, but white matter volume loss remained. These observations do not establish reversal of structural brain injury.'
phenotype_term:
preferred_term: Abnormal cerebral white matter morphology
term:
id: HP:0002500
label: Abnormal cerebral white matter morphology
evidence:
- reference: PMID:30475435
reference_title: Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Neuroimaging variably demonstrates white matter abnormalities, prominent Virchow-Robin spaces, periventricular cysts, and abnormalities of the corpus callosum.
explanation: Lists white matter abnormalities first among the neuroimaging findings.
- reference: PMID:34282722
reference_title: Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: A neonatal brain MRI showed abnormal cerebral white matter and subependymal cysts
explanation: Patient-level neonatal MRI documentation of the white matter abnormality.
- name: Dilation of Virchow-Robin spaces
category: Neurologic
description: Prominent perivascular (Virchow-Robin) spaces are one of the variable neuroimaging findings of the syndrome.
phenotype_term:
preferred_term: Dilation of Virchow-Robin spaces
term:
id: HP:0012520
label: Dilation of Virchow-Robin spaces
evidence:
- reference: PMID:30475435
reference_title: Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Neuroimaging variably demonstrates white matter abnormalities, prominent Virchow-Robin spaces, periventricular cysts, and abnormalities of the corpus callosum.
explanation: Names prominent Virchow-Robin spaces among the neuroimaging findings.
- name: Subependymal cysts
category: Neurologic
description: Subependymal and other periventricular cysts are reported on imaging. Cysts present on the index patient’s neonatal MRI were absent on a later scan after treatment; the long interval and lack of a comparator limit attribution to eflornithine.
phenotype_term:
preferred_term: Subependymal cysts
term:
id: HP:0002416
label: Subependymal cysts
evidence:
- reference: PMID:34282722
reference_title: Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: A neonatal brain MRI showed abnormal cerebral white matter and subependymal cysts
explanation: Documents subependymal cysts on the neonatal MRI of a genotyped patient.
- reference: PMID:30475435
reference_title: Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Neuroimaging variably demonstrates white matter abnormalities, prominent Virchow-Robin spaces, periventricular cysts, and abnormalities of the corpus callosum.
explanation: This evidence is limited because this cohort describes the cysts as periventricular rather than specifically subependymal.
- name: Abnormal corpus callosum morphology
category: Neurologic
description: Corpus callosum abnormalities are among the variable neuroimaging findings.
phenotype_term:
preferred_term: Abnormal corpus callosum morphology
term:
id: HP:0001273
label: Abnormal corpus callosum morphology
evidence:
- reference: PMID:30475435
reference_title: Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Neuroimaging variably demonstrates white matter abnormalities, prominent Virchow-Robin spaces, periventricular cysts, and abnormalities of the corpus callosum.
explanation: Names corpus callosum abnormalities among the neuroimaging findings.
- name: Polyhydramnios
category: Prenatal
description: Polyhydramnios is a recurrent prenatal finding; the 2023 expanded series reported it in seven of ten pregnancies with information available.
phenotype_term:
preferred_term: Polyhydramnios
term:
id: HP:0001561
label: Polyhydramnios
evidence:
- reference: PMID:37092498
reference_title: Two New Cases of Bachmann-Bupp Syndrome Identified through the International Center for Polyamine Disorders.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Additionally, though non-specifically, 7/10 patients so far have had polyhydramnios prenatally.
explanation: 7/10 is 70%, mapping to FREQUENT in the reported series. The denominator includes pregnancies with available prenatal data, not population prevalence.
frequency: FREQUENT
- name: Keratosis pilaris
category: Dermatologic
description: Keratosis pilaris has affected the limbs and face. It is distinct from recurrent follicular cysts; a combined skin-abnormality count cannot be assigned to either finding alone.
phenotype_term:
preferred_term: Keratosis pilaris
term:
id: HP:0032152
label: Keratosis pilaris
evidence:
- reference: PMID:34477286
reference_title: 'Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Past medical history also includes hypotonia, ataxia, significant constipation, keratosis pilaris on the upper and lower limbs and cheeks, significantly reduced sweating, and reduced sensitivity to pain.
explanation: The case narrative documents keratosis pilaris and its distribution. Table 1 also reports it in a previously published individual.
- name: Sparse eyebrow
category: Dermatologic
description: Sparse eyebrows occur in addition to completely absent eyebrows in other individuals.
phenotype_term:
preferred_term: Sparse eyebrow
term:
id: HP:0045075
label: Sparse eyebrow
evidence:
- reference: PMID:34477286
reference_title: 'Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Sparse hair is now present throughout the scalp with very little eyebrow hair and eyelashes.
explanation: The clinical narrative explicitly documents reduced rather than absent eyebrow hair.
- name: Sparse or absent eyelashes
category: Dermatologic
description: Eyelashes may be sparse or congenitally absent, while scalp hair loss is often postnatal.
phenotype_term:
preferred_term: Sparse or absent eyelashes
term:
id: HP:0200102
label: Sparse or absent eyelashes
evidence:
- reference: PMID:37092498
reference_title: Two New Cases of Bachmann-Bupp Syndrome Identified through the International Center for Polyamine Disorders.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Some individuals have regrowth of scalp hair that typically remains sparse, with congenital absence of the eyebrows and eyelashes.
explanation: The expanded clinical series describes congenital eyelash absence. Its individual cases and earlier tables also include sparse eyelashes.
- name: Broad forehead
category: Craniofacial
description: A broad forehead is recurrent, although there is no uniform facial gestalt.
phenotype_term:
preferred_term: Broad forehead
term:
id: HP:0000337
label: Broad forehead
evidence:
- reference: PMID:34477286
reference_title: 'Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Dysmorphic features include a long face, broad forehead, sagittal craniosynostosis, cryptorchidism, and choanal atresia.
explanation: This patient narrative directly documents the broad forehead; the comparative table reports it in several additional individuals.
- name: Hypertelorism
category: Craniofacial
description: Hypertelorism was reported in six of eleven individuals in the 2023 expanded series.
phenotype_term:
preferred_term: Hypertelorism
term:
id: HP:0000316
label: Hypertelorism
evidence:
- reference: PMID:37092498
reference_title: Two New Cases of Bachmann-Bupp Syndrome Identified through the International Center for Polyamine Disorders.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 8/11 forehead differences 6/11 hypertelorism
explanation: Table 1 reports hypertelorism in 6/11 (55%), mapping to FREQUENT; the broader forehead-difference count is not substituted for this specific feature.
frequency: FREQUENT
- name: Long face
category: Craniofacial
description: An elongated face has been documented in multiple individuals.
phenotype_term:
preferred_term: Long face
term:
id: HP:0000276
label: Long face
evidence:
- reference: PMID:34477286
reference_title: 'Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Dysmorphic features include a long face, broad forehead, sagittal craniosynostosis, cryptorchidism, and choanal atresia.
explanation: The patient narrative records a long face; Table 1 separately records an elongated face in another individual.
- name: Ptosis
category: Ophthalmologic
description: Ptosis has been reported in the founding clinical series.
phenotype_term:
preferred_term: Ptosis
term:
id: HP:0000508
label: Ptosis
evidence:
- reference: PMID:34477286
reference_title: 'Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: High forehead, hypertelorism, mild ptosis, down‐slanting palpebral fissures, cryptorchidism
explanation: The comparative clinical table records mild ptosis in one founding case and ptosis in another.
- name: Deeply set eye
category: Craniofacial
description: Deeply set eyes have been reported in two individuals summarized in the comparative table.
phenotype_term:
preferred_term: Deeply set eye
term:
id: HP:0000490
label: Deeply set eye
evidence:
- reference: PMID:34477286
reference_title: 'Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: High and broad forehead, hypertelorism, deep‐set eyes, blepharophimosis, tapering of the arms and legs
explanation: Table 1 documents deeply set eyes in this founding case and one other; no population frequency is inferred.
- name: High palate
category: Craniofacial
description: A high palate has been documented in the index patient and an older affected individual.
phenotype_term:
preferred_term: High palate
term:
id: HP:0000218
label: High palate
evidence:
- reference: PMID:34477286
reference_title: 'Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Dysmorphic facial features noted include bilateral epicanthal folds, high palate, slight facial asymmetry with drooping of the left mouth corner, frontal bossing, dolichocephaly, and kyphosis (Figure 1).
explanation: The older patient narrative supports this finding; the comparative table also reports a high arched palate in the index case.
- name: Cryptorchidism
category: Genitourinary
description: Cryptorchidism was reported in three of six males in the 2021 series.
phenotype_term:
preferred_term: Cryptorchidism
term:
id: HP:0000028
label: Cryptorchidism
evidence:
- reference: PMID:34477286
reference_title: 'Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Cryptorchidism is present in three of six males.
explanation: 3/6 is 50%, mapping to FREQUENT among males in that series; female individuals are excluded from the denominator.
frequency: FREQUENT
- name: Hypohidrosis
category: Dermatologic
description: Reduced sweating has been described; another individual had anhidrosis with episodes of hyperthermia.
phenotype_term:
preferred_term: Hypohidrosis
term:
id: HP:0000966
label: Hypohidrosis
evidence:
- reference: PMID:34477286
reference_title: 'Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Past medical history also includes hypotonia, ataxia, significant constipation, keratosis pilaris on the upper and lower limbs and cheeks, significantly reduced sweating, and reduced sensitivity to pain.
explanation: Reduced sweating is explicitly described in this individual.
- reference: PMID:37092498
reference_title: Two New Cases of Bachmann-Bupp Syndrome Identified through the International Center for Polyamine Disorders.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Her past medical history also includes hyperlaxity and anhidrosis with hyperthermia episodes.
explanation: A second individual had absent sweating and hyperthermia, expanding the severity of the sweating phenotype.
- name: Joint hypermobility
category: Musculoskeletal
description: Joint hypermobility or hyperlaxity was documented in both individuals in the 2023 report.
phenotype_term:
preferred_term: Joint hypermobility
term:
id: HP:0001382
label: Joint hypermobility
evidence:
- reference: PMID:37092498
reference_title: Two New Cases of Bachmann-Bupp Syndrome Identified through the International Center for Polyamine Disorders.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Her past medical history also includes hypotonia, feeding difficulties, food aspiration, marked joint hypermobility, and hepatic calcifications.
explanation: The younger patient had marked hypermobility; the older patient is separately described as having hyperlaxity.
- name: Myopathy
category: Neuromuscular
description: One 12-year-old individual developed proximal myopathy identified by EMG, progressive walking difficulty, and a need for a wheelchair over longer distances. This is not established as the course of all BABS cases.
phenotype_term:
preferred_term: Myopathy
term:
id: HP:0003198
label: Myopathy
evidence:
- reference: PMID:37092498
reference_title: Two New Cases of Bachmann-Bupp Syndrome Identified through the International Center for Polyamine Disorders.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: She has had an increase in hypotonia over time and has developed proximal myopathy identified by electromyogram EMG, bilateral medius lameness, and bilateral heel defects leading to walking degradation and the need of a wheelchair for long distances along with difficulty climbing stairs.
explanation: The case documents progressive proximal myopathy and walking impairment; no general frequency or inevitable progression is inferred.
- name: Intellectual disability
category: Neurologic
description: Intellectual disability varies in severity. Some individuals remain minimally verbal, while a reported 12-year-old could read and write.
phenotype_term:
preferred_term: Intellectual disability
term:
id: HP:0001249
label: Intellectual disability
evidence:
- reference: PMID:37092498
reference_title: Two New Cases of Bachmann-Bupp Syndrome Identified through the International Center for Polyamine Disorders.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: At 12 years of age, she has moderate developmental delay and intellectual disability, with the ability to read and write.
explanation: Direct clinical documentation supports intellectual disability without treating all developmental delay as a formal cognitive diagnosis.
- name: Delayed speech and language development
category: Neurologic
description: Expressive language development is delayed and some individuals remain nonverbal; reported first-word ages vary.
phenotype_term:
preferred_term: Delayed speech and language development
term:
id: HP:0000750
label: Delayed speech and language development
evidence:
- reference: PMID:34477286
reference_title: 'Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Speech appears limited with first words at 2–3 years and some patients remain nonverbal.
explanation: The series summarizes speech delay and variable acquisition rather than implying that all patients eventually develop speech.
- name: Fragile nails
category: Dermatologic
description: Brittle nails have been described in individuals with recurrent follicular cysts.
phenotype_term:
preferred_term: Fragile nails
term:
id: HP:0001808
label: Fragile nails
evidence:
- reference: PMID:37469105
reference_title: Bachmann-Bupp syndrome and treatment.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Before DFMO treatment, two patients with BABS had a history of recurring follicular cysts, also observed in the transgenic mouse model,87, 89 and brittle fingernails.
explanation: The clinical review documents brittle fingernails in two patients. This finding is distinct from accelerated nail growth.
- name: Hypoplastic toenails
category: Dermatologic
description: Hypoplastic toenails were documented in a founding patient.
phenotype_term:
preferred_term: Hypoplastic toenails
term:
id: HP:0001800
label: Hypoplastic toenails
evidence:
- reference: PMID:34477286
reference_title: 'Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: ESES on EEG, myringotomy, celiac disease, hypoplastic toenails
explanation: Table 1 explicitly specifies toenail hypoplasia in this individual; another patient’s unspecified hypoplastic nails are not assumed to be toenails.
- name: Ventriculomegaly
category: Neurologic
description: Enlargement of the cerebral ventricles can be identified prenatally or postnatally and occurs with variable additional brain abnormalities.
phenotype_term:
preferred_term: Ventriculomegaly
term:
id: HP:0002119
label: Ventriculomegaly
evidence:
- reference: PMID:37092498
reference_title: Two New Cases of Bachmann-Bupp Syndrome Identified through the International Center for Polyamine Disorders.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Concerning prenatal findings included cerebral ventricular enlargement, cerebral cysts, polyhydramnios, and a ventricular septal defect.
explanation: The prenatal findings explicitly include cerebral ventricular enlargement.
- name: Hypoplasia of the corpus callosum
category: Neurologic
description: Hypoplasia of the middle corpus callosum was documented in one individual. Other patients have different callosal abnormalities, so the entire callosal spectrum is not assigned this specific term.
phenotype_term:
preferred_term: Hypoplasia of the corpus callosum
term:
id: HP:0002079
label: Hypoplasia of the corpus callosum
evidence:
- reference: PMID:37092498
reference_title: Two New Cases of Bachmann-Bupp Syndrome Identified through the International Center for Polyamine Disorders.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: A brain MRI identified myelination impairment with dilated Virchow–Robin spaces, bilateral paraventricular cysts, enlargement of subarachnoid spaces associated with ventricular dilatation, and hypoplasia of the middle part of the corpus callosum.
explanation: The imaging description supports the specific callosal hypoplasia finding in this patient.
- name: Ventricular septal defect
category: Cardiovascular
description: Ventricular septal defects have been reported, including a spontaneously closed defect and a prenatal finding in another individual.
phenotype_term:
preferred_term: Ventricular septal defect
term:
id: HP:0001629
label: Ventricular septal defect
evidence:
- reference: PMID:37092498
reference_title: Two New Cases of Bachmann-Bupp Syndrome Identified through the International Center for Polyamine Disorders.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Concerning prenatal findings included cerebral ventricular enlargement, cerebral cysts, polyhydramnios, and a ventricular septal defect.
explanation: A clinical case with a confirmed ODC1 variant documents a prenatal ventricular septal defect.
- name: Valvular pulmonary stenosis
category: Cardiovascular
description: Mild pulmonary valve stenosis was reported in one individual.
phenotype_term:
preferred_term: Valvular pulmonary stenosis
term:
id: HP:0034350
label: Valvular pulmonary stenosis
evidence:
- reference: PMID:37469105
reference_title: Bachmann-Bupp syndrome and treatment.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Additionally, one individual has unilateral congenital sensorineural hearing loss, two individuals have congenital heart disease (one with mild pulmonary valve stenosis, the other with spontaneously resolved ventricular septal defect), three individuals have nail differences, and one individual has vision differences.
explanation: The review specifies a valvular pulmonary lesion; it does not establish a high frequency of this particular defect.
- name: Aggressive behavior
category: Behavioral
description: Aggressive behavior has been reported in several individuals, with variable severity.
phenotype_term:
preferred_term: Aggressive behavior
term:
id: HP:0000718
label: Aggressive behavior
evidence:
- reference: PMID:34477286
reference_title: 'Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: At age 19, he had a psychological evaluation that diagnosed him with anxiety, disruptive behavior, mild aggression, poor social and coping skills, difficulties in academic performance, and self‐injurious behaviors.
explanation: The full-text clinical narrative or comparative table documents this specific finding; no population frequency is inferred.
- name: Self-injurious behavior
category: Behavioral
description: Self-injurious behavior was documented in one older individual.
phenotype_term:
preferred_term: Self-injurious behavior
term:
id: HP:0100716
label: Self-injurious behavior
evidence:
- reference: PMID:34477286
reference_title: 'Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: At age 19, he had a psychological evaluation that diagnosed him with anxiety, disruptive behavior, mild aggression, poor social and coping skills, difficulties in academic performance, and self‐injurious behaviors.
explanation: The full-text clinical narrative or comparative table documents this specific finding; no population frequency is inferred.
- name: High forehead
category: Craniofacial
description: A high forehead was described in several founding cases; this is distinct from forehead breadth.
phenotype_term:
preferred_term: High forehead
term:
id: HP:0000348
label: High forehead
evidence:
- reference: PMID:34477286
reference_title: 'Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: High forehead, hypertelorism, mild ptosis, down‐slanting palpebral fissures, cryptorchidism
explanation: The full-text clinical narrative or comparative table documents this specific finding; no population frequency is inferred.
- name: Delayed visual maturation
category: Ophthalmologic
description: Delayed visual maturation was reported in the index patient. The report does not establish a specific retinal, optic-nerve or cortical cause.
phenotype_term:
preferred_term: Delayed visual maturation
notes: Needs a specific HPO term. Searches `runoak -i sqlite:obo:hp search 't~visual maturation'` and `runoak -i ols:hp search 'visual maturation'` returned no match. HP:0000505 Visual impairment includes additional severity and uncorrectability criteria not established by this report, so it is not substituted.
evidence:
- reference: PMID:30239107
reference_title: Novel de novo pathogenic variant in the ODC1 gene in a girl with developmental delay, alopecia, and dysmorphic features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Phenotypic manifestations include macrosomia, macrocephaly, developmental delay, alopecia, spasticity, hypotonia, cutaneous vascular malformation, delayed visual maturation, and sensorineural hearing loss.
explanation: The index case report explicitly lists delayed visual maturation; no frequency or specific visual-pathway lesion is inferred.
biochemical:
- name: Elevated plasma N-acetylputrescine
notes: Elevated plasma N-acetylputrescine is a supportive biochemical finding. In the index treatment study it was the polyamine measurement meeting CAP/CLIA standards and was used as a surrogate readout of putrescine metabolism; this assay-specific statement is not a universal restriction on other laboratories.
biomarker_term:
preferred_term: N-acetylputrescine
term:
id: CHEBI:17768
label: N-acetylputrescine
presence: INCREASED
evidence:
- reference: PMID:30475435
reference_title: Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Plasma clinical metabolomics analysis demonstrates elevation of N-acetylputrescine, the acetylated form of putrescine, with otherwise normal polyamine levels.
explanation: Establishes the elevation in plasma and its selectivity within the polyamine panel.
- reference: PMID:34282722
reference_title: Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: N-acetylputrescine, the only polyamine that meets CAP/CLIA standards in this analysis, served as the primary indicator of putrescine levels.
explanation: Explains why this metabolite, rather than putrescine itself, is the clinical readout.
- reference: PMID:36007106
reference_title: Bachmann-Bupp Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The finding of abnormal polyamine pathway metabolites (including increased N-acetylputrescine) on metabolomic profiling is suggestive of a diagnosis of BABS.
explanation: GeneReviews uses this metabolite as the biochemical trigger for genetic confirmation.
- name: Elevated erythrocyte and fibroblast ODC enzyme activity
notes: The index patient’s ODC activity was 12-17-fold above controls in cultured dermal fibroblasts and 125-137-fold in red blood cells using a radiolabeled ornithine assay. These values are not diagnostic cutoffs. Research assays have also been used to monitor treatment and investigate uncertain variants.
presence: INCREASED
evidence:
- reference: PMID:31249027
reference_title: Biochemical features of primary cells from a pediatric patient with a gain-of-function ODC1 genetic mutation.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Importantly, the accumulated ODC protein variant remained functionally active as we detected exceptionally high ODC enzyme activity in both primary dermal fibroblasts (12-17-fold of controls) and red blood cells (RBCs) (125-137-fold of controls), using a specific 14C radioactive ODC activity assay.
explanation: Supplies the quantitative fold-change and the assay used.
- reference: PMID:40382142
reference_title: Monitoring ODC activity and polyamines in Bachmann-Bupp syndrome patient biological samples.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Here we describe how to quantitatively measure ODC enzymatic activity and the polyamines by a radiolabeled 14C-ornithine assay and by reverse phase (RP)-HPLC, respectively.
explanation: Documents the standardised protocol for measuring the enzyme activity and polyamines in BABS patient samples.
- name: Elevated erythrocyte polyamines
notes: Red blood cells from the index patient contained elevated ODC protein and polyamine levels compared with controls.
presence: INCREASED
evidence:
- reference: PMID:30239107
reference_title: Novel de novo pathogenic variant in the ODC1 gene in a girl with developmental delay, alopecia, and dysmorphic features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Red blood cells obtained from our patient showed elevated ODC protein and polyamine levels compared to healthy controls.
explanation: Direct measurement of raised polyamines in a patient's circulating cells.
- name: Elevated plasma acisoga
presence: INCREASED
notes: Acisoga was elevated before treatment in the index patient and declined after eflornithine. It is an exploratory pharmacodynamic readout, without established diagnostic specificity or a validated relationship to developmental outcome.
evidence:
- reference: PMID:34282722
reference_title: Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The initial elevation of bothN-acetylputrescine as well as the polyamine metaboliteN-(3-acetamidopropyl) pyrrolidin-2-one (acisoga), which were above the 97.5th percentile, decreased at initiation of therapy and remained reduced at all time points
explanation: The serial metabolomic study documents acisoga as a second treatment-responsive metabolite; the finding is from a single treated patient.
genetic:
- name: ODC1
gene_term:
preferred_term: ODC1
term:
id: hgnc:8109
label: ODC1
association: Causative
relationship_type: CAUSATIVE
variant_origin: DE_NOVO
inheritance:
- name: Autosomal dominant
evidence:
- reference: PMID:36007106
reference_title: Bachmann-Bupp Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: BABS is expressed in an autosomal dominant manner and typically caused by a de novo ODC1 pathogenic variant.
explanation: GeneReviews states both the dominant mode and the de novo origin.
features: 'Reported BABS alleles include nonsense, frameshift, and splice-site variants affecting the C-terminal region of ODC1. They produce a gain of function through protein stabilization with retained catalysis. The index allele is c.1342A>T (p.Lys448Ter). The recurrent splice acceptor c.1242-2A>G has been reported in three individuals. Other ODC1 findings require independent interpretation: the G84R hypomorphic variant has functional and association data, but causal segregation and in-vivo validation of a separate Mendelian disorder were not established in the cited study.'
evidence:
- reference: PMID:30239107
reference_title: Novel de novo pathogenic variant in the ODC1 gene in a girl with developmental delay, alopecia, and dysmorphic features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The ODC1 gene mutation (c.1342 A>T) was identified by whole-exome sequencing and confirmed by Sanger sequencing.
explanation: Names the index allele and the method by which it was identified and confirmed.
- reference: PMID:30475435
reference_title: Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: In this report, we present four patients with a distinct neurometabolic disorder associated with de novo heterozygous, gain-of-function variants in the ODC1 gene.
explanation: Independent replication establishing the gene-disease relationship in four further patients with de novo gain-of-function alleles.
- reference: PMID:36007106
reference_title: Bachmann-Bupp Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Heterozygous pathogenic variants in ODC1 that cause BABS are typically gain-of-function variants.
explanation: GeneReviews states the direction of effect explicitly, which is the single most important fact to preserve when reading ODC1 literature.
- reference: PMID:40382142
reference_title: Monitoring ODC activity and polyamines in Bachmann-Bupp syndrome patient biological samples.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: ODC1 gene mutations that are linked to BABS always produce C-terminally truncated versions of the enzyme ornithine decarboxylase (ODC).
explanation: States that C-terminal truncation is invariant across the BABS allele spectrum.
- reference: PMID:33806076
reference_title: Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development.
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: An analysis of variants from ClinVar, Geno2MP, TOPMed, gnomAD, and COSMIC revealed an intellectual disability and seizure connected loss-of-function variant, ODC G84R (rs138359527, NC_000002.12:g.10444500C > T).
explanation: The association analysis concerns a hypomorphic allele, not an established alternative Mendelian syndrome. The authors explicitly call for co-segregation and in-vivo studies of causality.
- reference: PMID:11533243
reference_title: The ornithine decarboxylase gene is essential for cell survival during early murine development.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: ODC-heterozygous mice were viable, normal, and fertile.
explanation: The knockout study describes a different perturbation from BABS. Normal heterozygous mice and lethal homozygous nulls do not independently establish human dosage tolerance or a therapeutic safety threshold.
- reference: PMID:11533243
reference_title: The ornithine decarboxylase gene is essential for cell survival during early murine development.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Therefore, ODC plays an essential role in murine development, and proper homeostasis of polyamine pools appears to be required for cell survival prior to gastrulation.
explanation: The knockout study describes a different perturbation from BABS. Normal heterozygous mice and lethal homozygous nulls do not independently establish human dosage tolerance or a therapeutic safety threshold.
treatments:
- name: Eflornithine (difluoromethylornithine, DFMO)
description: Eflornithine is an irreversible ODC inhibitor used experimentally for BABS. The index compassionate-use regimen began at 500 mg/m2 per dose twice daily by gastrostomy, escalating to 750 and then 1000 mg/m2 per dose twice daily with a concurrent low-polyamine diet. Hair regrowth, cessation of follicular cysts, biochemical normalization, and developmental gains were reported. The 2025 series described six treated individuals, five under US single-patient IND protocols and one outside the US. These uncontrolled observations do not establish efficacy for all manifestations or comparative benefit at different ages.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: eflornithine
term:
id: CHEBI:41948
label: eflornithine
target_mechanisms:
- target: Elevated ODC Enzyme Activity
treatment_effect: INHIBITS
description: Eflornithine irreversibly inhibits ODC, so it suppresses the catalytic activity of the accumulated truncated enzyme rather than restoring its degradation.
evidence:
- reference: PMID:31249027
reference_title: Biochemical features of primary cells from a pediatric patient with a gain-of-function ODC1 genetic mutation.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Exposure of primary dermal fibroblasts to ODC inhibitor α-difluoromethylornithine (DFMO) reduced the ODC activity and putrescine to levels observed in controls without adversely affecting cell morphology or inducing cell death.
explanation: Demonstrates in the patient's own cells that DFMO normalises the raised enzyme activity without cytotoxicity.
- target: Putrescine Accumulation
treatment_effect: INHIBITS
description: Inhibiting the enzyme lowers the putrescine pool and its measurable acetylated derivative back toward the reference range.
evidence:
- reference: PMID:34282722
reference_title: Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Eflornithine normalized polyamine levels without disrupting other pathways.
explanation: In-patient confirmation that the drug corrects the polyamine disturbance selectively.
- target: Hair Follicle Dysfunction
treatment_effect: INHIBITS
description: Suppressing follicular ODC activity restores hair growth, an effect first shown in the truncated-ODC mouse and then reproduced in patients.
evidence:
- reference: PMID:8618048
reference_title: Modulation of murine hair follicle function by alterations in ornithine decarboxylase activity.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: 2-Difluoromethylornithine could also reactivate hair growth in animals with complete hair loss.
explanation: The model result that motivated trying the drug in patients with established alopecia.
evidence:
- reference: PMID:34282722
reference_title: Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Eflornithine normalized polyamine levels without disrupting other pathways. She demonstrated remarkable improvement in both neurological symptoms and cortical architecture. She gained fine motor skills with the capacity to feed herself and sit with support.
explanation: The primary treated-patient report, giving biochemical, neurological and functional outcomes in the first patient treated.
- reference: PMID:34282722
reference_title: Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: At age 4 years and 8 months, we started eflornithine (Sanofi Aventis) treatment with 500 mg/m2/dose bid twice daily via a gastrostomy tube along with a low polyamine diet on November 14, 2019, for 3 months, increasing to 750 mg/m2/dose twice daily, and a final increase to 1000 mg/m2/dose twice daily after 3.5 months.
explanation: Documents the actual regimen, route and escalation schedule used in the index treated case.
- reference: PMID:34282722
reference_title: Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Dosing was based on what had been demonstrated to be safe in pediatric patients in maintenance therapy for neuroblastoma treated with eflornithine (Saulnier Sholler et al., 2015).
explanation: Records that the paediatric dose and safety basis was borrowed from the neuroblastoma maintenance literature, not generated in BABS.
- reference: PMID:34282722
reference_title: Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: One month into treatment, hair growth was noted, with eyebrows appearing first
explanation: Timing of the first visible dermatological response.
- reference: PMID:34282722
reference_title: Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Upon initiation of eflornithine, the formation of cysts ceased immediately
explanation: Documents cessation of the recurrent follicular cysts on treatment.
- reference: PMID:34282722
reference_title: Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Repeat MRI done at the end of the 9-month treatment trial with eflornithine demonstrated normalization of the cerebral white matter signal with decrease in volume with white matter loss and resolution of all previously noted cysts.
explanation: The report documents normalized signal and cyst resolution alongside white matter volume loss; comparison to a neonatal scan limits causal attribution to treatment.
- reference: PMID:36443247
reference_title: Improvement of dermatological symptoms in patients with Bachmann-Bupp syndrome using difluoromethylornithine treatment.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: In both patients, treatment with difluoromethylornithine has resulted in improved dermatologic signs, including regrowth of eyebrow and scalp hair and cessation of recurrent follicular cyst development.
explanation: A two-patient dermatologic report supports treatment-associated improvement; patients overlap earlier reports and are not counted as two additional independent cases.
- reference: PMID:37469105
reference_title: Bachmann-Bupp syndrome and treatment.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Patients with BABS have been treated with DFMO and have shown improvement in hair growth, muscle tone, and development.
explanation: Review-level summary of the three outcome domains reported across treated patients.
- reference: PMID:40167220
reference_title: 'Repurposing With Purpose: Treatment of Bachmann-Bupp Syndrome With Eflornithine and Implications for Other Polyaminopathies.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Currently, five additional patients with BABS are being treated with DFMO.
explanation: Establishes that the treated cohort has grown beyond the index case.
- reference: PMID:36007106
reference_title: Bachmann-Bupp Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: An experimental targeted treatment with difluoromethylornithine (DFMO) is being explored on a compassionate use basis; it is not currently an FDA-approved treatment for BABS.
explanation: GeneReviews classifies DFMO as experimental compassionate-use treatment, qualifying the reported outcomes.
- reference: PMID:40167220
reference_title: 'Repurposing With Purpose: Treatment of Bachmann-Bupp Syndrome With Eflornithine and Implications for Other Polyaminopathies.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: To date, 6 patients with BABS are being treated with the repurposed drug, DFMO. Five of those patients are being treated in the United States under FDA-approved single patient investigational new drug (IND) protocols. The 6th patient is being treated outside of the U.S.
explanation: The 2025 report provides a dated treated-patient count and distinguishes single-patient IND authorization from approval of a BABS indication.
notes: 'Developmental assessment was disrupted by COVID-19 in the index study, and concurrent dietary and rehabilitation interventions complicate attribution. MRI compared neonatal imaging with a later scan after nine months of treatment: cysts resolved and white matter signal normalized, but white matter volume loss was present. This is not proof of restored cortical architecture. The cited GeneReviews chapter classifies treatment as experimental rather than an approved BABS indication.'
- name: Low-polyamine diet
description: Dietary restriction of polyamines was given alongside eflornithine in the index treated patient. It has never been tested as monotherapy in BABS, and the review literature raises dietary intervention and gut-flora-directed antibiotics only as candidate approaches to lowering putrescine.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: Dietary Intervention
term:
id: NCIT:C15447
label: Dietary Intervention
target_mechanisms:
- target: Putrescine Accumulation
treatment_effect: INHIBITS
description: Reducing dietary and gut-derived polyamine input is intended to lower the systemic putrescine burden.
evidence:
- reference: PMID:30475435
reference_title: Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Therapies aimed at reducing putrescine levels, including ODC1 inhibitors, dietary interventions, and antibiotics to reduce polyamine production by gastrointestinal flora could be considered as disease-modifying therapies.
explanation: This evidence is limited because this is a proposal for what could be considered, not a report of a tested dietary intervention.
evidence:
- reference: PMID:34282722
reference_title: Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: At age 4 years and 8 months, we started eflornithine (Sanofi Aventis) treatment with 500 mg/m2/dose bid twice daily via a gastrostomy tube along with a low polyamine diet on November 14, 2019, for 3 months, increasing to 750 mg/m2/dose twice daily, and a final increase to 1000 mg/m2/dose twice daily after 3.5 months.
explanation: This evidence is limited because the diet was co-administered with eflornithine, so no independent effect can be attributed to it.
- name: Supportive and symptom-directed management
description: 'Standard multidisciplinary care for the individual manifestations: feeding therapy with a low threshold for gastrostomy placement, nutritional intervention for obesity, a constipation ladder of stool softeners, prokinetics, osmotic agents and laxatives, and standard treatment for epilepsy, developmental delay and intellectual disability, refractive error, strabismus, hearing loss, follicular cysts and congenital heart defects. At each visit, GeneReviews recommends monitoring growth, feeding safety, constipation, mobility, development, and new neurological manifestations; skin and behavioral assessments are at least annual.'
therapeutic_modality: OTHER
treatment_term:
preferred_term: Supportive Care
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: PMID:36007106
reference_title: Bachmann-Bupp Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Feeding therapy with a low threshold for a clinical feeding evaluation and/or gastrostomy tube placement; nutritional intervention for those with obesity; stool softeners, prokinetics, osmotic agents or laxatives for constipation; standard treatment for epilepsy, developmental delay / intellectual disability, refractive error, strabismus, hearing loss, follicular cysts, and congenital heart defects.
explanation: The GeneReviews management paragraph is the source for every element of this supportive-care package.
- reference: PMID:36007106
reference_title: Bachmann-Bupp Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Ophthalmology and audiology evaluations annually or as clinically indicated.
explanation: Specifies the recommended sensory surveillance cadence.
- reference: PMID:36007106
reference_title: Bachmann-Bupp Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Measurement of growth parameters, evaluation of nutritional status and safety of oral intake, monitoring for signs and symptoms of constipation, assessment of mobility and self-help skills, monitoring of developmental progress and educational needs, and assessment for new manifestations (seizures, changes in tone) at each visit.
explanation: GeneReviews specifies clinical surveillance beyond annual ophthalmology and audiology.
- reference: PMID:36007106
reference_title: Bachmann-Bupp Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Complete skin evaluation for follicular cysts at least annually.
explanation: GeneReviews recommends annual surveillance for this domain.
- reference: PMID:36007106
reference_title: Bachmann-Bupp Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Behavioral assessment for signs of autism spectrum disorder, attention, and aggressive or self-injurious behaviors annually.
explanation: GeneReviews recommends annual surveillance for this domain.
- name: Genetic counseling
description: BABS is autosomal dominant and typically de novo, so the recurrence risk to other family members is presumed low. Once the familial ODC1 variant is known, prenatal and preimplantation genetic testing are possible.
therapeutic_modality: OTHER
treatment_term:
preferred_term: Genetic Counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: PMID:36007106
reference_title: Bachmann-Bupp Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Therefore, the risk to other family members is presumed to be low. Once an ODC1 pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic testing are possible.
explanation: GeneReviews states the recurrence-risk counselling message and the reproductive testing options.
- name: Physical Therapy
description: Physical therapy addresses motor development and functional mobility; the clinical series recommends individualized developmental intervention.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: Physical Therapy
term:
id: NCIT:C15302
label: Physical Therapy
evidence:
- reference: PMID:34477286
reference_title: 'Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Developmental assessment and intervention, such as physical and speech therapy are recommended; particularly as developmental milestones vary in patients.
explanation: The clinical report documents the recommendation or use of this service without a controlled efficacy estimate.
- name: Speech Language Therapy
description: Speech and language intervention supports communication in individuals with variable expressive language development.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: Speech Language Therapy
term:
id: NCIT:C159273
label: Speech Language Therapy
evidence:
- reference: PMID:34477286
reference_title: 'Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Developmental assessment and intervention, such as physical and speech therapy are recommended; particularly as developmental milestones vary in patients.
explanation: The clinical report documents the recommendation or use of this service without a controlled efficacy estimate.
- name: Occupational Therapy
description: Occupational therapy was used alongside other rehabilitation services in a reported patient; independent treatment efficacy was not measured.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: Occupational Therapy
term:
id: NCIT:C121351
label: Occupational Therapy
evidence:
- reference: PMID:37092498
reference_title: Two New Cases of Bachmann-Bupp Syndrome Identified through the International Center for Polyamine Disorders.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: At the time of reporting, the patient is receiving physical, occupational, and speech therapy services.
explanation: The clinical report documents the recommendation or use of this service without a controlled efficacy estimate.
diagnosis:
- name: ODC1 molecular genetic testing
description: The diagnosis is established by identifying a heterozygous pathogenic ODC1 variant in a proband with suggestive findings. Exome sequencing identified the index allele, confirmed by Sanger sequencing.
presence: PRESENT
evidence:
- reference: PMID:36007106
reference_title: Bachmann-Bupp Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The diagnosis is established in a proband with suggestive findings and a heterozygous pathogenic variant in ODC1 identified by molecular genetic testing.
explanation: GeneReviews defines the diagnostic standard.
- reference: PMID:30239107
reference_title: Novel de novo pathogenic variant in the ODC1 gene in a girl with developmental delay, alopecia, and dysmorphic features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The ODC1 gene mutation (c.1342 A>T) was identified by whole-exome sequencing and confirmed by Sanger sequencing.
explanation: Illustrates the two-step molecular workflow used in the index case.
- name: Plasma metabolomic profiling for polyamine metabolites
description: Elevated N-acetylputrescine on plasma metabolomic profiling can support suspicion of BABS or characterize a molecular finding. Published diagnoses were made through broad sequencing; metabolomics is not an obligatory preceding step.
presence: PRESENT
evidence:
- reference: PMID:36007106
reference_title: Bachmann-Bupp Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The finding of abnormal polyamine pathway metabolites (including increased N-acetylputrescine) on metabolomic profiling is suggestive of a diagnosis of BABS.
explanation: GeneReviews positions metabolomic profiling as the suggestive biochemical test.
- reference: PMID:30475435
reference_title: Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Plasma clinical metabolomics analysis demonstrates elevation of N-acetylputrescine, the acetylated form of putrescine, with otherwise normal polyamine levels.
explanation: Documents the specific plasma metabolomic pattern in a genotyped cohort.
- reference: PMID:34477286
reference_title: 'Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: All diagnoses to date have been made using broad sequencing, such as WES or WGS.
explanation: The 2021 series establishes the diagnostic sequence actually used, rather than assuming that biochemical testing usually comes first.
- name: Erythrocyte ODC enzyme activity assay
description: A 14C-ornithine radiolabelled assay on red blood cells, with polyamines measured by reverse-phase HPLC, quantifies the enzymatic gain of function and is used to monitor response to eflornithine.
presence: PRESENT
evidence:
- reference: PMID:40382142
reference_title: Monitoring ODC activity and polyamines in Bachmann-Bupp syndrome patient biological samples.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The detailed protocols of this chapter provide step-by-step guidance detailing how to measure ODC activity and polyamines in human RBCs.
explanation: Establishes the red blood cell assay as the standardised BABS monitoring method.
animal_models:
- species: Mus musculus
genotype: K6/ODC transgenic
category: Transgenic
description: The K6/ODC mouse expresses a mouse ODC cDNA carrying a premature stop codon at position 427, driven by a bovine keratin 6 promoter, in outer root sheath keratinocytes of the hair follicle. The lesion is the same class as the human BABS allele - carboxyl truncation producing a stabilised, catalytically active enzyme - which is why this 1995-1996 model predicted the human syndrome. Mice have a normal first hair cycle, lose their hair completely from 2-3 weeks of age, and develop dermal follicular cysts. DFMO both prevents the hair loss and reactivates hair growth after complete loss. The model is skin-restricted, so it does not model the neurodevelopmental, growth or sensory features of BABS, and it also develops skin tumours, which has no established human BABS counterpart.
evidence:
- reference: PMID:8618048
reference_title: Modulation of murine hair follicle function by alterations in ornithine decarboxylase activity.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: The ODC inhibitor 2-difluoromethylornithine could prevent hair loss and partially normalize skin histology if administered before the onset of ODC overexpression.
explanation: Establishes the preventive arm of the DFMO effect in the model that motivated human treatment.
- reference: PMID:41925768
reference_title: 'The remarkable legacy of the K6/ODC mouse: mechanisms of polyamine-promoted tumorigenesis revealed.'
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Ornithine decarboxylase (ODC), a key regulating enzyme of polyamine biosynthesis, was constitutively expressed in the outer root sheath cells of hair follicles near the bulge stem cell niche using a keratin 6 promoter in K6/ODC mice.
explanation: Defines the transgene construct and the targeted cell population.
- reference: PMID:41925768
reference_title: 'The remarkable legacy of the K6/ODC mouse: mechanisms of polyamine-promoted tumorigenesis revealed.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Remarkably, the heterozygous de novo mutation in the ODC gene of this patient and others subsequently identified as having the Bachmann-Bupp syndrome (BABS) introduces a stop codon in the ODC gene, leading to premature abrogation and deletion of the c-terminal 14 amino acids of the ODC protein, as was originally designed in the K6/ODC mouse to stabilize the ODC protein and lead to elevated ODC enzyme activity
explanation: The review draws a mechanistic analogy between C-terminal truncations. The mouse p.427 stop and human p.Lys448Ter allele remove different lengths and are not identical variants.
quote_role: REVIEW_SYNTHESIS
- reference: PMID:30239107
reference_title: Novel de novo pathogenic variant in the ODC1 gene in a girl with developmental delay, alopecia, and dysmorphic features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: This is the first human case confirming similar symptoms observed in a transgenic ODC1 mouse model first described over 20 years ago.
explanation: The index human report explicitly frames itself as the human confirmation of the transgenic mouse phenotype.
- reference: PMID:41925768
reference_title: 'The remarkable legacy of the K6/ODC mouse: mechanisms of polyamine-promoted tumorigenesis revealed.'
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Many tumors arising in K6/ODC transgenic mice are keratoacanthomas that originated from the follicular cysts in the dermis.
explanation: 'Recorded as a model limitation: the model''s tumour phenotype is a property of the skin-targeted transgenic and has no established counterpart in reported BABS patients.'
- reference: PMID:7671221
reference_title: Increased frequency of spontaneous skin tumors in transgenic mice which overexpress ornithine decarboxylase.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Effects observed include development of dermal follicular cysts, excessive skin wrinkling, enhanced nail growth, alopecia, and spontaneous tumor development.
explanation: The original description of the transgenic phenotype, three of whose four non-tumour elements (follicular cysts, nail growth, alopecia) were later recognised in BABS patients.
name: Skin-restricted K6/ODC transgenic mouse
modeled_mechanisms:
- target: Hair Follicle Dysfunction
relationship: PARTIALLY_RECAPITULATES
description: Postnatal hair loss and DFMO-induced regrowth reproduce the ectodermal phenotype.
limitations: Skin-restricted transgene expression does not model the neural or systemic human phenotype.
evidence:
- reference: PMID:8618048
reference_title: Modulation of murine hair follicle function by alterations in ornithine decarboxylase activity.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Mice that overexpress a mutated ornithine decarboxylase (ODC) transgene in outer root sheath keratinocytes of the hair follicle were used to study the role of this enzyme in regulating hair follicle structure and function.
explanation: The promoter targets follicular keratinocytes.
- species: Mus musculus
genotype: Odc1 knockout
category: Knockout
description: Constitutive Odc1 knockout is a mechanistic contrast to BABS gain of function. Homozygous embryos failed to develop after implantation; heterozygotes were described as viable, normal, and fertile in the original study. This experiment neither models the BABS allele nor establishes a human pharmacological safety threshold. In cultured null blastocysts the inner cell mass degenerated despite initially preserved mitotic-cell counts; this loss-of-function observation is not a demonstrated neural-proliferation defect in BABS.
evidence:
- reference: PMID:11533243
reference_title: The ornithine decarboxylase gene is essential for cell survival during early murine development.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: ODC-heterozygous mice were viable, normal, and fertile.
explanation: Loss-of-function mouse evidence provides biological context; it is not evidence that a human BABS allele causes this phenotype or that a particular inhibitor dose is safe.
- reference: PMID:11533243
reference_title: The ornithine decarboxylase gene is essential for cell survival during early murine development.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Embryonic day E3.5 ODC-deficient embryos were capable of uterine implantation and induced maternal decidualization yet failed to develop substantially thereafter.
explanation: Loss-of-function mouse evidence provides biological context; it is not evidence that a human BABS allele causes this phenotype or that a particular inhibitor dose is safe.
- reference: PMID:11533243
reference_title: The ornithine decarboxylase gene is essential for cell survival during early murine development.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: No striking differences were observed in any of the embryos analyzed, and ODC-deficient blastocysts (n = 3) contained similar numbers of mitotic cells as their wild-type littermates (Fig. 5A).
explanation: Cultured/isolated blastocyst evidence distinguishes initial mitotic-cell counts from subsequent inner-cell-mass survival; it does not model BABS gain of function.
name: Constitutive Odc1-null mouse as a loss-of-function contrast
discussions:
- discussion_id: babs_k6odc_model_scope_and_cancer_risk
kind: HUMAN_MODEL_MISMATCH
status: OPEN
prompt: The K6/ODC mouse reproduces the alopecia and follicular cysts of BABS and predicted the DFMO response, but it also develops skin tumours and is skin-restricted. Does whole-body expression of stabilised ODC in BABS patients carry a tumour risk, and does the absence of a whole-body model mean the neurodevelopmental arm of the disease has never been modelled?
rationale: 'The only well-characterised animal model of this exact lesion targets the transgene to hair follicle keratinocytes. Its tumour phenotype has been interpreted as evidence that polyamine excess promotes tumorigenesis, and the index human cohort report raised cancer surveillance as a consideration on that basis. But no BABS patient tumour series exists, GeneReviews does not recommend tumour surveillance, and there is no whole-body C-terminally-truncated-ODC model in which the neurodevelopmental phenotype could be studied. The mismatch matters in both directions: it risks over-calling a cancer risk that has not been observed in patients, and it leaves the central neurodevelopmental mechanism without an in vivo model.'
attaches_to:
- pathophysiology#Dysregulated Neural Progenitor Proliferation
proposed_experiments:
- experiment_id: exp_babs_whole_body_truncation_knockin
name: Whole-body or CNS-conditional Odc1 C-terminal truncation knock-in
description: Generate a mouse carrying a knock-in of a human-equivalent C-terminally truncated Odc1 allele expressed ubiquitously or conditionally in neural lineages, rather than under a keratin 6 promoter, and characterise cortical progenitor proliferation, brain growth, white matter development and response to eflornithine started at different postnatal ages.
- experiment_id: exp_babs_tumour_surveillance_registry
name: Prospective tumour-surveillance registry across the BABS cohort
description: Assemble a prospective, standardised tumour-surveillance registry across the international BABS cohort to establish whether the mouse skin-tumour phenotype has any human counterpart, and whether long-term eflornithine exposure modifies it.
evidence:
- reference: PMID:30475435
reference_title: Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: As the ODC1 gene has been implicated in neoplasia, cancer surveillance may be important in this disorder.
explanation: The index cohort raises cancer surveillance as a hypothesis, phrased as a possibility rather than a recommendation.
- reference: PMID:41925768
reference_title: 'The remarkable legacy of the K6/ODC mouse: mechanisms of polyamine-promoted tumorigenesis revealed.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: However, unlike the K6/ODC mouse where this mutation was directed to the skin, the ODC mutation is expressed in all tissues of BABS patients resulting in macrosomia, macrocephaly, neurodevelopmental delay, spasticity, hypotonia, delayed visual maturation, and sensorineural hearing loss
explanation: States the exact scope difference between the model and the human disease.
quote_role: REVIEW_SYNTHESIS
- discussion_id: babs_treatment_window_neonatal_initiation
kind: KNOWLEDGE_GAP
status: OPEN
prompt: Does earlier initiation of eflornithine, for example in a neonate diagnosed before neurological damage accrues, change the neurodevelopmental trajectory of BABS?
rationale: The index patient began eflornithine at 4 years 8 months. A later treatment review reports diagnosis and treatment across ages from the neonatal period to adulthood, so a blanket absence of neonatal treatment is outdated. Whether earlier initiation changes neurodevelopmental outcomes remains unresolved without comparable longitudinal assessments.
attaches_to:
- pathophysiology#Abnormal Brain Development
proposed_experiments:
- experiment_id: exp_babs_early_versus_late_initiation_cohort
name: Natural-history cohort comparing early versus late eflornithine initiation
description: Establish a prospective international natural-history cohort with standardised developmental assessment at fixed ages, then compare developmental trajectories, MRI findings and N-acetylputrescine normalisation between patients started on eflornithine before and after 12 months of age.
evidence:
- reference: PMID:34282722
reference_title: Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: This could be especially consequential if we could initiate therapy in a neonate diagnosed early before neurological damage occurs.
explanation: The treating team states the open question directly.
- reference: PMID:40167220
reference_title: 'Repurposing With Purpose: Treatment of Bachmann-Bupp Syndrome With Eflornithine and Implications for Other Polyaminopathies.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The age of diagnosis and the onset of treatment has also varied from the neonatal period to adulthood.
explanation: The later review qualifies the original early-treatment question; it does not supply a controlled comparison of treatment windows.
differential_diagnoses:
- name: Alopecia-intellectual disability syndrome 4 (LSS-related)
description: LSS-related alopecia-intellectual disability is a recessive neuroectodermal syndrome affecting cholesterol biosynthesis. The cited cohort had congenital alopecia, intellectual disability or developmental delay, frequent early-onset epilepsy, and additional skin findings. Timing of scalp hair loss can help distinguish it from the typical postnatal shedding in BABS, but molecular testing establishes the diagnosis.
distinguishing_features:
- Biallelic LSS variants and autosomal recessive inheritance, compared with heterozygous ODC1 gain-of-function variants in BABS.
- Congenital alopecia in the cited LSS cohort, compared with typically postnatal scalp hair shedding in BABS.
- Early-onset epilepsy and ichthyosis or erythroderma were common in the LSS cohort.
- LSS affects cholesterol biosynthesis; the study does not establish a universal negative polyamine profile or a clinical contraindication to ODC inhibition.
disease_term:
preferred_term: Alopecia with intellectual disability syndrome 4
term:
id: MONDO:0030009
label: alopecia-intellectual disability syndrome 4
evidence:
- reference: PMID:30723320
reference_title: Biallelic pathogenic variants in the lanosterol synthase gene LSS involved in the cholesterol biosynthesis cause alopecia with intellectual disability, a rare recessive neuroectodermal syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: It is a rare autosomal recessive condition characterized by hypotrichosis and intellectual disability (ID) or developmental delay (DD), frequently associated with early-onset epilepsy and other dermatological features.
explanation: Gives the inheritance mode and the alopecia-plus-developmental-delay core that make this the closest non-polyaminopathy mimic of BABS.
- reference: PMID:30723320
reference_title: Biallelic pathogenic variants in the lanosterol synthase gene LSS involved in the cholesterol biosynthesis cause alopecia with intellectual disability, a rare recessive neuroectodermal syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Total alopecia with sparse eyelashes and eyebrows was noted at birth in all affected individuals.
explanation: Establishes the congenital timing of the alopecia, the discriminator against the non-congenital clump shedding of BABS.
- reference: PMID:36007106
reference_title: Bachmann-Bupp Syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Hair is typically present at birth but may be sparse and of an unexpected color with subsequent loss of hair in large clumps within the first few weeks of life.
explanation: 'The BABS side of the same discriminator, stated by GeneReviews: hair is present at birth and lost afterwards.'
- name: Snyder-Robinson syndrome
description: The first-described and best-known polyaminopathy, and the disorder whose prior research the BABS team explicitly credits with accelerating BABS from discovery to treatment. It shares intellectual disability and hypotonia with BABS, and its literature uses the same polyamine-pathway vocabulary, so mechanism sentences are easily misattributed between the two. It is separated from BABS by the affected enzyme (spermine synthase, several steps downstream of ODC), by the direction of effect (loss of function, not gain), and by X-linked hemizygous rather than autosomal dominant transmission. Alopecia is not its presenting feature.
distinguishing_features:
- Caused by SMS (spermine synthase), not ODC1
- Loss-of-function with decreased or absent enzyme activity, the opposite direction of effect to the ODC1 gain of function in BABS
- X-linked, affecting hemizygous males, rather than de novo autosomal dominant
- Osteoporosis, kyphoscoliosis, unsteady gait and facial asymmetry dominate; the non-congenital clump alopecia and macrocephaly/macrosomia of BABS are not its core
disease_term:
preferred_term: Snyder-Robinson syndrome
term:
id: MONDO:0010664
label: syndromic X-linked intellectual disability Snyder type
evidence:
- reference: PMID:41410504
reference_title: 'Genetic and Phenotypic Features of the Five Known Polyaminopathies: A Critical Narrative Review.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Snyder-Robinson syndrome results from hemizygous loss-of-function variants in the spermine synthase (SMS) gene, resulting in decreased or complete loss of spermine synthase enzyme activity.
explanation: Gives the gene, the zygosity and the direction of effect that separate Snyder-Robinson syndrome from BABS.
- reference: PMID:37092498
reference_title: Two New Cases of Bachmann-Bupp Syndrome Identified through the International Center for Polyamine Disorders.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Recent identification of four additional polyaminopathies, including Bachmann-Bupp syndrome, have benefited from previous research on Snyder-Robinson syndrome in order to advance from research to treatment more quickly.
explanation: Documents the direct research lineage between the two disorders, which is precisely why their literatures are intertwined and confusable.
- reference: PMID:40167220
reference_title: 'Repurposing With Purpose: Treatment of Bachmann-Bupp Syndrome With Eflornithine and Implications for Other Polyaminopathies.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: DFMO usage in SRS has been considered and further study is ongoing (Gilmour, 2023; Stewart, 2023).
explanation: ODC inhibition is under investigation in SRS; biochemical differences do not justify a blanket contraindication.
quote_role: REVIEW_SYNTHESIS
- name: Faundes-Banka syndrome
description: Faundes-Banka syndrome is a neurodevelopmental polyaminopathy caused by heterozygous EIF5A variants that impair eIF5A function. The eIF5A protein is the substrate for DHPS- and DOHH-mediated hypusination; it is not itself the hypusination enzyme. Gene, molecular consequence, and phenotype distinguish it from ODC1 gain-of-function BABS.
distinguishing_features:
- Heterozygous EIF5A variants impair eIF5A translation-factor function.
- The affected protein requires spermidine-dependent hypusination, distinct from ODC-mediated putrescine synthesis.
- Micrognathia and microcephaly are characteristic in the reviewed FABAS cohort.
disease_term:
preferred_term: Faundes-Banka syndrome
term:
id: MONDO:0859163
label: Faundes-Banka syndrome
evidence:
- reference: PMID:41410504
reference_title: 'Genetic and Phenotypic Features of the Five Known Polyaminopathies: A Critical Narrative Review.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Faundes-Banka syndrome results from heterozygous loss-of-function variants in the eukaryotic translation initiation factor 5A (EIF5A) gene, impairing eIF5A protein function.
explanation: Gives the gene and the direction of effect that separate Faundes-Banka syndrome from BABS.
- reference: PMID:41410504
reference_title: 'Genetic and Phenotypic Features of the Five Known Polyaminopathies: A Critical Narrative Review.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The five known syndromes associated with the polyamine pathway share many similar clinical phenotypes, and yet patients with each syndrome present with distinctive syndromic features.
explanation: Establishes that the five polyaminopathies overlap clinically, which is the condition under which their evidence gets mixed up.
- name: Deoxyhypusine synthase (DHPS) deficiency
description: An autosomal recessive polyaminopathy caused by bi-allelic hypomorphic DHPS variants. It sits on the same hypusination branch as Faundes-Banka syndrome and, like BABS, presents as a Mendelian neurodevelopmental disorder with seizures and developmental impairment, so it appears in the same polyaminopathy tables. It is separated from BABS by the gene, by recessive rather than dominant inheritance, and by reduced rather than increased enzyme activity.
distinguishing_features:
- Caused by DHPS (deoxyhypusine synthase), not ODC1
- Autosomal recessive with bi-allelic hypomorphic variants, not de novo heterozygous
- Reduced enzyme activity, the opposite direction of effect to BABS
- Acts on the spermidine-dependent hypusination of eIF5A rather than on polyamine synthesis, so putrescine and N-acetylputrescine are not the diagnostic signature
- Seizures and speech and walking impairment define the phenotype; the BABS alopecia and macrocephaly/macrosomia combination is not its core
disease_term:
preferred_term: Deoxyhypusine synthase deficiency
term:
id: MONDO:0032775
label: neurodevelopmental disorder with seizures and speech and walking impairment
evidence:
- reference: PMID:41410504
reference_title: 'Genetic and Phenotypic Features of the Five Known Polyaminopathies: A Critical Narrative Review.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: DHPS (deoxyhypusine synthase) deficiency is an autosomal recessive disease and results from bi-allelic hypomorphic variants in the deoxyhypusine synthase (DHPS) gene, which results in reduced deoxyhypusine synthase enzyme activity.
explanation: Gives the gene, the inheritance mode and the direction of effect that separate DHPS deficiency from BABS.
- name: Deoxyhypusine hydroxylase (DOHH) disorder
description: The fifth recognised polyaminopathy, caused by bi-allelic loss-of-function DOHH variants, and the second step of the hypusination branch. It is the newest member of the family and is grouped with BABS in every polyaminopathy review, which is the setting in which its findings can be misattributed. It is separated from BABS by the gene, by autosomal recessive inheritance, by decreased rather than increased enzyme activity, and by a microcephaly-with-cerebral-atrophy brain phenotype that is close to the inverse of the BABS macrocephaly.
distinguishing_features:
- Caused by DOHH (deoxyhypusine hydroxylase), not ODC1
- Autosomal recessive bi-allelic loss of function, not de novo heterozygous gain of function
- Decreased enzyme activity, the opposite direction of effect to BABS
- Microcephaly with cerebral atrophy and visual impairment, the inverse of the absolute or relative macrocephaly and macrosomia of BABS
disease_term:
preferred_term: Deoxyhypusine hydroxylase disorder
term:
id: MONDO:0859293
label: neurodevelopmental disorder with microcephaly, cerebral atrophy, and visual impairment
evidence:
- reference: PMID:41410504
reference_title: 'Genetic and Phenotypic Features of the Five Known Polyaminopathies: A Critical Narrative Review.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Finally, DOHH (deoxyhypusine hydroxylase) disorder is an autosomal recessive disorder caused by bi-allelic loss-of-function variants in the deoxyhypusine hydroxylase (DOHH) gene, which causes decreased deoxyhypusine hydroxylase enzyme activity.
explanation: Gives the gene, the inheritance mode and the direction of effect that separate DOHH disorder from BABS.
- name: ODC1 G84R hypomorphic variant association
description: G84R is a population missense variant with reduced activity of purified recombinant enzyme and exploratory neurological phenotype associations. It is not an established BABS allele or a validated separate Mendelian diagnosis. The study calls for co-segregation and in-vivo experiments to establish causality.
distinguishing_features:
- C-terminal truncation and increased enzyme abundance define the established BABS mechanism; purified G84R enzyme instead showed reduced catalytic activity.
- Association and functional evidence for G84R do not establish Mendelian pathogenicity or a clinical treatment recommendation.
notes: Kept unbound because the cited evidence does not establish a separate disease entity.
evidence:
- reference: PMID:33806076
reference_title: Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: A functional enzyme assay for recombinant ODC WT or ODC G84R showed a 2.5-fold reduction of enzyme activity because of the variant, confirming alteration of enzymatic function due to the variant (Figure 1I).
explanation: Purified recombinant enzyme assay demonstrates hypomorphic activity; this experiment is in vitro rather than solely computational.
- reference: PMID:33806076
reference_title: Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development.
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: However, future in vivo analyses and co-segregation strategies should be performed to establish the causal roles of ODC G84R into phenotypic changes.
explanation: The authors explicitly distinguish association from established causality.
references:
- reference: PMID:36007106
title: Bachmann-Bupp Syndrome.
tags:
- GeneReviews
findings: []
- reference: PMID:30239107
title: Novel de novo pathogenic variant in the ODC1 gene in a girl with developmental delay, alopecia, and dysmorphic features.
findings: []
- reference: PMID:30475435
title: Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities.
findings: []
- reference: PMID:34282722
title: Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease.
findings: []
- reference: PMID:37469105
title: Bachmann-Bupp syndrome and treatment.
findings: []
- reference: PMID:41410504
title: 'Genetic and Phenotypic Features of the Five Known Polyaminopathies: A Critical Narrative Review.'
findings: []
- reference: PMID:31249027
title: Biochemical features of primary cells from a pediatric patient with a gain-of-function ODC1 genetic mutation.
findings: []
- reference: PMID:8618048
title: Modulation of murine hair follicle function by alterations in ornithine decarboxylase activity.
findings: []
- reference: PMID:2928784
title: Prevention of rapid intracellular degradation of ODC by a carboxyl-terminal truncation.
findings: []
- reference: PMID:34477286
title: 'Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome.'
- reference: PMID:37092498
title: Two New Cases of Bachmann-Bupp Syndrome Identified through the International Center for Polyamine Disorders.
- reference: PMID:40167220
title: 'Repurposing With Purpose: Treatment of Bachmann-Bupp Syndrome With Eflornithine and Implications for Other Polyaminopathies.'
- reference: PMID:33806076
title: Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development.
- reference: PMID:40382142
title: Monitoring ODC activity and polyamines in Bachmann-Bupp syndrome patient biological samples.
- reference: PMID:36443247
title: Improvement of dermatological symptoms in patients with Bachmann-Bupp syndrome using difluoromethylornithine treatment.
- reference: PMID:41925768
title: 'The remarkable legacy of the K6/ODC mouse: mechanisms of polyamine-promoted tumorigenesis revealed.'
- reference: PMID:11533243
title: The ornithine decarboxylase gene is essential for cell survival during early murine development.
- reference: PMID:30723320
title: Biallelic pathogenic variants in the lanosterol synthase gene LSS involved in the cholesterol biosynthesis cause alopecia with intellectual disability, a rare recessive neuroectodermal syndrome.
experimental_models:
- name: Index-patient dermal fibroblasts and DFMO rescue
experimental_model_type: PRIMARY_CELL_CULTURE
cell_source: Primary dermal fibroblasts from the index patient with ODC1 c.1342A>T (p.Lys448Ter); neonatal and adult control fibroblasts
description: Patient fibroblasts accumulated ODC and putrescine and had elevated ODC activity. DFMO reduced activity and putrescine to control levels. This is a non-neural, single-patient model; controls were not described as isogenic.
publication: PMID:31249027
modeled_mechanisms:
- target: ODC Protein Accumulation
relationship: RECAPITULATES
description: Patient fibroblasts contain elevated ODC protein.
evidence:
- reference: PMID:31249027
reference_title: Biochemical features of primary cells from a pediatric patient with a gain-of-function ODC1 genetic mutation.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: In this study, we show that primary dermal fibroblasts derived from a skin biopsy of a 3-year-old patient contain large amounts of ODC protein and putrescine compared with primary dermal (neonatal and adult) fibroblast control cells.
explanation: Patient-derived fibroblasts provide direct cellular evidence from the index p.Lys448Ter case.
- target: Elevated ODC Enzyme Activity
relationship: RECAPITULATES
description: Radiolabeled ornithine assay detected elevated catalytic activity.
evidence:
- reference: PMID:31249027
reference_title: Biochemical features of primary cells from a pediatric patient with a gain-of-function ODC1 genetic mutation.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Importantly, the accumulated ODC protein variant remained functionally active as we detected exceptionally high ODC enzyme activity in both primary dermal fibroblasts (12-17-fold of controls) and red blood cells (RBCs) (125-137-fold of controls), using a specific 14C radioactive ODC activity assay.
explanation: Assay results are from one patient, with separate fibroblast and erythrocyte preparations.
- target: Putrescine Accumulation
relationship: RESCUES
description: DFMO reduced the elevated putrescine pool to control levels in culture.
limitations: Biochemical rescue in fibroblasts does not establish neural or whole-patient efficacy.
evidence:
- reference: PMID:31249027
reference_title: Biochemical features of primary cells from a pediatric patient with a gain-of-function ODC1 genetic mutation.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Exposure of primary dermal fibroblasts to ODC inhibitor α-difluoromethylornithine (DFMO) reduced the ODC activity and putrescine to levels observed in controls without adversely affecting cell morphology or inducing cell death.
explanation: Drug exposure normalized these measured biochemical readouts; absence of reported morphological change or cell death is not a comprehensive safety assay.
evidence:
- reference: PMID:31249027
reference_title: Biochemical features of primary cells from a pediatric patient with a gain-of-function ODC1 genetic mutation.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: In this study, we show that primary dermal fibroblasts derived from a skin biopsy of a 3-year-old patient contain large amounts of ODC protein and putrescine compared with primary dermal (neonatal and adult) fibroblast control cells.
explanation: Patient-derived fibroblasts provide direct cellular evidence from the index p.Lys448Ter case.
- reference: PMID:31249027
reference_title: Biochemical features of primary cells from a pediatric patient with a gain-of-function ODC1 genetic mutation.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Importantly, the accumulated ODC protein variant remained functionally active as we detected exceptionally high ODC enzyme activity in both primary dermal fibroblasts (12-17-fold of controls) and red blood cells (RBCs) (125-137-fold of controls), using a specific 14C radioactive ODC activity assay.
explanation: Assay results are from one patient, with separate fibroblast and erythrocyte preparations.
- reference: PMID:31249027
reference_title: Biochemical features of primary cells from a pediatric patient with a gain-of-function ODC1 genetic mutation.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Exposure of primary dermal fibroblasts to ODC inhibitor α-difluoromethylornithine (DFMO) reduced the ODC activity and putrescine to levels observed in controls without adversely affecting cell morphology or inducing cell death.
explanation: Drug exposure normalized these measured biochemical readouts; absence of reported morphological change or cell death is not a comprehensive safety assay.
- name: Reference-line cerebral organoids for ODC1 expression
experimental_model_type: ORGANOID
cell_source: Human iPSC line AICS-0011; not a BABS patient line
culture_system: STEMdiff cerebral organoid differentiation with single-cell RNA sequencing
description: Reference-line cerebral organoids were profiled to relate ODC1 expression to immature SOX-expressing cells. These are observational expression data; no disease allele was introduced and neural over-proliferation was not experimentally demonstrated.
publication: PMID:33806076
modeled_mechanisms:
- target: Dysregulated Neural Progenitor Proliferation
relationship: MEASURES
description: Measures expression associations underlying the proposed neural mechanism, not the putative proliferation defect itself.
limitations: Unperturbed reference line; expression is not a proliferation assay or proof of disease causation.
evidence:
- reference: PMID:33806076
reference_title: Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development.
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: There was also a higher expression of ODC1 in cells expressing pluripotent SOX gene markers, with both the number of cells and total expression levels of ODC1 lower in cells that did not have SOX gene expression (Figure 2D).
explanation: Single-cell expression associations support a developmental hypothesis; no BABS perturbation was tested.
evidence:
- reference: PMID:33806076
reference_title: Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: To test the hypothesis that ODC1 expression correlates with the maturity of neurons, we developed induced pluripotent stem cells (iPSCs) differentiated into cerebral organoids followed by single cell RNA-Seq.
explanation: The study generated organoids; it was not solely a reanalysis of published organoid data.
- name: Engineered murine ODC C-terminal truncation in mammalian cells
experimental_model_type: OTHER
cell_source: Mammalian cells expressing engineered murine ODC
description: Deletion of the final 37 residues stabilized ODC in a classical cellular experiment. This demonstrates the function of the C-terminal degradation region, but is not a patient-derived BABS model and is not the same truncation length as p.Lys448Ter.
publication: PMID:2928784
modeled_mechanisms:
- target: Escape from Antizyme-Mediated Proteasomal Degradation
relationship: PERTURBS
description: Engineered tail deletion increases intracellular stability; the quoted experiment does not isolate antizyme binding as the affected step.
evidence:
- reference: PMID:2928784
reference_title: Prevention of rapid intracellular degradation of ODC by a carboxyl-terminal truncation.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Ornithine decarboxylase (ODC) was converted from a protein with a short intracellular half-life in mammalian cells to a stable protein by truncating 37 residues at its carboxyl terminus.
explanation: An engineered truncation establishes the contribution of the C terminus to ODC turnover.
evidence:
- reference: PMID:2928784
reference_title: Prevention of rapid intracellular degradation of ODC by a carboxyl-terminal truncation.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Thus, a carboxyl-terminal domain is responsible for the rapid intracellular degradation of murine ODC.
explanation: Cellular turnover experiment; human tissue consequences are not assessed.
variants:
- name: NM_002539.3:c.1342A>T (p.Lys448Ter)
gene:
preferred_term: ODC1
term:
id: hgnc:8109
label: ODC1
variant_type: single nucleotide variant
type: Nonsense
clinical_significance: PATHOGENIC
description: Index de novo allele removing the final 14 amino acids. ClinVar RCV001263232 reports pathogenic from one OMIM literature-only submission with no assertion criteria, not expert-panel review. The 2021 table printed A>G; the published correction confirms A>T.
evidence:
- reference: PMID:30239107
reference_title: Novel de novo pathogenic variant in the ODC1 gene in a girl with developmental delay, alopecia, and dysmorphic features.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The ODC1 gene mutation (c.1342 A>T) was identified by whole-exome sequencing and confirmed by Sanger sequencing.
explanation: Primary report establishes the nucleotide substitution.
- reference: url:https://www.ncbi.nlm.nih.gov/clinvar/RCV001263232/
reference_title: NM_002539.3(ODC1):c.1342A&gt;T (p.Lys448Ter) AND Neurodevelopmental disorder with alopecia and brain abnormalities - ClinVar - NCBI
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'Germline classification: ... Pathogenic (1 submission) ... no assertion criteria provided'
explanation: ClinVar classification is represented with its single-submitter, no-criteria limitations in the description.
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC10479987/
reference_title: 'Correction to “Expanding the phenotype: Four new cases and hope for treatment in Bachmann–Bupp syndrome” - PMC'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: In the originally published article, Table 1 contained the variant c.1342A&gt;G. This variant should have been 1342A&gt;T.
explanation: The published erratum resolves the nucleotide discrepancy as A>T. HTML entity spelling in the snippet follows the generated cache.
- name: ODC1 c.1242-2A>G
gene:
preferred_term: ODC1
term:
id: hgnc:8109
label: ODC1
variant_type: single nucleotide variant
type: Splice acceptor
description: Recurrent de novo intron-11 splice acceptor variant reported in three individuals. The predicted splice consequence is not represented as an experimentally demonstrated transcript change. No formal ACMG class is assigned from the case narrative alone.
evidence:
- reference: PMID:37092498
reference_title: Two New Cases of Bachmann-Bupp Syndrome Identified through the International Center for Polyamine Disorders.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: After trio exome sequencing, she was diagnosed as having a de novo heterozygous variant in the ODC1 gene, c.1242-2A > G, (IVS11-2A > G), which is predicted to destroy a canonical splice acceptor site in intron 11.
explanation: The paper describes a predicted acceptor disruption and de novo origin.
- reference: PMID:41410504
reference_title: 'Genetic and Phenotypic Features of the Five Known Polyaminopathies: A Critical Narrative Review.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: One variant, c.1242–2A>G (p.IVS11–2A>G), has been reported in 3 individuals (Michael et al., 2023; VanSickle et al., 2021).
explanation: A recurrent allele is not proof of a mutational hotspot or shared founder.
- name: ODC1 c.1252C>T (p.Gln418Ter)
gene:
preferred_term: ODC1
term:
id: hgnc:8109
label: ODC1
variant_type: single nucleotide variant
type: Nonsense
description: De novo premature-termination variant reported in patient 9 of the 2021 cohort. The table uses NM_001287190.1. No formal ACMG class is inferred solely from inclusion in this case series.
evidence:
- reference: PMID:34477286
reference_title: 'Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Trio WES demonstrated a de novo heterozygous variant in the ODC1 gene, c.1252C>T (p.Gln418*), which causes premature termination of the protein.
explanation: Patient-level molecular result establishes the variant and predicted protein consequence.
- name: ODC1 c.1307_1311delinsT (p.Thr436IlefsTer11)
gene:
preferred_term: ODC1
term:
id: hgnc:8109
label: ODC1
type: Deletion-insertion causing frameshift
description: De novo frameshift from the 2023 patient narrative. The table contains c.1307_3111delinsT, whereas the narrative gives c.1307_1311delinsT, consistent with the reported protein effect. The narrative spelling is retained; no formal ACMG class is inferred.
evidence:
- reference: PMID:37092498
reference_title: Two New Cases of Bachmann-Bupp Syndrome Identified through the International Center for Polyamine Disorders.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: After trio whole genome sequencing, she was diagnosed as having a de novo heterozygous variant in the ODC1 gene, c.1307_1311delinsT (p.Thr436IlefsX11), which is predicted to shift the reading frame, resulting in premature truncation of the protein on genome sequencing.
explanation: The narrative provides the allele; its predicted reading-frame effect is distinguished from a directly assayed transcript or protein.
- name: NM_001287189.1:c.1217A>T (p.Tyr406Phe)
gene:
preferred_term: ODC1
term:
id: hgnc:8109
label: ODC1
variant_type: single nucleotide variant
type: Missense
clinical_significance: UNCERTAIN_SIGNIFICANCE
description: Reported in an individual with an atypical phenotype, without elevated erythrocyte ODC activity. This remains an uncertain variant and is not counted as a confirmed BABS allele or as evidence of DFMO responsiveness. The paper contradicts itself about population presence; no frequency assertion is imported.
evidence:
- reference: PMID:40167220
reference_title: 'Repurposing With Purpose: Treatment of Bachmann-Bupp Syndrome With Eflornithine and Implications for Other Polyaminopathies.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: She was originally connected to our team at the age of 5 months, when exome sequencing identified a de novo heterozygous variant in the ODC1 gene, c.1217A > T (NM_001287189.1), which is predicted to result in the amino acid substitution (p.Tyr406Phe).
explanation: The molecular result is a de novo missense finding, not an established diagnosis.
- reference: PMID:40167220
reference_title: 'Repurposing With Purpose: Treatment of Bachmann-Bupp Syndrome With Eflornithine and Implications for Other Polyaminopathies.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: was classified as a variant of uncertain significance.
explanation: The source explicitly assigns uncertain significance; no population-frequency assertion is adopted.
- reference: PMID:40167220
reference_title: 'Repurposing With Purpose: Treatment of Bachmann-Bupp Syndrome With Eflornithine and Implications for Other Polyaminopathies.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Unlike other patients with BABS who demonstrated elevated baseline ODC activity, the patient’s ODC activity levels were not greater than unaffected control patients’ samples (Figure 1).
explanation: The negative biochemical result limits the BABS interpretation; it does not alone establish a benign ACMG class.
datasets:
- accession: bioproject:PRJNA640661
title: Multi-transcriptomic analysis of diesel particulate matter exposed cerebral organoids
data_type: SINGLE_CELL_RNA_SEQ
description: Broader cerebral-organoid project cited for the ODC1 developmental-expression analysis. The repository title describes a diesel-particle exposure experiment; this is not a BABS patient or ODC1-mutant dataset, and the cited ODC1 paper does not identify the exact subset reused.
publication: PMID:33806076
notes: The accession resolves in NCBI BioProject. No sample count, disease-control contrast, or exposure effect is assigned to the ODC1 analysis without subset-level provenance.
evidence:
- reference: PMID:33806076
reference_title: Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development.
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: Data are available within BioProject PRJNA640661.
explanation: The paper names this project as the data location; the project’s broader scope limits disease-specific interpretation.
- reference: url:https://www.ncbi.nlm.nih.gov/bioproject/PRJNA640661
reference_title: Homo sapiens (ID 640661) - BioProject - NCBI
supports: SUPPORT
evidence_source: IN_VITRO
snippet: We used multiple RNAseq platforms (ribosomal reduced, single-cell, and direct nanopore) to examine the toxicogenomic effects of diesel particulate matter(DPM) on human cerebral organoids.
explanation: The BioProject describes a broader multi-platform exposure experiment. Its relationship to the ODC1 expression analysis is reuse of a referenced project, not a BABS disease cohort.

📚

References & Deep Research

References

18

PMID:36007106

Bachmann-Bupp Syndrome.

No top-level findings curated for this source.

PMID:30239107

Novel de novo pathogenic variant in the ODC1 gene in a girl with developmental delay, alopecia, and dysmorphic features.

No top-level findings curated for this source.

PMID:30475435

Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities.

No top-level findings curated for this source.

PMID:34282722

Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease.

No top-level findings curated for this source.

PMID:37469105

Bachmann-Bupp syndrome and treatment.

No top-level findings curated for this source.

PMID:41410504

Genetic and Phenotypic Features of the Five Known Polyaminopathies: A Critical Narrative Review.

No top-level findings curated for this source.

PMID:31249027

Biochemical features of primary cells from a pediatric patient with a gain-of-function ODC1 genetic mutation.

No top-level findings curated for this source.

PMID:8618048

Modulation of murine hair follicle function by alterations in ornithine decarboxylase activity.

No top-level findings curated for this source.

PMID:2928784

Prevention of rapid intracellular degradation of ODC by a carboxyl-terminal truncation.

No top-level findings curated for this source.

PMID:34477286

Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome.

No top-level findings curated for this source.

PMID:37092498

Two New Cases of Bachmann-Bupp Syndrome Identified through the International Center for Polyamine Disorders.

No top-level findings curated for this source.

PMID:40167220

Repurposing With Purpose: Treatment of Bachmann-Bupp Syndrome With Eflornithine and Implications for Other Polyaminopathies.

No top-level findings curated for this source.

PMID:33806076

Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development.

No top-level findings curated for this source.

PMID:40382142

Monitoring ODC activity and polyamines in Bachmann-Bupp syndrome patient biological samples.

No top-level findings curated for this source.

PMID:36443247

Improvement of dermatological symptoms in patients with Bachmann-Bupp syndrome using difluoromethylornithine treatment.

No top-level findings curated for this source.

PMID:41925768

The remarkable legacy of the K6/ODC mouse: mechanisms of polyamine-promoted tumorigenesis revealed.

No top-level findings curated for this source.

PMID:11533243

The ornithine decarboxylase gene is essential for cell survival during early murine development.

No top-level findings curated for this source.

PMID:30723320

Biallelic pathogenic variants in the lanosterol synthase gene LSS involved in the cholesterol biosynthesis cause alopecia with intellectual disability, a rare recessive neuroectodermal syndrome.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Review Bachmann-Bupp clinical cohorts, ODC1 variants, experimental models and treatment evidence · 2026-09-27T17:25:10Z · View source

Reviewed the existing entry, both prior CREATE/EDIT histories, and the matching claude_code deep-research report and citation sidecar. This is a Mendelian ODC1 gain-of-function disorder, eligible for the review sweep excluding infectious and environmental diseases/poisonings. Rebased onto origin/main before edits and again before finalization (116b24e6501). Evidence consumption: read the recovered scientific bodies and relevant tables of PMID:37092498, 34477286, 40167220, 37469105, 41410504, 33806076, 11533243, 40382142, 34282722 and 41925768, plus the BABS-relevant clinical sections of the full LSS article PMID:30723320. Read the remaining cited cached abstracts. Read GeneReviews PMID:36007106 and its accessible chapter opening/table; complete chapter cache retrieval encountered a challenge page, so no challenge content is committed or cited. Primary clinical tables supply the additional phenotypes and denominators. Generated and read the published erratum PMC10479987, ClinVar RCV001263232, and BioProject PRJNA640661 source records. All reference files were generated by fetch-reference or normalized by repository tooling, never hand-edited. Content-completeness assessment: 1. Phenotypes — adequate after adding 25 features (51 total), including prenatal polyhydramnios, specific craniofacial and ectodermal features, cryptorchidism, behavioral findings, brain abnormalities and specific congenital cardiac defects. Frequency bands now use identified small-cohort denominators where available, with overlapping cohorts, stillbirth inclusion and age dependence stated. Corrected seizures from a qualitative VERY_RARE assignment to the reported 1/12 series and onset at 14 years, rather than age 23 at evaluation. Alopecia 12/12 and developmental delay 8/8 liveborn are observations in cited series, not established population penetrance. Vascular skin abnormality and cutaneous cyst replace unsupported narrower capillary-malformation and epidermoid-cyst bindings. 2. Subtypes — N/A: no established mechanistically distinct BABS subtypes in the sources. ODC1 G84R has association and recombinant-enzyme evidence but is not established as a separate Mendelian diagnosis or a BABS allele. 3. Pathophysiology — adequate with explicit limits. C-terminal truncation, impaired degradation, enzyme accumulation and polyamine excess are distinguished from provisional neural progenitor hypotheses. Skin-restricted K6/ODC is distinct from the ODC-ER model used to study stem-cell recruitment; the latter finding does not establish the K6 alopecia mechanism. Odc1-null early embryonic apoptosis is contextual evidence, not a BABS model or a human therapeutic threshold. Added patient fibroblast, reference-line organoid and engineered truncated-enzyme cell models. Treatment/model links are retained only where supported. 4. Treatments/trials — adequate. Eflornithine evidence is uncontrolled, includes concurrent dietary intervention, and does not establish restored brain architecture, a developmental effect size or an optimal window. The 2025 review describes six treated individuals; published dermatology cases are not assumed to be additional nonoverlapping patients. Added physical, speech and occupational therapies and completed GeneReviews surveillance domains. The recorded ClinicalTrials.gov condition search returned zero studies; oncology/chemoprevention NCT identifiers from the research are not BABS trials. Experimental AMXT1501/polyamine-transport and microbiome proposals lack BABS clinical efficacy evidence. Removed the unsupported blanket DFMO contraindication in Snyder-Robinson syndrome. 5. Genetics — adequate. Five variant records separate an explicitly qualified ClinVar pathogenic assertion, reported truncating/splice alleles without invented ACMG classes, and a p.Tyr406Phe VUS with normal erythrocyte ODC activity. The published 2021-table erratum establishes c.1342A>T, not A>G. Recurrent splice effects remain predicted when not experimentally assayed; inconsistent table spellings are not silently treated as distinct alleles. 6. Biomarkers/diagnostics — adequate. Molecular diagnosis is distinguished from supportive metabolomics; no unsupported claim that metabolomics typically precedes sequencing remains. ODC activity fold changes are scoped to the index patient's specific preparations. Plasma polyamine findings are not generalized to every tissue. Acisoga remains an exploratory pharmacodynamic marker without an established specificity or clinical-outcome relationship. 7. References — adequate. Recovered full text materially changes clinical and mechanistic curation; high-value sources and GeneReviews are represented. PMID:41931584 and the PubMed erratum record yielded no quotable text on attempted fetches and are excluded; the full erratum URL is cited instead. The BioProject is verified against NCBI and described as a broader organoid exposure study, not a BABS patient dataset; its total sample count is not assigned to the cited ODC1 expression analysis. 8. Overall consumption — adequate for central research themes after correcting source errors and adding previously omitted clinical and experimental content. Secondary GeneReviews-table differentials CHD3, DCAF17, PAK1 and PTEN remain non-blocking leads without cached discriminating chapter passages; the existing molecularly informative polyaminopathy and LSS differentials are retained and corrected. No cancer surveillance standard is inferred from a suggestion or transgenic tumor susceptibility. Source discrepancies resolved include the published variant correction, seizure onset versus current age, table/narrative frameshift spelling, the 2026 review's inconsistent developmental-delay percentage and absence rows contradicted by primary cases, and the distinction between ODC-ER and K6/ODC skin models. Where a source is internally inconsistent, unsupported conclusions are not adopted. Validation before final commit: schema, ontology terms and references passed (233 snippets, 251 titles; zero skipped, unavailable or failed items); scoped disorder tests passed (2 tests); causal-target, coarse-phenotype and GeneReviews baseline checks passed; scoped snippet grading found no violations. Formatting preserved the parsed disorder content. Final commit hooks and independent PR review remain separate gates. Historical provenance archive follows. These are the original entry's process notes, preserved verbatim as an obsolete record of the earlier curation. Their statements about missing full text, five frequency bands, unconsumed variants and unavailable case counts are superseded by the review above and MUST NOT be interpreted as the current evidence assessment. Scope, provenance and named-entity-confusion notes for this entry. (1) GeneReviews baseline. A GeneReviews chapter exists (PMID:36007106, "Bachmann-Bupp Syndrome", Bupp, Michael, VanSickle, Rajasekaran and Bachmann, 2022 Aug 25) and was used as the mandatory phenotype baseline. Every clinical feature named in its Clinical Characteristics paragraph is represented in the phenotypes block: the distinctive alopecia, global developmental delay in the moderate to severe range, hypotonia, nonspecific dysmorphic features, behavioural abnormalities (autism spectrum disorder and attention-deficit/hyperactivity disorder are curated as two separate phenotype entries), feeding difficulties, the birth-hair-then-clump-loss natural history, and the rare findings of later-childhood seizures and conductive hearing loss. Features named only in its Management paragraph (obesity, constipation, refractive error, strabismus, follicular cysts, congenital heart defects) are also curated, sourced to that same paragraph. Nothing in the GeneReviews abstract is knowingly omitted. The cached record is the structured PubMed abstract, not the full chapter body, so features present only in the chapter body may still be missing. (2) Named-entity-confusion discipline - this is the central risk for ODC1. ODC1 is a heavily studied oncology and polyamine-pharmacology gene, and the overwhelming majority of its literature is cancer biology, DFMO chemoprevention or basic polyamine metabolism with no bearing on this neurodevelopmental disorder. Every citation in this entry was checked to be either (a) about genotyped human BABS patients, (b) the disease-specific review literature from the International Center for Polyamine Disorders, or (c) the C-terminally-truncated-ODC animal model that is the accepted mechanistic model of this exact lesion. No chemoprevention trial (colorectal adenoma, skin cancer) and no neuroblastoma efficacy trial is cited as evidence for a BABS claim; the neuroblastoma literature is referred to only where the BABS papers themselves invoke it as the source of the paediatric dose and safety data, and that is stated explicitly in the eflornithine treatment entry rather than cited directly. (3) The direction-of-effect trap. BABS is a GAIN-of-function disorder. ODC1 knockout and loss-of-function data must not be imported as if they modelled the patient state, and none is. The one loss-of-function observation that is curated (the ODC G84R hypomorph in PMID:33806076) is deliberately modelled as a differential-diagnosis entry and as a contrast, never as support for a BABS mechanism, because the same paper reports that the two directions have opposite predicted consequences for neural progenitors: gain-of-function with over-proliferation and loss-of-function with depletion. Likewise the mouse evidence used here is the K6/ODC transgenic, which carries a premature stop codon producing a carboxyl-truncated, stabilised ODC - the same class of lesion as the human variants - and not an Odc1 null. (4) Mouse-model fidelity and its limits. The K6/ODC mouse (PMID:8618048, reviewed in PMID:41925768) reproduces the alopecia and follicular cysts and their reversal with DFMO, and was the direct basis for the drug-repurposing decision. It is a keratin-6-promoter-driven, skin-restricted transgenic, whereas BABS patients express the truncated enzyme in every tissue, so it models only the cutaneous arm. All neurodevelopmental claims in this entry therefore rest on human evidence, and the mouse evidence carries evidence_source MODEL_ORGANISM and is confined to the hair-follicle and follicular-cyst nodes. (5) Frequency derivation. Frequency bands are recorded on only five phenotypes and are omitted everywhere else. The five that carry a band are derived from GeneReviews qualitative language using the standard prose-to-FrequencyEnum mapping: features the chapter says the syndrome "is characterized by" (alopecia, global developmental delay, hypotonia) take VERY_FREQUENT, and features it explicitly calls "rare findings" (later-onset seizures, conductive hearing loss) take VERY_RARE. No numeric denominator underlies these bands. The published case denominators are tiny and inconsistent: PMID:30475435 reported four patients, PMID:30239107 one, PMID:34477286 four more, PMID:37092498 two more, and PMID:34282722 described the cohort as "less than 10 known cases". The deep-research report surfaced a per-feature frequency table (n=9) from the body of the GeneReviews chapter, giving alopecia 9/9, dysmorphic features 9/9, developmental delay 8/8, hypotonia 8/8, macrocephaly 6/9 and seizures 1/8. Those numbers are consistent with the bands recorded here, but the cached PubMed record for PMID:36007106 contains only the structured abstract, so the table itself could not be verified byte-exactly and its numbers are therefore NOT asserted as evidence anywhere in this entry. A future curator with access to the full chapter should be able to upgrade these bands to denominator-backed ones. (5a) Two phenotypes that the deep-research report supports but this entry does NOT curate, because no cached abstract contains a quotable sentence for them. Polyhydramnios (reported at 55-80% of pregnancies) and the HPO annotation set for OMIM:619075 (hypertelorism, high forehead, sparse eyelashes, cryptorchidism, ptosis and others) are both real and both well-attested in the sources the report cites, but grepping every cached reference used by this entry for "polyhydramnios" returns zero hits, and the HPOA annotations are database records rather than quotable abstract text. They are omitted rather than sourced to a citation that does not contain them. This is a recorded gap, not a claim that the evidence does not exist. (6) Prevalence derivation. No population-based rate has ever been published. The prevalence record therefore uses the qualitative ULTRA_RARE tier with the case-count denominators recorded in its notes. The counts themselves conflict across sources and are not summed into a single asserted total. (7) No structured-source (ORPHA:544488, CGGV, CGDS) citation is included. Neither an ORPHA_544488 nor any ClinGen cache file for ODC1 is present in references_cache, and generating one would require a data MANIFEST bump, which is blocked by the stale, un-refreshable pins tracked in #7622. The structured-source citation is skipped rather than fabricated. (8) Two claims that are true in the literature but are NOT asserted here for lack of a quotable BABS-specific source. First, an exact number of reported BABS patients: the sources disagree and none of the cached abstracts states a current cumulative total, so no total is asserted. Second, an oncology surveillance recommendation: PMID:30475435 raises cancer surveillance only as a suggestion ("cancer surveillance may be important in this disorder") and the GeneReviews surveillance paragraph does not include tumour screening, so this is curated as a discussion item and an explicitly hedged treatment note rather than as a recommendation. (9) Prenatal presentation. PMID:41931584 reports a prenatally diagnosed BABS fetus with macrocephaly and a ventricular septal defect. That record has no abstract in PubMed - fetching it yields only a bibliographic header with no quotable body - so it is not cited for any evidence item and its cache file is deliberately not committed. The congenital heart defect phenotype is instead sourced to the GeneReviews management paragraph, which does list congenital heart defects. The same applies to PMID:34318586 (LSS hypotrichosis families), which also has no abstract; the LSS differential is therefore sourced to PMID:30723320 instead. (10) Scope of differential_diagnoses. Six differentials are modelled. The four other recognised polyaminopathies (Snyder-Robinson syndrome, Faundes-Banka syndrome, DHPS deficiency and DOHH disorder) are bound to MONDO terms, because PMID:41410504 explicitly groups all five as one family that "share many similar clinical phenotypes" - which is exactly the setting in which evidence gets misattributed. Each is discriminated by its gene, its direction of effect and its position in the polyamine pathway. LSS-related alopecia-intellectual disability syndrome 4 is bound as the closest mimic outside the pathway, discriminated on congenital versus non-congenital alopecia. The sixth, the ODC1 loss-of-function/hypomorphic neurological phenotype, is left UNBOUND: it is the single most dangerous confusion for this entry because it involves the same gene, but it has no OMIM entry and no MONDO term of its own, so binding it to any existing term would be a fabrication. Note that MONDO:0800159 (disorder of polyamine metabolism) and MONDO:0100500 (Mendelian neurodevelopmental disorder) are this entry's own asserted superclasses and are therefore deliberately absent from the differential list. Four further differentials named in the GeneReviews differential table and relayed by the deep-research report (CHD3 / Snijders Blok-Campeau syndrome, DCAF17 / Woodhouse-Sakati syndrome, PAK1 / IDDMSSD and PTEN / Cowden syndrome) are NOT modelled here, because that table lives in the chapter body and not in the cached abstract, so no verbatim discriminating sentence is available for any of them from a reference this entry cites. They are named here so the next curator knows where to look rather than having to rediscover them. (11) Provenance of this entry. The deep-research provider was claude_code, run via `just research-disorder claude_code Bachmann-Bupp_Syndrome` on 2026-08-01 (report at research/Bachmann-Bupp_Syndrome-deep-research-claude_code.md; 8 web searches, 77 turns, 38 citations). The report was read in full and treated as leads rather than ground truth: every PMID it supplied was fetched with `just fetch-reference` and every snippet used here was copy-pasted from the cached file. Claims the report made that could not be verified against a cached abstract - the GeneReviews frequency table, the GeneReviews differential table, the cumulative case counts of 12 published / 18 worldwide across eight countries, polyhydramnios frequencies, ClinVar accessions and the full variant table - are recorded in these notes as leads and are not asserted as evidence anywhere in the entry.

Create: Bachmann-Bupp_Syndrome · 2026-08-01T14:40:36Z · View source

Created kb/disorders/Bachmann-Bupp_Syndrome.yaml for Bachmann-Bupp syndrome (MONDO:0033642, ODC1 / hgnc:8109). Preflight re-run with 'uv run runoak -i sqlite:obo:mondo info MONDO:0033642 -O obo' confirmed RO:0004003 -> HGNC:8109 ODC1. Deep research provider: claude_code (just research-disorder claude_code Bachmann-Bupp_Syndrome; 18 min, 8 web searches, 77 turns, 38 citations), report committed at research/Bachmann-Bupp_Syndrome-deep-research-claude_code.md and read in full; every PMID it supplied was independently fetched and every snippet copy-pasted from the cached abstract. GeneReviews baseline PMID:36007106 fetched, tagged, and cross-checked feature by feature against the phenotypes block. Curated: 11-node single-root connected pathophysiology DAG (ODC1 C-terminal truncation -> escape from antizyme-mediated ubiquitin-independent 26S proteasomal degradation -> ODC protein accumulation -> elevated enzyme activity -> putrescine accumulation -> N-acetylputrescine elevation / hair follicle dysfunction with bulge stem cell recruitment -> follicular cysts / dysregulated neural progenitor proliferation -> abnormal brain development, plus an ornithine substrate depletion branch); 24 phenotypes with HPO bindings; 3 biochemical markers; genetic section with the gain-of-function variant class and an explicit loss-of-function contrast; 4 treatments led by eflornithine/DFMO with treated-patient outcomes; 3 diagnostic modalities; 2 animal models including the Odc1 knockout curated as a negative control; 2 discussions (HUMAN_MODEL_MISMATCH on the skin-restricted K6/ODC model and its tumour phenotype, KNOWLEDGE_GAP on the neonatal treatment window); 6 differential diagnoses, 5 MONDO-bound (Snyder-Robinson, Faundes-Banka, DHPS deficiency, DOHH disorder, LSS-related alopecia-intellectual disability syndrome 4) and 1 deliberately unbound (the ODC1 loss-of-function neurological phenotype, which has no MONDO term). Validation: 'just validate' clean (schema, terms, references); scripts/check_snippets_verbatim.py 159/159 verified, 0 failed; scripts/check_folded_hyphens.py OK; 'just compliance' 97.7 percent global / 98.0 percent weighted.

Claude Code ▸

1. Disease Information

claude-haiku-4-5-20251001, claude-opus-5[1m] 38 citations 2026-08-01T07:28:29.091479

1. Disease Information

1.1 Overview

Bachmann–Bupp syndrome (BABS) is an ultra-rare autosomal dominant neurodevelopmental disorder caused by de novo gain-of-function variants in the 3′ end of ODC1, the gene encoding ornithine decarboxylase (ODC), the first and rate-limiting enzyme of polyamine biosynthesis. It is one of five recognized "polyaminopathies."

The canonical clinical triad is global developmental delay + hypotonia + a distinctive non-congenital alopecia (hair present at birth, then shed in large clumps within the first weeks of life), usually with macrocephaly/macrosomia, dysmorphic facies, and nonspecific brain MRI abnormalities.

"Bachmann-Bupp syndrome (BABS) is a neurodevelopmental disorder characterized by developmental delay, hypotonia, and varying forms of non-congenital alopecia. The condition is caused by 3'-end mutations of the ornithine decarboxylase 1 (ODC1) gene, which produce carboxy (C)-terminally truncated variants of ODC, a pyridoxal 5'-phosphate-dependent enzyme. C-terminal truncation of ODC prevents its ubiquitin-independent proteasomal degradation and leads to cellular accumulation of ODC enzyme that remains catalytically active." — Bachmann & Bupp, Dev Med Child Neurol 2024 (PMID:37469105)

BABS is of outsized translational significance because it is the first polyaminopathy with a viable targeted treatment: the ODC suicide inhibitor eflornithine (α-difluoromethylornithine, DFMO), repurposed from oncology/trypanosomiasis, moved from disease description (2018) to first patient dosed in 16 months (PMID:40167220).

1.2 Key identifiers

Resource	Identifier
MONDO	MONDO:0033642 — "neurodevelopmental disorder with alopecia and brain abnormalities"
OMIM (phenotype)	619075 — BACHMANN-BUPP SYNDROME; BABS
OMIM (gene)	165640 — ORNITHINE DECARBOXYLASE 1; ODC1
Orphanet	ORPHA:544488
MedGen	C5436741 / UID 1775930
UMLS	C5436741
GARD	0017987
SNOMED CT	1222658006
ICD-10	E72.4 (disorders of ornithine metabolism) — via Orphanet mapping
ICD-11	Not established in retrieved sources; likely maps under 5C50.Cx (disorders of ornithine metabolism) — verify before asserting
MeSH	No dedicated MeSH descriptor found; indexed via Ornithine Decarboxylase (D009952) + Alopecia + Neurodevelopmental Disorders
Gene	ODC1 — HGNC:8109, NCBI Gene 4953, Ensembl ENSG00000115758, UniProt P11926

1.3 Synonyms

Bachmann–Bupp syndrome (BABS) — the eponymic/clinical name in wide use
Neurodevelopmental disorder with alopecia and brain abnormalities (NEDABA) — the MONDO/OMIM/MedGen preferred label
ODC1-related neurodevelopmental disorder — GeneReviews dyadic name
Global developmental delay–alopecia–macrocephaly–facial dysmorphism–structural brain anomalies syndrome — Orphanet label
Gene aliases in NCBI: ODC, BABS, NEDBA, NEDBIA

1.4 Provenance of information

Essentially all knowledge is derived from individual patient reports and small case series, not from EHR-scale or registry-scale aggregation. The aggregating structures are: - GeneReviews chapter (Bupp, VanSickle, Bachmann; PMID:36007106, NBK583220) - The International Center for Polyamine Disorders (ICPD) — a Corewell Health / Michigan State University collaboration with the Snyder-Robinson Foundation, which performs "comprehensive data generation and local as well as remote sample collection from patients with known or suspected polyamine disorders around the world" (PMID:37092498) - A 2026 systematic narrative review of all five polyaminopathies (PMID:41410504)

There is no EHR-derived cohort, no ICEES/COHD comorbidity signal, and no population registry for BABS.

2. Etiology

2.1 Primary cause

Heterozygous, almost always de novo, gain-of-function variants clustered in the 3′ end of ODC1 — specifically in exon 12 or the intron 11 splice sites immediately preceding it — that remove or disrupt the C-terminal ~37-residue degradation domain (amino acids ~425–461) of the 461-aa ODC protein.

Because these variants fall in the last exon, the transcripts escape nonsense-mediated decay; a truncated but catalytically fully active ODC protein is produced that can no longer be degraded by the antizyme/26S-proteasome route. The result is massive cellular accumulation of active ODC and putrescine overproduction.

"We hypothesized that this new mutation (c.1342 A>T) leads to a C-terminal truncation variant of the ODC protein that is resistant to normal proteasomal degradation, leading to putrescine accumulation in cells." — Schultz et al., Biochem J 2019 (PMID:31249027)

This is a true molecular gain of function (protein stabilization → enzyme over-accumulation), not haploinsufficiency. Critically, ODC1 loss-of-function produces a mechanistically opposite and phenotypically distinct picture (see §4.4).

2.2 Genetic risk factors

Causal variants: see §4.2. All reported pathogenic variants are 3′-end truncating/splice variants.
Susceptibility loci / modifier genes: None identified. No GWAS, no reported modifiers.
Parental age: Not studied. A paternal-age effect is plausible for a de novo dominant condition but has not been demonstrated for BABS.
Family history: Essentially absent — all molecularly tested probands to date have de novo variants.

2.3 Environmental risk factors

None known. BABS is a monogenic Mendelian disorder with no established environmental contribution to occurrence. Polyhydramnios (58–80% of pregnancies) is a consequence, not a cause.

One theoretical, unproven environmental modifier exists on the downstream side: dietary and gut-microbial polyamines contribute meaningfully to the body polyamine pool, and Rodan et al. explicitly proposed them as therapeutic levers:

"Therapies aimed at reducing putrescine levels, including ODC1 inhibitors, dietary interventions, and antibiotics to reduce polyamine production by gastrointestinal flora could be considered as disease-modifying therapies." — Rodan et al., Am J Med Genet A 2018 (PMID:30475435)

This makes dietary polyamine load and gut flora composition biologically plausible severity modifiers, but no human data support this in BABS.

2.4 Protective factors

Genetic protective factors: none identified.
Environmental protective factors: none validated. Polyamine-restricted diets are listed by GeneReviews under "therapies under investigation," not as established protection.

2.5 Gene–environment interactions

No documented GxE interaction. The single actionable "interaction" is pharmacological: the disease phenotype is at least partly reversible by pharmacologic ODC inhibition (eflornithine), demonstrating that the phenotype depends on ongoing polyamine flux rather than solely on fixed developmental damage — a point strongly supported by both the human treatment response (PMID:34282722) and the K6/ODC mouse (PMID:8618048, see §15).

3. Phenotypes

3.1 Frequency table — GeneReviews cohort (n=9 published individuals; primary source)

Feature	Frequency	Suggested HPO term
Alopecia (non-congenital, clumped shedding)	9/9 (100%)	HP:0001596 Alopecia; HP:0002293 Alopecia of scalp
Dysmorphic features	9/9 (100%)	HP:0001999 Abnormal facial shape
Developmental delay	8/8 (100%)	HP:0001263 Global developmental delay
Hypotonia	8/8 (100%)	HP:0001290 Generalized hypotonia
Macrocephaly	6/9 (66%)	HP:0000256 Macrocephaly
Polyhydramnios (pregnancy history)	5/9 (55.5%)	HP:0001561 Polyhydramnios
Skin findings (keratosis pilaris / follicular cysts)	4/8 (50%)	HP:0032152 Keratosis pilaris; HP:0025249 Follicular cyst (verify)
Macrosomia in infancy	2/5 (40%)	HP:0001520 Large for gestational age
Constipation	3/8 (37.5%)	HP:0002019 Constipation
Seizures	1/8 (12.5%)	HP:0001250 Seizure

Source: GeneReviews Table 2 (PMID:36007106, NBK583220).

3.2 Frequency table — 2026 systematic review (n=12 published BABS cases)

Feature	Reported	HPO
Hair abnormalities / alopecia	12/12 (100%)	HP:0001596
Brain MRI abnormalities	12/12 (100%)	HP:0012443 Abnormal brain morphology
Hypotonia	11/12	HP:0001290
Global developmental delay	11/12	HP:0001263
Dysmorphic features	10/12 (83.3%)	HP:0001999
Macrocephaly	9/12 (75%)	HP:0000256
Prenatal polyhydramnios	7/12 (58.3%)	HP:0001561
Skin abnormalities (incl. follicular cysts)	6/12 (50%)	HP:0011368 Abnormal epidermis morphology
Behavioral (ADHD/ASD)	4/12 (33.3%)	HP:0007018 / HP:0000717
Epilepsy	1/12 (8.3%)	HP:0001250

Source: VanSickle et al., Am J Med Genet A 2026 (PMID:41410504, PMC13270430, DOI 10.1002/ajmga.70029).

⚠️ Verification flag: the extracted percentages in this table were internally inconsistent for GDD (listed as "11/12 | 83.3%", where 11/12 = 91.7%). Re-verify the exact n/N against the published Table before committing frequencies from this source to the KB. The GeneReviews table (§3.1) is the safer primary frequency source.

3.3 HPO disease-annotation set (HPOA, OMIM:619075) — with explicit n/N and onset

HPO ID	Term	Frequency	Onset
HP:0002223	Absent eyebrow	5/5	—
HP:0000653	Sparse eyelashes	4/4	—
HP:0001263	Global developmental delay	4/4	—
HP:0000316	Hypertelorism	4/4	—
HP:0000348	High forehead	4/4	—
HP:0001561	Polyhydramnios	4/5	Prenatal
HP:0000750	Delayed speech and language development	3/3	—
HP:0031936	Delayed ability to walk	3/3	—
HP:0001290	Generalized hypotonia	3/3	—
HP:0012520	Dilation of Virchow-Robin spaces	3/4	—
HP:0007018	Attention deficit hyperactivity disorder	2/3	—
HP:0000028	Cryptorchidism	2/3	—
HP:0001558	Decreased fetal movement	2/5	Prenatal
HP:0001792	Small nail	2/4	—
HP:0000508	Ptosis	2/4	—
HP:0000490	Deeply set eye	2/4	—
HP:0002209	Sparse scalp hair	1/4	—
HP:0000256	Macrocephaly	1/1	—
HP:0004488	Macrocephaly at birth	1/4	Prenatal
HP:0001520	Large for gestational age	1/4	Birth
HP:0001319	Neonatal hypotonia	1/1	Neonatal
HP:0002061	Lower limb spasticity	1/1	—
HP:0008872	Feeding difficulties in infancy	1/1	Neonatal
HP:0000407	Sensorineural hearing impairment	1/1	—
HP:0000378	Cupped ear	1/1	—
HP:0000218	High palate	1/1	—
HP:0002904	Hyperbilirubinemia	1/1	Neonatal
HP:0001943	Hypoglycemia	1/1	Neonatal
HP:0007109	Periventricular cysts	1/1; 1/4	Neonatal; —
HP:0002195	Dysgenesis of the cerebellar vermis	1/4	—
HP:0032471	Focal polymicrogyria	1/4	—
HP:0002514	Cerebral calcification	1/4	—
HP:0032152	Keratosis pilaris	1/4	—
HP:0000958	Dry skin	1/4	—
HP:0004209	Clinodactyly of the 5th finger	1/4	—
HP:0000581	Blepharophimosis	1/4	—
HP:0000494	Downslanted palpebral fissures	1/4	—
HP:0000219	Thin upper lip vermilion	1/4	—
HP:0000718	Aggressive behavior	1/3	—

Source: HPO annotation network, ontology.jax.org (OMIM:619075).

Orphanet-sourced HPOA bands (via Monarch, MONDO:0033642) additionally list as Frequent (HP:0040282): HP:0000400 Macrotia, HP:0001488 Bilateral ptosis, HP:0030890 Hyperintensity of cerebral white matter on MRI; and as Occasional (HP:0040283): HP:0000023 Inguinal hernia, HP:0000278 Retrognathia, HP:0001257 Spasticity, HP:0002465 Poor speech.

3.4 Per-phenotype characterization

Alopecia (the pathognomonic sign) — HP:0001596 / HP:0002293 - Type: physical/ectodermal manifestation - Onset: non-congenital, first weeks of life. GeneReviews: hair "is sometimes sparse and sometimes has atypical color" at birth, then lost "in large clumps" within weeks. Eyebrows and eyelashes are typically congenitally absent/sparse (HP:0002223, HP:0000653). - Severity/progression: variable; often near-total scalp alopecia. Reversible on eflornithine. - Frequency: 100% - QoL impact: cosmetic and psychosocial; hair regrowth is consistently reported by families as one of the most visible and valued treatment effects.

Global developmental delay / intellectual disability — HP:0001263, HP:0001249 - Onset: infancy - Severity: "moderate to severe range" (GeneReviews). Independent walking achieved between 17 months and 4 years; three reported individuals remained nonverbal at last report. A 12-year-old (Patient 10) had "moderate developmental delay and intellectual disability, with the ability to read and write" (PMID:37092498) — demonstrating real variable expressivity. - Progression: static/non-degenerative; improvement documented with treatment. - QoL impact: the dominant driver of lifelong disability, caregiver burden, and educational need.

Hypotonia — HP:0001290 / HP:0001319 - Onset: neonatal/infantile; Frequency: ~92–100%; Progression: generally static, improves with therapy and with DFMO. - One patient developed proximal myopathy confirmed on EMG with progressive weakness and wheelchair use for distance (PMID:37092498) — HP:0003701 Proximal muscle weakness.

Macrocephaly / overgrowth — HP:0000256, HP:0001520 - Onset: prenatal to infantile; the index patient had macrosomia and macrocephaly (PMID:30239107); Patient 10 had OFC >99th centile (38 cm) at birth. - Frequency: 66–75%. Absolute or relative macrocephaly (Rodan et al.). - Overgrowth may give way to obesity risk in later childhood (GeneReviews lists caloric management).

Brain MRI abnormalities — HP:0012443 - Frequency: abnormal in essentially all imaged patients, but without a consistent pattern.

"Every patient had a brain MRI performed at some time point, and neuroimaging abnormalities are common, but not with a particular pattern or recurrence of findings." — VanSickle et al. 2021 (PMID:34477286) - Reported findings: white matter signal abnormality (HP:0002500 / HP:0030890), prominent Virchow-Robin/perivascular spaces (HP:0012520), periventricular and germinal-matrix cysts (HP:0007109), porencephalic cysts (HP:0002132), corpus callosum abnormalities incl. hypoplasia of the mid-body (HP:0002079), ventriculomegaly (HP:0002119), cerebellar vermis dysgenesis (HP:0002195), focal polymicrogyria (HP:0032471), cerebral calcification (HP:0002514), hypoplastic optic chiasm, hippocampal volume loss.

Seizures/epilepsy — HP:0001250 - Rare (1/12, 8.3%) but can be severe and late-onset. The oldest reported patient (male, 23 y) developed absence seizures at age 14, evolving to "multiple seizure types but atypical absence, atonic, and generalized tonic–clonic," refractory to ketogenic diet and multiple ASMs (PMID:34477286). This was the first epilepsy report in BABS. - Contrast: epilepsy is far more prominent in Snyder-Robinson syndrome (~63%), which is a useful discriminator (PMID:41410504).

Behavioral phenotypes - ADHD (HP:0007018, 2/3 in HPOA), autism spectrum disorder (HP:0000717), aggression (HP:0000718). Aggregate ADHD/ASD ~33%.

Dermatologic (beyond alopecia) - Follicular cysts (~50% with skin findings), keratosis pilaris (HP:0032152), dry skin (HP:0000958), hypoplastic/small nails (HP:0001792). Follicular cysts directly phenocopy the K6/ODC mouse.

"In both patients, treatment with difluoromethylornithine has resulted in improved dermatologic signs, including regrowth of eyebrow and scalp hair and cessation of recurrent follicular cyst development." — Afrin et al., Pediatr Dermatol 2023 (PMID:36443247)

Feeding / GI - Feeding difficulties in infancy (HP:0008872), aspiration (HP:0002835), constipation (HP:0002019, 37.5%). NG/G-tube may be required.

Sensory - Sensorineural hearing loss (HP:0000407) — present in index patient; refractive error and strabismus (HP:0000486) warrant annual ophthalmology.

Prenatal - Polyhydramnios (HP:0001561) 55–80%, decreased fetal movement (HP:0001558), prenatal ventriculomegaly/cerebral cysts, and — in one 2026 report — macrocephaly plus ventricular septal defect (HP:0001629) detected on second-trimester ultrasound (PMID:41931584).

Genitourinary/skeletal - Cryptorchidism (HP:0000028, 2/3), inguinal hernia (HP:0000023), fifth-finger clinodactyly (HP:0004209), joint hypermobility (HP:0001382).

3.5 Quality of life

No BABS-specific QoL instrument data (EQ-5D, PROMIS, SF-36, PedsQL) exist in the literature. QoL statements are qualitative and family-reported. Reported functionally meaningful post-treatment gains in the index patient — self-feeding with a spoon, sitting unsupported, walker use — are the closest available surrogates for QoL benefit (PMID:34282722, PMID:37469105). This is a genuine evidence gap.

4. Genetic / Molecular Information

4.1 Causal gene

Attribute	Value
Symbol / name	ODC1 / ornithine decarboxylase 1
HGNC	hgnc:8109
NCBI Gene	4953
OMIM gene	165640
Locus	2p25.1
Genomic span (GRCh38.p14)	chr2:10,439,968–10,448,327 (minus strand)
Exons	13
Canonical transcript / protein	NM_002539.3 / NP_002530.1 (461 aa)
Other RefSeqs	NM_001287188.2, NM_001287189.2, NM_001287190.2
UniProt	P11926
EC	4.1.1.17
Cofactor	pyridoxal 5′-phosphate (CHEBI:18405); binding at residues 200, 237, 274–277, 389
Quaternary structure	Homodimer; both monomers contribute residues to each of two active sites
Expression	Broad; highest in testis (RPKM 67.6) and bone marrow (54.4); strongly elevated in proliferating fetal brain ventricular zone

4.2 Pathogenic variants (compiled from all sources)

All are heterozygous, de novo, germline, and all cluster in exon 12 / intron 11 of NM_002539.3 — the 3′ region encoding the C-terminal degron.

#	cDNA (NM_002539.3)	Protein (NP_002530.1)	Type	ClinVar	Source
1	c.1342A>T	p.(Lys448Ter)	nonsense	VCV000983289, Pathogenic	Bupp 2018 index case (PMID:30239107)
2	c.1241+1G>T (IVS11+1G>T)	splice donor loss	splice	VCV000983285, Pathogenic	Rodan 2018 (PMID:30475435)
3	c.1240_1241dupTG	*p.(Trp414Cysfs17)**	frameshift	VCV000983286, Pathogenic	Rodan 2018
4	c.1255C>T	p.(Gln419Ter)	nonsense	VCV000983287, Pathogenic	Rodan 2018
5	c.1242_1263del22 (NC_000002.12:g.10440850_10440871del)	p.(Trp414Ter) as reported	deletion	VCV000983288, Pathogenic	Rodan 2018
6	c.1242-2A>G (IVS11-2A>G)	splice acceptor loss	splice	VCV001074405, Pathogenic (multiple submitters, no conflicts)	Recurrent — ≥3 individuals; VanSickle 2021 (PMID:34477286), Michael 2023 (PMID:37092498)
7	c.1313_1316delCTGT	p.(438Rfs9) as reported*	frameshift	—	VanSickle 2021 Patient 7
8	c.1252C>T	p.(Gln418Ter)	nonsense	—	VanSickle 2021 Patient 9
9	c.1307_1311delinsT	*p.(Thr436Ilefs11)**	indel/frameshift	—	Michael 2023 Patient 11
—	c.1217A>T	p.(Tyr406Phe)	missense	VUS	Bupp 2025 (PMID:40167220) — functionally excluded, see below

⚠️ Nomenclature verification flags for the curator: 1. One secondary source rendered the index variant as "c.1342A>G (p.Lys448*)". The primary paper and ClinVar both say c.1342A>T — use c.1342A>T. 2. Variants #5 and #7 have protein annotations that are inconsistent with their cDNA positions as extracted (c.1242_1263del22 → p.Trp414* and c.1313_1316del → p.438Rfs*9). Re-derive or re-verify from the source tables before committing HGVS protein strings. 3. c.1242-2A>G is the single recurrent variant and is the most likely candidate for a "hotspot" claim.

The instructive negative — functional testing overrides sequence intuition. Bupp et al. 2025 report a patient with the missense VUS c.1217A>T (p.Tyr406Phe) and an atypical presentation whose ODC enzyme activity was "not greater than unaffected control patients' samples," arguing against pathogenicity. This establishes that the biochemical assay, not the variant location alone, adjudicates BABS (PMID:40167220).

4.3 Variant classification, allele frequency, origin

ACMG/AMP classification: BABS variants are classified Pathogenic. Note that PVS1 (null variant) is NOT the operative criterion here — the mechanism is gain-of-function via stabilization, so PS3 (functional evidence: elevated ODC protein/activity/putrescine), PS2 (de novo with confirmed parentage), PM1 (mutational hotspot in the C-terminal degron), and PP4 (highly specific phenotype) carry the weight. Applying PVS1 to an ODC1 3′-truncating variant would be a mechanistic error.
Allele frequency: All reported BABS variants are absent from gnomAD/1000 Genomes/TOPMed (private de novo events). gnomAD constraint metrics (pLI, LOEUF, missense Z) for ODC1 could not be retrieved programmatically for this report and should be looked up directly before being asserted. Note that constraint metrics are of limited interpretive value here, since the disease mechanism is last-exon NMD-escaping GoF rather than haploinsufficiency.
Germline vs somatic: BABS variants are germline (de novo). Separately, somatic ODC1 alterations occur in sporadic tumors (colorectal, gastric, skin, breast, prostate, neuroblastoma) and are not heritable and not BABS (GeneReviews).
Functional consequence: Gain of function via loss of degradation. The truncated enzyme retains full catalytic activity; steady-state protein level rises dramatically.

4.4 Allelic disorders — the loss-of-function arm

ODC1 loss-of-function is mechanistically opposite and phenotypically distinct. Prokop et al. characterized p.Gly84Arg (NC_000002.12:g.10444500C>T, rs138359527, NP_002530.1:p.Gly84Arg):

"A functional enzyme assay…showed a 2.5-fold reduction of enzyme activity because of the variant." "The variant was found at the highest allele frequency within South Asian individuals (0.8%, specifically Gujarati Indians in Houston, TX (1.5%) and Punjabi in Lahore, Pakistan (1%)." — Prokop et al., Genes 2021 (PMID:33806076)

Overall gnomAD frequency 0.23%; TOPMed 0.18%; ~3-fold enrichment in Geno2MP, associated with intellectual disability and seizures. The authors propose a bidirectional model:

"…suggesting gain-of-function variants with neural over-proliferation and loss-of-function variants with neural depletion."

This is an important framing for the KB: ODC1 dosage is bidirectionally constrained in brain development.

4.5 Modifier genes

None validated. Mechanistically plausible but untested candidates within the pathway: OAZ1/OAZ2/OAZ3 (antizymes — the very machinery the truncation escapes), AZIN1 (antizyme inhibitor), AMD1, SRM, SMS, SAT1 (catabolic acetylation/export), and the polyamine transport system.

4.6 Epigenetics

No BABS-specific DNA methylation episignature has been published. (A DNA-methylation episignature screen would be a natural, tractable study.)
Indirect but relevant: polyamines are decarboxylated-SAM donors and chromatin-associated polycations; the K6/ODC mouse literature shows elevated polyamines "alter chromatin remodeling and cell signaling leading to metabolic reprogramming" (PMID:41925768).
Regulatory (eQTL) variation at ODC1 is extensive: Prokop et al. identified 900 variants associated with ODC1 expression across 1,414,872 bases around the locus, including rs2302615 (muscle, p=9.4×10⁻⁷) and rs77575195 (tibial nerve, p=8.3×10⁻⁹), "suggesting a high selection on ODC1 expression levels throughout human evolution" (PMID:33806076).

4.7 Chromosomal abnormalities

None reported. BABS is not caused by CNVs, translocations, or aneuploidy. GeneReviews explicitly states gene-targeted deletion/duplication analysis is "not required" given the gain-of-function mechanism — an intragenic deletion would not produce BABS.

5. Environmental Information

Environmental factors: Not applicable. No toxin, radiation, pollutant, or occupational exposure is implicated in BABS causation.
Lifestyle factors: Not applicable to causation. Post-diagnosis, caloric management matters for the overgrowth/obesity trajectory, and dietary polyamine restriction is an investigational (unproven) adjunct.
Infectious agents: Not applicable. No infectious trigger. (Note the ironic pharmacological link in the other direction: eflornithine's original indication is Trypanosoma brucei gambiense African sleeping sickness, where trypanosomal ODC's stability — it lacks the antizyme system, PMID:7730330 — is the drug's selectivity basis.)

6. Mechanism / Pathophysiology

6.1 The causal chain (upstream → downstream)

[MOLECULAR — trigger]
de novo heterozygous 3'-end ODC1 variant (exon 12 / intron 11 splice site)
↓  (last-exon location → escapes nonsense-mediated decay)
[MOLECULAR]
Production of C-terminally truncated ODC protein lacking the 37-residue
degradation domain (aa ~425–461), but retaining full catalytic activity
↓
[MOLECULAR]
Loss of antizyme-stimulated, ubiquitin-INDEPENDENT 26S proteasomal
degradation of ODC  (GO:0010499)
↓
[MOLECULAR]
Cellular accumulation of enzymatically active ODC protein
(12–17× normal activity in dermal fibroblasts; 125–137× in RBCs)
↓
[MOLECULAR / metabolic]
Excess flux: L-ornithine → putrescine  (GO:0009446 putrescine biosynthetic process;
GO:0004586 ornithine decarboxylase activity)
→ putrescine accumulation; compensatory SAT1 acetylation and cellular export
→ elevated plasma N-acetylputrescine and acisoga
↓
[CELLULAR]
Polyamine-driven dysregulation of cell proliferation and differentiation
   ├── neural progenitor over-proliferation / disturbed neurodevelopment
   └── hair follicle outer root sheath keratinocyte dysfunction
↓
[TISSUE]
   ├── Abnormal cortical/white-matter architecture, perivascular space dilation,
   │   periventricular cysts, callosal dysgenesis
   ├── Hair follicle failure → anagen disruption → clumped hair shedding;
   │   follicular cyst formation
   └── Somatic overgrowth / macrocephaly
↓
[ORGANISM]
Global developmental delay, ID, hypotonia, alopecia, dysmorphism,
± epilepsy, ± behavioral phenotypes

Therapeutic interruption point: eflornithine irreversibly inhibits the accumulated ODC enzyme at the first metabolic node, collapsing putrescine production and normalizing downstream metabolites — with demonstrable reversal of hair, tone, developmental, and even white-matter MRI phenotypes.

6.2 Molecular pathway detail

Polyamine biosynthesis (KEGG hsa00330 arginine & proline metabolism; Reactome "Metabolism of polyamines" R-HSA-351202):

L-arginine → L-ornithine (ARG1/ARG2; also LACC1 from L-citrulline)
L-ornithine --[ODC1, PLP-dependent, EC 4.1.1.17]--> putrescine + CO2   ← RATE-LIMITING; the BABS lesion
putrescine + dcSAM --[SRM]--> spermidine
spermidine + dcSAM --[SMS]--> spermine
(catabolic arm: SAT1 acetylation → PAOX/SMOX back-conversion or export)
(spermidine → hypusination of eIF5A via DHPS + DOHH)

The degradation circuit that BABS breaks (this is the mechanistic heart of the disease and is supported by classic, well-quotable primary literature):

"Ornithine decarboxylase (ODC) was converted from a protein with a short intracellular half-life in mammalian cells to a stable protein by truncating 37 residues at its carboxyl terminus. Cells expressing wild-type protein lost ODC activity with a half-life of approximately 1 hour. Cells expressing the truncated protein, however, retained full activity for at least 4 hours…Thus, a carboxyl-terminal domain is responsible for the rapid intracellular degradation of murine ODC." — Ghoda et al., Science 1989 (PMID:2928784)

"…purified 26S proteasome complex, but not the 20S proteasome, catalyses ODC degradation in the absence of ubiquitin. These results strongly suggest that the 26S proteasome, widely viewed as specific for ubiquitin-conjugated proteins, is the main enzyme responsible for ODC degradation." — Murakami et al., Nature 1992 (PMID:1334232)

And the mapping onto BABS:

"Antizyme binds to transient ODC monomer, which results in the exposure of the ODC carboxy (C)-terminal tail that is subsequently recognized by the 26S proteasome for degradation…the final 37 amino-acid residues of the ODC carboxy (C)-terminal tail constitute an ODC destabilization domain that is required for antizyme-stimulated ODC degradation…If absent/deleted, enzymatically active ODC protein is not properly degraded and consequently accumulates in cells." — Bachmann & Bupp 2024 (PMID:37469105)

Note the elegance for KB modeling: the 1989 Ghoda experiment is, in effect, an in vitro pre-enactment of the human BABS allele — the same 37-residue truncation, three decades earlier.

6.3 Cellular processes

Process	GO term	Direction	Evidence
Ornithine decarboxylase activity	GO:0004586	INCREASED	PMID:31249027
Putrescine biosynthetic process	GO:0009446	INCREASED	PMID:30239107, 31249027
Polyamine biosynthetic process	GO:0006596 (verify label)	INCREASED	PMID:37469105
Proteasomal ubiquitin-independent protein catabolic process	GO:0010499	DECREASED	PMID:1334232, 2928784
Positive regulation of cell population proliferation	GO:0008284	INCREASED	PMID:33806076
Nervous system development / neurogenesis	GO:0007399 / GO:0022008	ABNORMAL	PMID:33806076
Hair follicle development / hair cycle	GO:0001942 / GO:0042633	ABNORMAL	PMID:8618048, 7671221
Protein stabilization	GO:0050821	INCREASED (pathological)	PMID:2928784

6.4 Protein dysfunction

The wild-type ODC monomer is 461 aa; the functional enzyme is an obligate homodimer with two shared active sites (UniProt P11926). BABS variants truncate at residues ~406–448, i.e., after the catalytic core but within the C-terminal degron, which is exactly why the protein is simultaneously stable and active — the worst combination. Prokop et al. note the C-terminus is under strong evolutionary conservation, including a predicted S-farnesylation site at C454, "the most conserved site of all C-terminal amino acids" (PMID:33806076).

This is neither misfolding nor aggregation nor loss of catalysis — it is loss of a degradation signal, a comparatively uncommon disease mechanism worth flagging as such in the KB.

6.5 Metabolic changes

Measured in patients: - RBC ODC enzyme activity: 125–137× control - Primary dermal fibroblast ODC activity: 12–17× control - Putrescine (CHEBI:17148): markedly elevated in fibroblasts and RBCs - Plasma N-acetylputrescine: >97.5th percentile (Z-score vs 866-child reference cohort) - Acisoga [N-(3-acetamidopropyl)pyrrolidin-2-one]: >97.5th percentile - Ornithine (CHEBI:15729) and N-acetylarginine: BELOW the 2.5th percentile at therapy start — consistent with substrate drawdown by the hyperactive enzyme; both normalized on eflornithine (PMID:34282722) - Spermidine (CHEBI:16610) and spermine (CHEBI:15746): "otherwise normal polyamine levels" in plasma clinical metabolomics (PMID:30475435) — an important specificity point: the biochemical signature is putrescine/N-acetylputrescine-selective, not a global polyamine elevation.

"Plasma clinical metabolomics analysis demonstrates elevation of N-acetylputrescine, the acetylated form of putrescine, with otherwise normal polyamine levels." — Rodan et al. 2018 (PMID:30475435)

"…we detected exceptionally high ODC enzyme activity in both primary dermal fibroblasts (12-17-fold of controls) and red blood cells (RBCs) (125-137-fold of controls), using a specific 14C radioactive ODC activity assay." — Schultz et al. 2019 (PMID:31249027)

6.6 Immune system involvement

Not a primary feature of BABS. No immunodeficiency or autoimmunity reported. However, ODC1/polyamine metabolism is deeply embedded in myeloid immunometabolism — LACC1 converts L-citrulline to L-ornithine and "serv[es] as a bridge between proinflammatory nitric oxide synthase (NOS2) and polyamine immunometabolism," with LACC1 phenotypes requiring downstream ODC1 (PMID:35978195); and AhR-driven Odc1 transcription suppresses macrophage pyroptosis via spermine-mediated NLRP3 inhibition (PMID:39113799). These make immune phenotyping of BABS patients a reasonable unexplored question, but there is currently no evidence of clinical immune dysfunction — do not assert one.

6.7 Tissue damage mechanisms

BABS is a developmental/dysregulation disorder rather than a degeneration/necrosis disorder. There is no evidence for oxidative stress, ischemia, fibrosis, or necrosis as primary mechanisms. The tissue-level abnormalities are maldevelopmental (cortical architecture, white matter myelination, follicular structure) and — critically — at least partly reversible, which argues against fixed structural destruction:

"Repeat MRI…demonstrated normalization of the cerebral white matter signal with decrease in volume…resolution of all previously noted cysts." — Rajasekaran et al. 2021 (PMID:34282722)

6.8 Molecular profiling

Transcriptomics: Prokop et al. mined fetal-brain RNA-seq and cerebral organoid data; ODC1 expression is "markedly elevat[ed] correlating to early development, while neurons/glia progenitors are still proliferating and maturing," and elevated in ventricular zones and in SOX-marker-positive pluripotent/immature cells (PMID:33806076). No BABS patient transcriptome has been published.
Proteomics: No BABS proteomic dataset. Patient-level protein data are targeted Western blots of ODC (PMID:30239107, PMID:31249027).
Metabolomics: The best-developed omic layer. Untargeted UPLC-MS clinical metabolomics with Z-scores against an 866-child reference cohort is the established diagnostic/monitoring modality (PMID:34282722). Dansyl-chloride derivatization HPLC is the improved reference method for polyamine quantitation (PMID:40382146); the RP-HPLC + ¹⁴C-ornithine ODC activity protocol is published in detail (PMID:40382142).
Lipidomics: none.
Single-cell / spatial: none in BABS patients. Cerebral organoid single-cell data inform the neural-progenitor hypothesis (PMID:33806076).
Functional genomics screens: No BABS-specific CRISPR/RNAi screen. Extensive ODC1 dependency data exist in DepMap for cancer contexts (not disease-relevant here).

6.9 Cell types and anatomical processes — suggested ontology bindings

Entity	Term	Note
Outer root sheath cell	CL:0002561	The K6/ODC transgene's target cell; direct mouse-human correspondence
Keratinocyte	CL:0000312
Neural progenitor cell	CL:0011020	verify canonical label casing
Radial glial cell	CL:0000681	Ventricular zone
Fibroblast (skin)	CL:0002620	The accessible patient biopsy cell for ODC assay
Erythrocyte	CL:0000232	The accessible patient blood cell for ODC activity/putrescine
Hair follicle	UBERON:0002073
Hair follicle bulge	UBERON:0005975	Stem cell niche implicated in K6/ODC
Cerebral white matter	UBERON:0002316
Corpus callosum	UBERON:0002336
Lateral ventricle	UBERON:0002285
Cerebellar vermis	UBERON:0004720

7. Anatomical Structures Affected

7.1 Organ level

Primary: - Central nervous system (UBERON:0001017) — the dominant burden: cerebral cortex (UBERON:0000956), cerebral white matter (UBERON:0002316), corpus callosum (UBERON:0002336), periventricular/germinal matrix regions, lateral ventricles (UBERON:0002285), cerebellar vermis (UBERON:0004720), hippocampus (UBERON:0002421), optic chiasm (UBERON:0000959) - Skin and appendages (UBERON:0002097) — hair follicle (UBERON:0002073), scalp (UBERON:0000403), eyebrow (UBERON:0001710), eyelash (UBERON:0001711), nail (UBERON:0001705)

Secondary / systemic: - Musculoskeletal — generalized hypotonia; one case with proximal myopathy and heel/ankle contractures - Craniofacial skeleton — macrocephaly, high forehead, high palate, retrognathia, cupped/large ears - Gastrointestinal — feeding difficulty, aspiration, constipation - Special senses — cochlea/inner ear (sensorineural hearing loss), eye (ptosis, blepharophimosis, refractive error, strabismus) - Genitourinary — cryptorchidism (testis, UBERON:0000473) - Cardiovascular — one prenatal case with ventricular septal defect (PMID:41931584); the index patient had a cutaneous vascular malformation (PMID:30239107). Not established as a recurrent feature. - Hepatic — hepatic calcifications in one case (PMID:37092498); isolated finding

Body systems: nervous, integumentary, musculoskeletal, digestive, sensory; cardiovascular and hepatobiliary only anecdotally.

7.2 Tissue and cell level

Hair follicle epithelium, specifically outer root sheath keratinocytes (CL:0002561) — the cell type in which the K6 promoter drove ODC in the transgenic mouse that phenocopies BABS skin/hair
Neural progenitor cells (CL:0011020) / radial glia (CL:0000681) of the ventricular and subventricular zones
Oligodendrocytes / myelinating glia — implicated by the white-matter signal abnormalities and their normalization on treatment
Dermal fibroblasts (CL:0002620) and erythrocytes (CL:0000232) — biochemically abnormal and diagnostically accessible

7.3 Subcellular level

Cytosol (GO:0005829) — ODC is a cytosolic enzyme; this is where the pathological accumulation occurs
Proteasome complex (GO:0000502), specifically the 26S proteasome — the machinery whose substrate recognition is evaded
Nucleus (GO:0005634) — polyamines are chromatin-associated polycations

7.4 Localization / lateralization

Brain findings are predominantly bilateral (bilateral paraventricular cysts, bilateral perivascular space dilation, diffuse white matter change), though asymmetric/unilateral lesions occur (right subependymal cyst; focal polymicrogyria; porencephalic cyst). Alopecia is diffuse/generalized with occasional preserved tufts — e.g., "scalp alopecia outside of tuft of long and coarse hair on central posterior scalp" (PMID:37092498).

8. Temporal Development

8.1 Onset

Prenatal: polyhydramnios (55–80%), decreased fetal movement, and — in the 2026 report — second-trimester macrocephaly and VSD detectable by ultrasound (PMID:41931584). Prenatal ventriculomegaly and cerebral cysts have been detected (PMID:37092498).
Birth: macrosomia/large for gestational age, macrocephaly at birth, hair present (may be sparse or atypically colored), congenitally absent/sparse eyebrows and eyelashes.
Neonatal: hypotonia, feeding difficulty, hypoglycemia, hyperbilirubinemia; respiratory distress with NICU stay in one case.
First weeks of life: the defining event — hair loss in large clumps (HP:0003623 Neonatal onset / HP:0011463 Childhood onset for later features).
Infancy onward: developmental delay becomes evident.
Adolescence/adulthood: late-onset epilepsy possible (age 14 in the one reported case).

Onset pattern: congenital/insidious, not acute. Suggested HPO onset term: HP:0003577 Congenital onset for the syndrome; HP:0003623 Neonatal onset for the alopecia.

8.2 Progression

Stages: no formal staging system exists.
Progression rate: the neurodevelopmental phenotype is static-with-slow-acquisition, not neurodegenerative. Skills are gained slowly (walking 17 months–4 years) rather than lost. One patient showed progressive motor decline with myopathy and loss of ambulation over 12 years, indicating that a subset may have a progressive motor course (PMID:37092498).
Course pattern: chronic, lifelong, generally non-progressive on the cognitive axis; epilepsy, when present, can be progressive and refractory.
Duration: lifelong.

8.3 Patterns

Remission: no spontaneous remission. Treatment-induced improvement is well documented — hair regrowth by 1–2 months of eflornithine, motor gains by 4 months, MRI normalization by ~6 months, sustained at >3 years (PMID:34282722, PMID:37469105).
Critical periods: This is the most clinically consequential open question. The mouse data are unusually informative here:

"The ODC inhibitor 2-difluoromethylornithine could prevent hair loss and partially normalize skin histology if administered before the onset of ODC overexpression. 2-Difluoromethylornithine could also reactivate hair growth in animals with complete hair loss." — Soler et al., J Invest Dermatol 1996 (PMID:8618048)

That is: for the follicular phenotype, both prevention and rescue are achievable. Whether the same holds for the neurodevelopmental phenotype — and whether there is a closing window for cortical/white-matter benefit — is unknown and is the central natural-history question for the field. The prenatal-diagnosis capability now demonstrated (PMID:41931584) makes very-early or even prenatal intervention a live question.

9. Inheritance and Population

9.1 Epidemiology

Prevalence: UNKNOWN. GeneReviews: "The prevalence of Bachmann-Bupp syndrome is unknown."
Cumulative reported cases (a moving target — cite the year):

Source (year)	Published cases	Known worldwide
GeneReviews (2022)	9	+3 unreported known to authors
Wikipedia / secondary (Nov 2022)	—	"<30 individuals"
Bachmann & Bupp, DMCN (2024)	11	<30
Bupp et al., AJMG-C (2025)	11	11 + 6 unreported = 17
VanSickle et al., AJMG-A (2026)	12	18, spanning eight countries

Best current statement: ~12 published cases; ~18–20 known worldwide across ≥8 countries as of 2026. Suggested prevalence_class: BELOW_1_IN_1000000 with measure_type: CASES_IN_LITERATURE and prevalence_class: NOT_YET_DOCUMENTED as an alternative honest encoding.
Incidence: not estimable.
Ascertainment caveat: BABS is diagnosable only by sequencing, and the phenotype (DD + alopecia) is distinctive enough that it is likely under-ascertained rather than over-ascertained. Expect the count to rise with exome/genome uptake.

9.2 Inheritance genetics

Pattern: Autosomal dominant (HP:0000006), essentially always de novo.

"All probands reported to date with BABS whose parents have also undergone molecular genetic testing have the disorder as the result of a de novo ODC1 pathogenic variant." — GeneReviews (PMID:36007106)
Penetrance: Believed complete (100%) — but note this is inferred from a tiny, ascertainment-biased de novo case series with no transmitted families; treat "100% penetrance" as provisional.
Expressivity: Variable — spanning nonverbal severe ID to a 12-year-old who reads and writes; epilepsy in only ~8%; macrocephaly in only 66–75%.
Genetic anticipation: Not applicable (not a repeat expansion).
Germline mosaicism: Not documented, but assumed possible; drives the recurrence-risk counseling figure.
Recurrence risk:
Parents test negative → ~1% sibling recurrence risk (germline mosaicism allowance)
A parent carries the variant → 50%
Offspring of an affected individual → 50% (no reported reproduction to date)
Founder effects: None. All variants are private de novo events; the only recurrence (c.1242-2A>G in ≥3 individuals) reflects a mutational hotspot at a canonical splice acceptor, not a shared haplotype.
Consanguinity: No role — dominant de novo mechanism.
Carrier frequency: Not applicable.

9.3 Population demographics

Ethnic/ancestry predilection: None known. Cases span eight countries (PMID:41410504), including the US, EU, and a Chinese prenatal case (PMID:41931584). The index case was described as Caucasian; no ancestry enrichment has been reported.
Geographic distribution: worldwide, no clustering. Apparent geographic distribution reflects where genomic sequencing and the ICPD network reach, not true biology.
Sex ratio: Reported cases include both sexes (the index case and several others are female; the 23-year-old epilepsy case is male; HPOA lists cryptorchidism in 2/3 males). No sex bias is established; the sample is far too small to estimate a ratio. Do not assert one.
Age distribution: reported ages at description range from prenatal/12 months to 23 years. No adult natural-history data beyond age 23.

10. Diagnostics

10.1 Suggestive clinical findings (GeneReviews)

Consider BABS in an individual with: 1. "An unusual pattern of noncongenital alopecia due to sudden-onset hair loss shortly after birth" — the single most specific pointer 2. Developmental delay, typically moderate to severe 3. Hypotonia 4. Supportive: "metabolomic profile showing abnormal polyamine pathway metabolites, including increased N-acetylputrescine"

10.2 Establishing the diagnosis

Requires all three of: consistent clinical/laboratory findings + a heterozygous pathogenic/likely pathogenic ODC1 variant + abnormal polyamine-pathway metabolomics. "Heterozygous pathogenic variants in ODC1 that cause BABS are typically gain-of-function variants."

10.3 Genetic testing

Modality	Utility in BABS	Notes
Exome sequencing (ES)	High — the historical diagnostic route	All index cases found by WES (PMID:30239107, PMID:34282722)
Genome sequencing (GS)	High	Better for the intron-11 splice variants
*Single-gene ODC1* sequencing**	100% detection (9/9) per GeneReviews Table 1	Appropriate when the alopecia+DD gestalt is recognized
Multigene panel	Useful if ODC1 is on the ID/alopecia panel	Confirm gene content before ordering
Deletion/duplication analysis	NOT required	GoF mechanism; CNVs do not cause BABS
Chromosomal microarray	Low yield for BABS (may be done as first-tier DD workup)	Normal in BABS
Karyotype / FISH	Not indicated
mtDNA testing	Not indicated
Repeat expansion testing	Not indicated

Reference sequence for reporting: NM_002539.3 / NP_002530.1.

10.4 Biochemical / omics diagnostics — the BABS-distinctive layer

BABS is one of the few neurodevelopmental disorders with a directly measurable, treatment-responsive enzymatic biomarker. Three assays:

Plasma untargeted clinical metabolomics (UPLC-MS) with Z-scores vs a pediatric reference cohort (n=866). Signature: ↑ N-acetylputrescine, ↑ acisoga, ↓ ornithine, ↓ N-acetylarginine — with normal spermidine/spermine. Suitable for both diagnosis and treatment monitoring (PMID:34282722).
ODC enzyme activity assay — ¹⁴C-ornithine radioassay on red blood cells (125–137× control) or primary dermal fibroblasts (12–17× control). Detailed protocol published (PMID:40382142). This is the assay that adjudicates VUSs (PMID:40167220).
Polyamine quantitation by RP-HPLC with dansyl chloride derivatization (PMID:40382146).

Also: Western blot for ODC protein in RBCs/fibroblasts (elevated).

Sample collection, shipment, consent, and biobanking protocols for international polyaminopathy patients are published (PMID:40382145) and coordinated through the ICPD.

10.5 Imaging, electrophysiology, other clinical tests

Brain MRI — abnormal in nearly all; no pathognomonic pattern. Findings listed in §3.4. MRI also serves as a treatment-response readout (white matter normalization, cyst resolution).
Prenatal ultrasound — polyhydramnios, macrocephaly, ventriculomegaly, cerebral cysts, VSD; can prompt prenatal diagnosis (PMID:41931584).
EEG — indicated only if seizures are suspected.
EMG/NCS — one patient's proximal myopathy was identified by EMG (PMID:37092498).
Audiology (sensorineural hearing loss) and ophthalmology (refractive error, strabismus, ptosis) — annually.
Skin biopsy — for fibroblast culture (research/functional assay), not for histopathology per se. No diagnostic histopathologic signature has been defined; follicular cysts are the notable dermatopathologic finding.
Echocardiogram — only if a cardiac anomaly is suspected; not routine.

10.6 Differential diagnosis (GeneReviews Table 3)

Gene	Disorder	Distinguishing from BABS
*LSS*	LSS-related neurodevelopmental disorder	Alopecia is CONGENITAL (BABS alopecia is post-natal onset)
*CHD3*	Snijders Blok-Campeau syndrome	Ventriculomegaly, joint laxity, different dysmorphic gestalt; no clumped hair loss
*DCAF17*	Woodhouse-Sakati syndrome	Hypogonadism, diabetes mellitus; later onset
*PAK1*	IDDMSSD	Ataxia; no consistent hair/skin abnormality
*PTEN*	Cowden syndrome	Facial trichilemmomas, cancer predisposition
Multiple	Ectodermal dysplasias	Congenital alopecia; dental anomalies (BABS is not associated with dental issues)

Also worth listing: other polyaminopathies — Snyder-Robinson syndrome (SMS, X-linked, ~63% epilepsy, no alopecia), Faundes-Banka syndrome (EIF5A), DHPS deficiency, DOHH disorder. Per the 2026 review, macrocephaly + non-congenital alopecia is what separates BABS from the other four:

"The majority of patients (9/12, 75%) also presented with macrocephaly, which would be considered a distinctive feature of BABS, as this was not reported in any patients with DHPS deficiency, FABAS, or DOHH disorder." (PMID:41410504)

10.7 Screening of asymptomatic individuals

Newborn screening: BABS is not on any NBS panel. It is, however, an intriguing theoretical candidate given (a) a measurable metabolite in blood and (b) an available treatment with a possible early-intervention window — but no NBS pilot exists and this should be framed as a hypothesis, not a recommendation.
Carrier screening: not applicable (de novo dominant).
Cascade screening: not applicable in practice; parental testing is done to establish de novo status and refine recurrence risk.

11. Outcome / Prognosis

11.1 Survival and mortality

No BABS-specific mortality data, survival curves, or life-expectancy estimates exist. The oldest reported patient is 23 years. No deaths have been reported in the published series. Do not assert a life expectancy.
Mortality risk, where present, would be expected to derive from aspiration/feeding complications and refractory epilepsy, not from a disease-intrinsic lethal process.

11.2 Morbidity and function

Dominant morbidity: moderate-to-severe intellectual disability, motor delay/hypotonia, communication impairment (three individuals nonverbal at last report), feeding difficulty, and — in one long-followed patient — loss of independent ambulation.
Functional range is wide: from nonverbal and wheelchair-dependent to literate with moderate ID.
Disability outcomes: lifelong need for special education, PT/OT/SLP, and in some cases assistive mobility and enteral feeding.
No validated QoL instrument data. (ICF-based functional characterization has not been done.)

11.3 Complications

Aspiration and recurrent respiratory events; refractory epilepsy (rare but severe); constipation; obesity secondary to overgrowth; recurrent follicular cysts requiring dermatologic/surgical drainage; refractive error/strabismus; sensorineural hearing loss; contractures/orthopedic sequelae of hypotonia and immobility.

11.4 Cancer risk — an unresolved, important question

ODC1 is a canonical c-Myc target and proto-oncogenic driver; K6/ODC mice develop spontaneous skin tumors (PMID:7671221) and are so tumor-prone they are used as a carcinogen-detection bioassay (PMID:10906419). Somatic ODC1/polyamine dysregulation is pervasive in human cancer.

Rodan et al. therefore raised surveillance explicitly:

"As the ODC1 gene has been implicated in neoplasia, cancer surveillance may be important in this disorder." (PMID:30475435)

However: no malignancy has been reported in any individual with BABS to date, GeneReviews' surveillance table does not include cancer screening, and the 2025 treatment review documents no cancer-monitoring protocol. With ~18 patients and a maximum reported age of 23, the cohort is far too small and young to detect an elevated cancer risk.

Recommended KB framing: encode this as an open mechanistic hypothesis / knowledge gap (kind: KNOWLEDGE_GAP, or HUMAN_MODEL_MISMATCH — strong mouse tumor phenotype, no human confirmation), not as an asserted phenotype. Note the pleasing irony that the treatment (DFMO) is itself an established chemopreventive agent (colorectal adenoma prevention, NCT00118365), so treated patients may be incidentally protected.

11.5 Recovery potential and prognostic factors

Recovery potential is genuinely favorable on treatment and this is the single most important prognostic modifier known:

"She demonstrated remarkable improvement in both neurological symptoms and cortical architecture. She gained fine motor skills with the capacity to feed herself and sit with support." (PMID:34282722) "Treated patients have consistently shown improvement in muscle tone, developmental milestones, and hair regrowth." (PMID:40167220)
Prognostic factors (all inferred, none validated): age at treatment initiation; presence of refractory epilepsy; severity of baseline structural brain abnormality; feeding/aspiration status.
Prognostic biomarkers: N-acetylputrescine Z-score and RBC ODC activity are pharmacodynamic markers with demonstrated normalization on therapy; whether they predict developmental outcome is untested.

12. Treatment

12.1 Targeted therapy — eflornithine (DFMO): the flagship

Attribute	Detail
Agent	Eflornithine / α-difluoromethylornithine (DFMO); brand Iwilfin® (oral, FDA-approved Dec 2023 for high-risk neuroblastoma maintenance)
CHEBI	CHEBI:41948 (eflornithine); CHEBI:749357 (hydrochloride)
NCIT	NCIT:C226 Eflornithine; NCIT:C1579 Eflornithine Hydrochloride
Mechanism	"DFMO is a specific, mechanism-based irreversible (suicide) inhibitor of ODC" (PMID:37469105). Directly inhibits the accumulated pathological enzyme.
Therapeutic modality	`SMALL_MOLECULE`
treatment_term	NCIT:C15986 Pharmacotherapy, with `therapeutic_agent` = CHEBI:41948
target_mechanisms	`INHIBITS` the ODC-accumulation / putrescine-overproduction node — a textbook drug-target pattern
Route/formulation	Oral. Solution (Orbus Therapeutics) and powder (ScinoPharm Taiwan) supplied for clinical use
Dosing (BABS protocol)	"Patients begin at a dose of 500 mg/m²/BID for 3 months, increase to 750 mg/m²/BID for another 3 months, and then finally increase to 1000 mg/m²/BID indefinitely" (PMID:40167220) — modeled on pediatric neuroblastoma dosing
Regulatory status for BABS	Not FDA-approved for BABS. Five US patients treated under FDA-approved single-patient Investigational New Drug (IND) protocols; ≥1 patient treated off-label outside the US. Earlier reports describe compassionate-use approval.
Number treated	6 as of the 2025 report (5 US IND + 1 ex-US); DMCN 2024 reported 4 US + 1 EU
Pharmacology	Rapid renal clearance necessitates sustained high dosing; pediatric range 1.0–6.0 g/m²/day
Safety	"DFMO has extraordinary safety and a specific long-term dosing strategy in children with neuroblastoma even if administered daily for several years." No adverse effects reported in the treated BABS patients. Known class effects to monitor (from oncology/trypanosomiasis use): reversible ototoxicity/hearing loss, myelosuppression, GI upset, and — for topical use — skin irritation. Ototoxicity monitoring is especially relevant given baseline SNHL risk in BABS.

Documented outcomes (index patient, Rajasekaran 2021 / Bachmann 2024):

Domain	Timeline & outcome
Eyebrows	Regrowth at 1 month
Scalp hair	Diffuse regrowth in normal pattern at 2 months
Motor	Self-feeding with spoon (with assistance) and unassisted sitting at 4 months; later walker use
Neuroimaging	"normalization of the cerebral white matter signal with decrease in volume…resolution of all previously noted cysts" at ~6 months
Metabolites	N-acetylputrescine and acisoga normalized at initiation and stayed reduced; ornithine and N-acetylarginine rose into normal range
Skin	"follicular cysts have not recurred for either patient" (PMID:37469105, PMID:36443247)
Durability	"just over 3 years into treatment and on maintenance dosing, the patient continues to show significant clinical improvement."

"This work highlights the strategy of repurposing drugs to treat a rare disease." — Rajasekaran et al. 2021 (PMID:34282722)

Caveats to encode honestly: all outcome data are uncontrolled single-arm case reports (n≤6) with no blinding, no comparator, and no pre-specified endpoints. Developmental gains in a young child on intensified therapy services are confounded. The MRI and metabolite changes are the most objective evidence. There is no randomized or controlled trial of DFMO in BABS, and none is registered on ClinicalTrials.gov (searches for BABS/ODC1/polyaminopathy return only oncology and chemoprevention DFMO trials: NCT00118365, NCT00086736, NCT03536728).

12.2 Other pharmacotherapy / investigational

Other ODC inhibitors and DFMO analogs — listed by GeneReviews as under investigation.
Polyamine transport inhibitors — e.g., AMXT 1501, studied with DFMO in oncology (NCT03536728); mechanistically rational for BABS (blocking uptake of dietary/microbial polyamines that could bypass ODC inhibition) but untested in BABS.
Polyamine-restricted diet — investigational (GeneReviews).
Gut-flora-directed antibiotics to reduce luminal polyamine production — proposed by Rodan et al. (PMID:30475435); never tested.
Anti-seizure medications — standard; note one reported case refractory to multiple agents and the ketogenic diet.

12.3 Advanced therapeutics

Gene therapy / gene editing: none developed. Conceptually, BABS is an allele-selective knockdown target (ASO or siRNA against the mutant allele) rather than a gene-replacement target — the pathology is a toxic stabilized protein, not absent protein. No such program exists. Note the KB's antisense_oligonucleotide_therapy module RNase-H-knockdown paradigm would be the natural conceptual fit if one were ever developed.
Cell therapy, RNA therapy, immunotherapy: none; not applicable.
Pharmacogenomics: no PharmGKB/CPIC guidance for eflornithine relevant to BABS.

12.4 Supportive, rehabilitative, and surgical management (GeneReviews Table 5)

Manifestation	Intervention	NCIT suggestion
Developmental delay / ID	Early intervention (0–3), developmental preschool (3–5), IEP, ABA and behavioral interventions	NCIT:C15315 Rehabilitation
Motor delay / hypotonia	Physical therapy; occupational therapy	NCIT:C15302 Physical Therapy; NCIT:C121351 Occupational Therapy
Speech delay / nonverbal	Speech-language pathology, AAC	NCIT:C159273 Speech Therapy
Feeding difficulties	Feeding therapy; NG/G-tube if needed	NCIT:C15433 Nutritional Support
Obesity / overgrowth	Nutritional intervention, caloric restriction	NCIT:C15447 Dietary Intervention
Constipation	Stool softeners, prokinetics, laxatives	NCIT:C15986 Pharmacotherapy
Epilepsy	Standard ASMs (one case refractory)	NCIT:C15986 Pharmacotherapy
Refractive error / strabismus	Standard ophthalmologic care	NCIT:C49236 Therapeutic Procedure
Hearing loss	Audiologic management / amplification	NCIT:C49236
Follicular cysts	Dermatologic treatment, surgical drainage	NCIT:C15329 Surgical Procedure
Family support	Social work	NCIT:C15747 Supportive Care
Reproductive counseling	Genetic counseling	NCIT:C15240 Genetic Counseling

12.5 Surveillance (GeneReviews Table 6)

Item	Frequency
Growth parameters	Each visit
Nutritional status / safety of oral intake	Each visit
Constipation assessment	Each visit
Mobility & self-help skills (OT/PT)	Each visit
Developmental progress / educational needs	Each visit
Behavioral assessment (ASD, attention, aggression)	Annually
Ophthalmology	Annually or as indicated
Audiology	Annually or as indicated
Complete skin examination for follicular cysts	At least annually
Seizure assessment	As clinically indicated
Family/social work support needs	Each visit

Notably absent from GeneReviews surveillance: cancer screening (see §11.4).

12.6 Treatment strategy

No formal algorithm exists. In practice: 1. Confirm diagnosis (variant + metabolomics + ODC activity — the latter is decisive for VUSs). 2. Institute full multidisciplinary supportive/rehabilitative care immediately. 3. Refer to the ICPD for biochemical characterization and biobanking. 4. Pursue eflornithine via single-patient IND (US) or off-label pathway; escalate 500 → 750 → 1000 mg/m² BID. 5. Monitor pharmacodynamically (N-acetylputrescine Z-score, RBC ODC activity) and clinically (hair, tone, milestones, MRI); monitor for DFMO class toxicity including audiometry and CBC.

Personalized-medicine framing: BABS is a genuine N-of-1-to-N-of-6 precision medicine exemplar — genotype-directed, biomarker-monitored, mechanism-matched.

13. Prevention

13.1 Primary prevention

Not possible. BABS arises from de novo germline variants with no known modifiable determinant. There is no vaccination, no risk-factor modification, and no environmental lever.

13.2 Secondary prevention (early detection)

Genomic: early ES/GS in an infant with the DD + post-natal clumped alopecia gestalt is the practical early-detection route.
Biochemical: plasma N-acetixputrescine on clinical metabolomics can flag the diagnosis; hypothetically a newborn-screening analyte, but no NBS program or pilot exists — this is speculation, not policy.
Prenatal: the 2026 report demonstrates that second-trimester ultrasound findings (macrocephaly, VSD) can trigger prenatal molecular diagnosis (PMID:41931584), and polyhydramnios/ventriculomegaly/cerebral cysts are recurrent prenatal signals.
Rationale for early detection is unusually strong here because a mechanism-matched treatment exists and mouse data show pre-onset DFMO prevents the follicular phenotype (PMID:8618048).

13.3 Tertiary prevention

This is where the actionable prevention lives: eflornithine to prevent progression/persistence of alopecia, hypotonia, follicular cysts, and possibly white-matter injury; aspiration precautions and feeding management; seizure control; caloric management to prevent obesity; annual skin/eye/ear surveillance.

13.4 Genetic screening and counseling

Genetic counseling (NCIT:C15240) is indicated for every family: confirm de novo status by parental testing; counsel ~1% sibling recurrence if parents are negative (germline mosaicism), 50% if a parent carries the variant, 50% for offspring of an affected individual.
Prenatal diagnosis and preimplantation genetic testing (PGT-M) are technically available once the familial variant is known: "Given this risk, prenatal and preimplantation genetic testing may be considered." (GeneReviews)
Carrier screening / population genetic screening: not applicable.

13.5 Immunization, public health, environmental interventions, prophylaxis

Immunization: routine childhood immunizations only; no disease-specific vaccine strategy. No contraindication known.
Public health / environmental interventions: not applicable.
Prophylaxis: no antimicrobial or other prophylaxis indicated. (Prophylactic antibiotics to suppress gut polyamine production is a mechanistic proposal, not a recommendation.)

14. Other Species / Natural Disease

14.1 Taxonomy and orthology

Species	NCBI Taxon	Gene	Notes
Homo sapiens	NCBITaxon:9606	ODC1 (Gene 4953)	The disease species
Mus musculus	NCBITaxon:10090	Odc1	The workhorse model; MGI ID MGI:97402 — verify
Rattus norvegicus	NCBITaxon:10116	Odc1	Antizyme biology largely worked out in rat systems
Danio rerio	NCBITaxon:7955	odc1	Used for other polyaminopathies (DHPS zebrafish model, PMID:39297975/PMC11429087); no BABS zebrafish model published
Trypanosoma brucei	NCBITaxon:5691	ODC	Pharmacologically pivotal — trypanosomal ODC lacks the antizyme degradation system and is thus constitutively stable, the basis for DFMO's selectivity (PMID:7730330)

The C-terminal degron is highly evolutionarily conserved — the predicted farnesylation site C454 is conserved in 215/220 sequences analyzed (PMID:33806076).

14.2 Natural disease in other species

None reported. There is no OMIA entry for a naturally occurring ODC1 disorder in companion animals, livestock, or wildlife found in this search. BABS-equivalent disease in animals exists only as engineered models. Veterinary relevance: nil.

14.3 Comparative biology

The comparative story is unusually clean and is the strongest cross-species evidence in the file: - The K6/ODC transgenic mouse (constitutive ODC in hair-follicle outer root sheath keratinocytes near the bulge stem cell niche) develops alopecia, dermal follicular cysts, excessive skin wrinkling, and enhanced nail growth — i.e., the exact dermatologic tetrad of BABS, including the follicular cysts and nail changes. - Bupp et al. framed the index human case explicitly against this:

"This is the first human case confirming similar symptoms observed in a transgenic ODC1 mouse model first described over 20 years ago." (PMID:30239107) - Evolutionary conservation of the mechanism is complete: the 37-residue C-terminal degron, antizyme-stimulated ubiquitin-independent 26S degradation, and DFMO sensitivity are all conserved mouse↔human. - Divergence: Trypanosoma brucei lacks antizyme-mediated ODC degradation entirely, which is why DFMO is a trypanocide — a natural "phenocopy" of the BABS lesion at the organismal level.

14.4 Transmission

Not applicable. BABS has no zoonotic potential and no cross-species transmissibility.

15. Model Organisms

15.1 The K6/ODC transgenic mouse — the phenocopy model

Construct: bovine keratin 6 promoter driving a mutated ODC transgene in outer root sheath keratinocytes (CL:0002561) of the hair follicle near the bulge stem cell niche. Model type: mammalian, transgenic (gain-of-function overexpression).

Phenotype recapitulation — excellent for the ectodermal arm:

"Effects observed include development of dermal follicular cysts, excessive skin wrinkling, enhanced nail growth, alopecia, and spontaneous tumor development. These results indicate that up-regulation of polyamine biosynthesis can profoundly disturb skin homeostasis and alter susceptibility to neoplastic development." — Megosh et al., Cancer Res 1995 (PMID:7671221)

"These transgenic mice have a normal first hair cycle, but lose their hair completely beginning 2-3 wk after birth… The ODC inhibitor 2-difluoromethylornithine could prevent hair loss and partially normalize skin histology if administered before the onset of ODC overexpression. 2-Difluoromethylornithine could also reactivate hair growth in animals with complete hair loss. Our results suggest that ODC is an important regulatory gene for the mouse hair follicle." — Soler et al., J Invest Dermatol 1996 (PMID:8618048)

Note the striking temporal parallel: mice have a normal first hair cycle then lose hair at 2–3 weeks; BABS infants have hair at birth then shed it in clumps within weeks.

Putrescine — not spermidine/spermine — is the effector, matching the human metabolomic signature:

"The regulatory polyamine in this model appears to be putrescine, the immediate product of ornithine decarboxylase." — Peralta Soler et al., Cancer Res 1998 (PMID:9563478)

Model limitations: (a) expression is skin/follicle-restricted (K6 promoter), so the model does not recapitulate the neurodevelopmental, macrocephaly, hypotonia, or brain-imaging phenotypes — the dominant human morbidity; (b) it is an overexpression model, not a knock-in of the human degron truncation, so the stoichiometry and cell-type distribution differ; (c) the tumor phenotype is prominent in mice but has not been observed in humans with BABS, a genuine human-model mismatch that should be recorded as such rather than translated forward.

Applications: hair-cycle biology; DFMO prevention-vs-rescue timing (directly informs the human critical-period question); skin carcinogenesis; and — as a 30-year retrospective published in 2026 — mechanisms of polyamine-promoted tumorigenesis including stem-cell recruitment, chromatin remodeling, metabolic reprogramming, angiogenesis, and immune modulation (PMID:41925768). Also validated as a sensitive carcinogen-identification bioassay (PMID:10906419).

15.2 The Odc1 knockout mouse — the loss-of-function arm

"Embryonic day E3.5 ODC-deficient embryos were capable of uterine implantation and induced maternal decidualization yet failed to develop substantially thereafter… loss of ODC does not affect cell growth per se but rather is required for survival of the pluripotent cells of the inner cell mass. Therefore, ODC plays an essential role in murine development." — Pendeville et al., Mol Cell Biol 2001 (PMID:11533243)

Odc1^-/-^ is embryonic lethal (peri-implantation); Odc1^+/-^ heterozygotes are "viable, normal, and fertile." This is directly relevant: it shows that (a) ODC1 haploinsufficiency does not produce BABS, reinforcing that BABS is GoF; and (b) complete ODC ablation is not survivable — which sets a theoretical floor on how aggressively ODC can be inhibited therapeutically (though DFMO's clinical safety record indicates a wide window).

15.3 Cellular and in vitro models

Patient-derived primary dermal fibroblasts — the best-characterized BABS cell model. Show 12–17× ODC activity, elevated ODC protein and putrescine; DFMO exposure "reduced the ODC activity and putrescine to levels observed in controls without adversely affecting cell morphology or inducing cell death" (PMID:31249027). This is the in vitro proof-of-concept that directly justified the human trial-of-one — an exemplary bench-to-bedside chain.
Patient RBCs — 125–137× ODC activity; a non-invasive biomarker source.
Cerebral organoids (not patient-derived) — used to link ODC1 expression to neural progenitor proliferation (PMID:33806076).
The 1989 Ghoda C-terminal truncation construct (PMID:2928784) is, retrospectively, the founding in vitro model of the BABS lesion.

15.4 Models that do NOT exist (gaps)

No knock-in mouse carrying a human BABS ODC1 C-terminal truncation allele — this is the most conspicuous missing model, and the only one that could address the neurodevelopmental phenotype and treatment-window question.
No BABS zebrafish model (in contrast to DHPS deficiency, which has one).
No patient-derived iPSC or iPSC-derived neuron/organoid model.
No conditional/neural-specific ODC overexpression model.
No MorPhiC ODC1 null-allele dataset identified.

15.5 Model resources

MGI (mouse), IMPC/KOMP (for Odc1 alleles), Alliance of Genome Resources, ZFIN, IMSR/JAX for strain availability. The ICPD (Corewell Health / Michigan State University / Snyder-Robinson Foundation) is the primary human-sample and biobanking resource (PMID:37092498, PMID:40382145).

Curation Notes: Evidence Classification and Verification Flags

Evidence-source tagging for KB items

Source type	PMIDs
HUMAN_CLINICAL	30239107, 30475435, 34477286, 34282722, 36443247, 37092498, 36007106, 37469105, 40167220, 41410504, 41931584
IN_VITRO	31249027, 2928784, 1334232, 40382142, 40382146
MODEL_ORGANISM	7671221, 8618048, 9563478, 11533243, 10906419, 9688139, 7730330, 41925768
COMPUTATIONAL	33806076 (molecular dynamics, eQTL mining, organoid RNA-seq reanalysis — mixed; split evidence items by claim)
OTHER	36007106 (GeneReviews — expert consensus review)

Do not let model-organism evidence stand alone for human phenotypes. The K6/ODC skin-tumor phenotype in particular must not be carried into the human entry as a phenotype; encode it as a HUMAN_MODEL_MISMATCH discussion.

Items requiring verification before commit

c.1342A>T vs c.1342A>G for the index variant — use A>T (primary source + ClinVar VCV000983289).
Protein HGVS for c.1242_1263del22 and c.1313_1316delCTGT — the extracted protein annotations do not reconcile with the cDNA positions. Re-derive from the source tables.
VanSickle 2026 frequency percentages — internally inconsistent as extracted (11/12 rendered as 83.3%). Prefer GeneReviews Table 2 as the frequency source; re-verify the 2026 table directly.
gnomAD constraint metrics for ODC1 — not retrieved; look up directly if needed (and note their limited relevance to a last-exon GoF mechanism).
ICD-11 code — not confirmed; do not assert.
MGI:97402 for mouse Odc1 — not verified in this session.
HP:0025249 "Follicular cyst" — term ID not verified via OAK; run just validate-terms before commit.
CL:0011020 label casing — OLS returned "Neural progenitor cell"; confirm canonical label with OAK.
Sex ratio — do not assert; the sample is too small.
Cancer risk — encode as knowledge gap, not phenotype.

Suggested module conformance

BABS does not map cleanly onto an existing kb/modules/ entry. The closest conceptual neighbors are metabolic_intoxication_decompensation (an enzymatic block in intermediary metabolism) — but BABS is a chronic overproduction, not an episodic catabolic-stress decompensation, so conformance would be a poor fit. Consider instead that BABS, Snyder-Robinson syndrome, Faundes-Banka syndrome, DHPS deficiency, and DOHH disorder together justify a new polyamine_pathway_dysregulation module and/or a Polyaminopathies Grouping (grouping_basis: SHARED_PATHWAY, with a NECESSARY HAS_BIOLOGICAL_PROCESS criterion on polyamine metabolic process) — the 2026 systematic review (PMID:41410504) is purpose-built as the curated rationale for exactly such a grouping.

Sources

Primary literature (PubMed): - Bupp CP et al. Am J Med Genet A 2018 — PMID:30239107 - Rodan LH et al. Am J Med Genet A 2018 — PMID:30475435 - Schultz CR et al. Biochem J 2019 — PMID:31249027 - Prokop JW et al. Genes (Basel) 2021 — PMID:33806076 - Rajasekaran S et al. eLife 2021 — PMID:34282722 - VanSickle EA et al. Am J Med Genet A 2021 — PMID:34477286 (correction: PMID:37078542) - Bupp C, VanSickle E, Bachmann AS. GeneReviews 2022 — PMID:36007106 / NBK583220 - Afrin A et al. Pediatr Dermatol 2023 — PMID:36443247 - Michael J et al. Med Sci (Basel) 2023 — PMID:37092498 - Bachmann AS, Bupp CP. Dev Med Child Neurol 2024 — PMID:37469105 - Wu B et al. Int J Mol Sci 2024 — PMID:38928047 - Bupp CP et al. Am J Med Genet C 2025 — PMID:40167220 - Schultz CR et al. Methods Enzymol 2025 — PMID:40382142 - VanSickle EA et al. Methods Enzymol 2025 — PMID:40382145 - Nwafor A et al. Methods Enzymol 2025 — PMID:40382146 - VanSickle EA et al. Am J Med Genet A 2026 — PMID:41410504 - Li R et al. Prenat Diagn 2026 — PMID:41931584 - Gilmour SK et al. Amino Acids 2026 — PMID:41925768

Mechanism / model organism: - Ghoda L et al. Science 1989 — PMID:2928784 - Murakami Y et al. Nature 1992 — PMID:1334232 - Megosh L et al. Cancer Res 1995 — PMID:7671221 - Hua SB et al. J Biol Chem 1995 — PMID:7730330 - Soler AP et al. J Invest Dermatol 1996 — PMID:8618048 - Peralta Soler A et al. Cancer Res 1998 — PMID:9563478 - Chen Y et al. Toxicol Lett 2000 — PMID:10906419 - Pendeville H et al. Mol Cell Biol 2001 — PMID:11533243 - Wei Z et al. Nature 2022 (LACC1–NOS2–ODC1) — PMID:35978195

Databases: - OMIM 619075 / 165640 · MONDO:0033642 (Monarch) · MedGen C5436741 · Orphanet 544488 · NCBI Gene 4953 (ODC1) · UniProt P11926 · HPO annotations, OMIM:619075 · ClinVar VCV000983285–983289, VCV001074405 · NORD · Wikipedia · ClinicalTrials.gov (NCT00118365, NCT00086736, NCT03536728 — DFMO oncology/chemoprevention only; no BABS trial registered)

PubMed metadata and abstracts in this report were retrieved via NCBI E-utilities and PubMed Central; DOIs are listed where retrieved.

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Pathograph

Phenotypes

Genetic Associations

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Medical Actions

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References & Deep Research

References

Deep Research

1. Disease Information

1.1 Overview

1.2 Key identifiers

1.3 Synonyms

1.4 Provenance of information

2. Etiology

2.1 Primary cause

2.2 Genetic risk factors

2.3 Environmental risk factors

2.4 Protective factors

2.5 Gene–environment interactions

3. Phenotypes

3.1 Frequency table — GeneReviews cohort (n=9 published individuals; primary source)

3.2 Frequency table — 2026 systematic review (n=12 published BABS cases)

3.3 HPO disease-annotation set (HPOA, OMIM:619075) — with explicit n/N and onset

3.4 Per-phenotype characterization

3.5 Quality of life

4. Genetic / Molecular Information

4.1 Causal gene

4.2 Pathogenic variants (compiled from all sources)

4.3 Variant classification, allele frequency, origin

4.4 Allelic disorders — the loss-of-function arm

4.5 Modifier genes

4.6 Epigenetics

4.7 Chromosomal abnormalities

5. Environmental Information

6. Mechanism / Pathophysiology

6.1 The causal chain (upstream → downstream)

6.2 Molecular pathway detail

6.3 Cellular processes

6.4 Protein dysfunction

6.5 Metabolic changes

6.6 Immune system involvement

6.7 Tissue damage mechanisms

6.8 Molecular profiling

6.9 Cell types and anatomical processes — suggested ontology bindings

7. Anatomical Structures Affected

7.1 Organ level

7.2 Tissue and cell level

7.3 Subcellular level

7.4 Localization / lateralization

8. Temporal Development

8.1 Onset

8.2 Progression

8.3 Patterns

9. Inheritance and Population

9.1 Epidemiology

9.2 Inheritance genetics

9.3 Population demographics

10. Diagnostics

10.1 Suggestive clinical findings (GeneReviews)

10.2 Establishing the diagnosis

10.3 Genetic testing

10.4 Biochemical / omics diagnostics — the BABS-distinctive layer

10.5 Imaging, electrophysiology, other clinical tests

10.6 Differential diagnosis (GeneReviews Table 3)

10.7 Screening of asymptomatic individuals

11. Outcome / Prognosis