Hypomyelinating Leukodystrophy 14

Mendelian MONDO:0033486 Pathograph 25 Show in embeddings browser leukodystrophy

Hypomyelinating leukodystrophy 14 (HLD14) is an autosomal recessive leukodystrophy caused by biallelic variants in UFM1, which encodes ubiquitin fold modifier 1, the small ubiquitin-like protein conjugated to target proteins by the UBA5 (E1), UFC1 (E2) and UFL1-UFBP1 (E3) UFMylation cascade. Almost all reported patients are homozygous for a Roma founder 3-bp deletion in the UFM1 promoter (c.-273_-271delTCA; also written c.-155_-153delTCA against a different transcript), which lowers UFM1 transcription in neural cell lines. These children present in the first months of life with inspiratory stridor, feeding and swallowing failure, absent visual and auditory development, axial hypotonia with limb hypertonia, dystonia and opisthotonus, and later drug-resistant epilepsy and progressive microcephaly; most die in infancy or early childhood, often of respiratory insufficiency. MRI shows hypomyelination with a very small or absent putamen, small caudate and evolving cerebellar atrophy, the pattern of hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) that is otherwise associated with dominant TUBB4A variants. A homozygous missense variant, p.Arg81Cys, found in two Sudanese families, causes a related early-onset encephalopathy with progressive microcephaly, delayed myelination and cerebellar hypoplasia but without the basal ganglia involvement of H-ABC. Mechanistically, UFMylation acts mainly at the endoplasmic reticulum, where modification of the ribosomal protein RPL26 supports ER-associated ribosome quality control and ER-phagy; UFM1 loss in neurons induces ER stress and the unfolded protein response and reduces protein translation. How these neuronal defects relate to the failure of myelination is not established.

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1
Inheritance
11
Pathophys.
27
Phenotypes
3
Gaps
25
Pathograph
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Genes
2
Variants
5
Medical Actions
4
Differentials
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Models
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Deep Research
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Inheritance

1
Autosomal Recessive HP:0000007
Biallelic UFM1 variants are required. The Roma founder promoter deletion was homozygous in every affected child in the index series, while healthy Roma controls included heterozygous carriers but no homozygotes.
Autosomal recessive inheritance
Show evidence (3 references)
PMID:34573312 SUPPORT BACKGROUND Human Clinical
"Hypomyelinating leukodystrophy type 14 (MIM # 617899) is caused by mutations in the UFM1 gene and is inherited in an autosomal recessive manner."
States the recessive mode of inheritance for HLD14 in the paper's introduction.
PMID:28931644 SUPPORT Human Clinical
"Sanger sequencing confirmed homozygosity for this variant in all 16 patients."
Every affected child in the index series was homozygous for the founder deletion.
PMID:28931644 SUPPORT Human Clinical
"The Taqman screening assay confirmed a high carrier frequency and absence of homozygosity for the mutation among healthy Roma controls."
Heterozygous carriers are unaffected, consistent with recessive inheritance.
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Discussions and Knowledge Gaps

3
How does reduced UFMylation cause hypomyelination: through a defect in oligodendrocytes themselves, or secondarily to neuronal loss and failed brain growth?
KNOWLEDGE GAP hld14_ufmylation_to_hypomyelination
Attached to
pathophysiology#Deficient CNS Myelination
Hypomyelination defines the disease, but every mechanistic study of UFM1 loss so far has looked at neurons or non-neural cells. The founder promoter deletion lowered reporter expression in neuroblastoma and astroglioma cells but not in an oligodendroglioma-derived line, which, if it holds in real oligodendrocytes, would argue for a secondary rather than a cell-autonomous myelin defect. Oligodendrocyte-specific Ufm1 loss in mice, or patient-derived oligodendrocytes, would settle it.
Is UFM1 p.Arg81Cys a partial loss-of-function allele, or does it have additional effects that make it behave differently from reduced UFM1 supply?
KNOWLEDGE GAP hld14_missense_not_simple_loss
Attached to
pathophysiology#ER Stress and Unfolded Protein Response Activation
The Arg81Cys protein is hypomorphic in thioester assays, yet UFM1-R81C neurons respond to ER stress differently from UFM1-null neurons, and the UPR inhibitor trazodone restored translation only in R81C neurons. If the two allele classes act differently, a treatment that helps one may not help the other.
Is there any disease-modifying treatment for HLD14?
KNOWLEDGE GAP hld14_no_disease_modifying_treatment
Attached to
treatments#
Only supportive care and genetic counselling are curated. Trazodone increased synapse numbers in cultured UFM1-deficient mouse neurons, but that is a cell-culture result, not a clinical treatment, and it is not curated as a treatment here.
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Pathophysiology

11
Biallelic UFM1 Variants
Biallelic hypomorphic UFM1 variants. The predominant allele is a Roma founder 3-bp promoter deletion that lowers transcription; a rarer homozygous missense variant, p.Arg81Cys, alters the UFM1 C-terminal tail that binds UBA5. Complete loss is not observed: biallelic null alleles in UFMylation genes are depleted from human population databases, and knockout of the pathway is embryonic lethal in mice.
Genetic context UFM1 hgnc:20597 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns UFM1 (hgnc:20597). hgnc:20597 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
Downstream
Reduced UFM1 Expression in Neural Cells Route taken by the Roma founder promoter deletion.
Impaired UFM1 Thioester Formation with UBA5 and UFC1 Route taken by the p.Arg81Cys missense variant.
Show evidence (3 references)
PMID:28931644 SUPPORT Human Clinical
"WES in 2 patients revealed a homozygous deletion in the promoter region of UFM1."
Identifies the founder promoter deletion as the disease allele.
PMID:29868776 SUPPORT Other
"the conspicuous depletion of biallelic null mutations in the components of this pathway in human genome databases suggest that it is necessary for embryonic survival, which is consistent with the embryonic lethal nature of knockout models for the orthologous genes"
Population-database depletion of null alleles and embryonic lethality of knockout models support describing disease alleles as hypomorphic rather than null.
PMID:29868776 SUPPORT In Vitro
"Our results show a reduction rather than abrogation of ufmylation with the activity of UFM1 and UFC1 mutants at 60-75% of their wild-type counterparts."
Quantifies residual activity of the mutant proteins.
Reduced UFM1 Expression in Neural Cells
The founder promoter deletion reduces UFM1 promoter activity in neuroblastoma (SH-SY5Y) and astroglioma (U373) cells but not in HeLa or oligodendroglioma-derived HOG cells, suggesting a cell-type-selective fall in UFM1 supply. That the oligodendroglial line was spared is notable given the hypomyelinating phenotype, although a single reporter assay in transformed cell lines is a weak guide to oligodendrocytes in vivo.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
Downstream
Impaired Protein UFMylation
Show evidence (1 reference)
PMID:28931644 SUPPORT In Vitro
"Transfection assays showed that the deletion significantly reduced expression in specific CNS cell lines."
Reporter-level evidence that the deletion lowers UFM1 expression in a CNS-cell-selective way.
Impaired UFM1 Thioester Formation with UBA5 and UFC1
UFM1 p.Arg81Cys forms thioester intermediates with the E1 UBA5 and the E2 UFC1 less efficiently than wild-type UFM1, reducing the amount of activated UFM1 available for conjugation. The molecular function below is UBA5's; the defect lies in the UFM1 substrate, so the annotation stands for reduced flux through the E1 step rather than a defective enzyme.
UFM1 activating enzyme activity GO:0071566 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased UFM1 activating enzyme activity (GO:0071566). GO:0071566 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Impaired Protein UFMylation
Show evidence (1 reference)
PMID:29868776 SUPPORT In Vitro
"Taken together, our data show that UFM1R81C has a hypomorphic effect on the UFM1-system and provide a plausible mechanistic explanation."
Characterizes the missense variant as hypomorphic.
Impaired Protein UFMylation
Reduced covalent conjugation of UFM1 to cellular substrates. Two substrates tie UFMylation to the endoplasmic reticulum: the 60S ribosomal protein RPL26, the principal UFMylation target, and the ER membrane reductase CYB5R3, whose UFMylation triggers ER-phagy. The molecular function below is UFM1's own: it is the covalent tag, so reduced UFM1 availability reduces the tagging activity itself rather than an enzyme acting on it.
UFM1 hgnc:20597 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves UFM1 (hgnc:20597). hgnc:20597 is a gene from the HUGO Gene Nomenclature Committee.
protein ufmylation GO:0071569 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein ufmylation (GO:0071569). GO:0071569 is a biological process from the Gene Ontology. ↓ DECREASED
UFM1 protein tag activity GO:0031386 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased UFM1 protein tag activity, annotated with protein tag activity (GO:0031386). GO:0031386 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Defective ER-Associated Ribosome Quality Control
Impaired ER-Phagy
Show evidence (2 references)
PMID:30626644 SUPPORT In Vitro
"Here, we show that a largely uncharacterized ribosomal protein, RPL26, is the principal target of UFM1 conjugation."
Identifies the dominant substrate of the process the disease impairs.
PMID:29868776 SUPPORT In Vitro
"We also found that the level of two UFM1-conjugates with cellular proteins in patient-derived lymphoblasts was significantly reduced compared to control lymphoblasts"
Reduced UFM1 conjugates measured in lymphoblasts from a patient homozygous for UFM1 p.Arg81Cys.
Defective ER-Associated Ribosome Quality Control
UFMylated RPL26 is enriched on ER membrane-bound ribosomes near the SEC61 translocon, and its modification is needed to release and degrade arrested nascent chains on translocon-bound 60S subunits. Loss of this step is expected to compromise cotranslational protein biogenesis at the ER.
ribosome-associated quality control at the ER GO:0072344 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased ribosome-associated quality control at the ER, annotated with rescue of stalled cytosolic ribosome (GO:0072344). GO:0072344 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
ER Stress and Unfolded Protein Response Activation Proposed link: ER protein-biogenesis failure is the natural source of the ER stress seen in UFM1-deficient neurons, but no study has shown the ribosome-quality-control defect itself drives the stress response in a disease model.
Show evidence (1 reference)
PMID:30626644 SUPPORT In Vitro
"These data suggest that UFMylation is a ribosomal modification specialized to facilitate metazoan-specific protein biogenesis at the ER."
Places RPL26 UFMylation in ER-coupled protein biogenesis.
Impaired ER-Phagy
UFMylation of CYB5R3 on the ER membrane marks it for lysosomal turnover through ER-phagy. Mice carrying a UFMylation-resistant Cyb5r3 develop microcephaly, linking this branch to brain growth.
reticulophagy GO:0061709 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased reticulophagy (GO:0061709). GO:0061709 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Neuronal Death and Impaired Brain Growth
Show evidence (1 reference)
PMID:36543799 SUPPORT In Vitro
"Ufmylated CYB5R3 is degraded in lysosomes, which depends on the autophagy-related protein Atg7- and the autophagy-adaptor protein CDK5RAP3."
Describes the ER-phagy pathway that depends on CYB5R3 UFMylation.
ER Stress and Unfolded Protein Response Activation
UFM1-deficient mouse neurons show ER stress and activation of the PERK arm of the unfolded protein response; ATF6 and IRE1alpha were also measured and did not rise. Neurons expressing UFM1 p.Arg81Cys respond to ER stress differently from UFM1-null neurons, so the missense allele is not simply a weaker version of loss.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
PERK-mediated unfolded protein response GO:0036499 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased PERK-mediated unfolded protein response (GO:0036499). GO:0036499 is a biological process from the Gene Ontology. ↑ INCREASED
Experimental models
Cultured UFM1-deficient mouse neurons PRIMARY CELL CULTURE Shows ER stress and UPR activation after UFM1 loss, and a distinct response with UFM1-R81C.
Downstream
Reduced Neuronal Protein Translation Supported for UFM1-R81C neurons only. The UPR inhibitor trazodone restored translation in R81C neurons but not in UFM1-null neurons, so the UPR does not account for the translation loss after complete UFM1 loss, and the change in phosphorylated eIF2alpha downstream of PERK did not reach significance.
Show evidence (3 references)
PMID:41731076 SUPPORT In Vitro
"Mechanistically, UFM1 loss is associated with induction of ER stress, activation of the unfolded protein response (UPR) pathway, and reduced protein translation."
Direct observation of ER stress and UPR activation in UFM1-deficient cultured mouse neurons.
PMID:41731076 SUPPORT In Vitro
"UFM1-deficient and UFM1-R81C-expressing neurons display distinct responses to ER stress, indicating that UFM1-R81C is not merely a loss-of-function variant."
Shows the missense and null states diverge at this node.
PMID:29868776 REFUTE In Vitro
"Neither did we note appreciable difference in endoplasmic reticulum stress-induced apoptosis in cells expressing UFM1 wild-type or UFM1 p.R81C, after 48 h incubation in tunicamycin at various concentrations."
In a non-neuronal overexpression system, p.Arg81Cys did not change ER stress-induced apoptosis, so the ER stress phenotype may be neuron-specific or depend on the model.
Reduced Neuronal Protein Translation
UFM1 loss reduces global protein synthesis in neurons. Wild-type UFM1 restores it; UFM1 p.Arg81Cys restores it only partly.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
translation GO:0006412 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased translation (GO:0006412). GO:0006412 is a biological process from the Gene Ontology. ↓ DECREASED
Experimental models
Cultured UFM1-deficient mouse neurons PRIMARY CELL CULTURE Reduced protein translation after UFM1 loss, rescued by wild-type UFM1 and partly by UFM1-R81C.
Downstream
Impaired Neuronal Development and Synapse Function
Show evidence (1 reference)
PMID:41731076 SUPPORT In Vitro
"These defects are rescued by wild-type UFM1, but only partially by UFM1-R81C."
Rescue experiments tie the translation defect to UFM1 and show the missense variant is hypomorphic.
Impaired Neuronal Development and Synapse Function
UFM1-deficient mouse neurons develop abnormally and have impaired synapse function; trazodone increases synapse numbers in both UFM1-null and UFM1-R81C neurons.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
Downstream
Profound Global Developmental Delay
Drug-Resistant Epilepsy
Show evidence (1 reference)
PMID:41731076 SUPPORT In Vitro
"We found that UFM1-deficiency confounds neuron development and synapse function."
Direct observation in cultured UFM1-deficient neurons.
Neuronal Death and Impaired Brain Growth
Loss of UFMylation in the developing mouse nervous system causes neuronal apoptosis and microcephaly, matching the progressive microcephaly and brain atrophy seen in patients.
neuron apoptotic process GO:0051402 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased neuron apoptotic process (GO:0051402). GO:0051402 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Progressive Microcephaly
Cerebral Atrophy
Cerebellar Atrophy
Very Small or Absent Putamen
Small Caudate Nucleus
Caudate Head Signal Abnormality
Corpus Callosum Atrophy
Enlarged Cisterna Magna
Developmental Regression
Show evidence (1 reference)
PMID:28931644 SUPPORT BACKGROUND Model Organism
"CNS-specific knockout of Ufm1 in mice caused neonatal death with microcephaly and apoptosis of neurons in specific brain regions."
Summarizes the CNS-specific Ufm1 knockout mouse, cited in the discussion of the human gene-discovery paper.
Deficient CNS Myelination
Permanent hypomyelination of the cerebral white matter, the defining MRI feature. The step from reduced UFMylation to failed myelination has not been studied in UFM1-deficient oligodendrocytes, so this node has no sourced upstream edge.
oligodendrocyte CL:0000128 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves oligodendrocyte (CL:0000128). CL:0000128 is a cell type from the Cell Ontology.
central nervous system myelination GO:0022010 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased central nervous system myelination (GO:0022010). GO:0022010 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
CNS Hypomyelination
Show evidence (1 reference)
PMID:35189806 SUPPORT Human Clinical
"Brain imaging revealed cortical atrophy (7/9), atrophic ventricular dilatation (4/9), macrocisterna magna (5/9), reduced myelination (6/6), corpus callosum atrophy (3/6) and abnormal putamen and caput nuclei caudati."
Reduced myelination in every patient imaged in this series.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Hypomyelinating Leukodystrophy 14 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

27
Digestive 1
Dysphagia VERY_FREQUENT HP:0002015 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysphagia (HP:0002015). HP:0002015 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35189806 SUPPORT Human Clinical
"Presentation is no later than 2 months with inspiratory stridor, impaired sucking, swallowing, vision and hearing, and reduced active movements."
Impaired sucking and swallowing are presenting features.
PMID:35189806 SUPPORT Human Clinical
"Dysphagia (7/9), inspiratory stridor (9/9), dyspnea (5/9), bradypnea (5/9), apnea (2/9) were major signs."
Dysphagia in 7 of 9 patients.
Ear 1
Hearing Impairment VERY_FREQUENT HP:0000365 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hearing impairment (HP:0000365). HP:0000365 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35189806 SUPPORT Human Clinical
"Vision and hearing were never achieved or lost by 4-8 mo."
Severe hearing impairment in the Bulgarian series.
Eye 2
Nystagmoid Eye Movements FREQUENT Nystagmus HP:0000639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nystagmoid ocular movements, annotated with Nystagmus (HP:0000639). HP:0000639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35189806 SUPPORT Human Clinical
"microcephaly (6/9), malnutrition (5/9), muscle hypertonia (9/9) and axial hypotonia (4/9), progressing to opisthotonus (6/9), dystonic posturing (5/9), nystagmoid ocular movements (6/9)"
Nystagmoid movements in 6 of 9 patients.
Visual Impairment VERY_FREQUENT HP:0000505 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Visual impairment (HP:0000505). HP:0000505 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35189806 SUPPORT Human Clinical
"Vision and hearing were never achieved or lost by 4-8 mo."
Severe visual impairment in the Bulgarian series.
Head and Neck 2
Enlarged Cisterna Magna FREQUENT HP:0002280 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Enlarged cisterna magna (HP:0002280). HP:0002280 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35189806 SUPPORT Human Clinical
"Brain imaging revealed cortical atrophy (7/9), atrophic ventricular dilatation (4/9), macrocisterna magna (5/9), reduced myelination (6/6), corpus callosum atrophy (3/6) and abnormal putamen and caput nuclei caudati."
Enlarged cisterna magna in 5 of 9 patients.
Progressive Microcephaly VERY_FREQUENT HP:0000253 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive microcephaly (HP:0000253). HP:0000253 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28931644 SUPPORT Human Clinical
"Stunted growth was frequent and all patients had microcephaly."
Microcephaly in all 16 patients.
PMID:29868776 SUPPORT Human Clinical
"Here, we establish a locus for severe early-onset encephalopathy with progressive microcephaly based on two families, and map the phenotype to a novel homozygous UFM1 mutation."
Progressive microcephaly with the homozygous p.Arg81Cys variant.
Musculoskeletal 3
Spasticity VERY_FREQUENT HP:0001257 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spasticity (HP:0001257). HP:0001257 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28931644 SUPPORT Human Clinical
"Almost all patients exhibited spasticity and extrapyramidal movement abnormalities, mostly dystonia."
Spasticity in almost all patients.
PMID:42195294 SUPPORT Human Clinical
"The disorder is severe, with most patients dying before one year of age, and is characterized by inspiratory stridor, axial hypotonia, spastic quadriparesis, pseudobulbar signs, and microcephaly."
Spastic quadriparesis in the largest HLD14 cohort (17 patients).
Axial Hypotonia with Limb Hypertonia VERY_FREQUENT HP:0008936 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Axial hypotonia (HP:0008936). HP:0008936 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35189806 SUPPORT Human Clinical
"microcephaly (6/9), malnutrition (5/9), muscle hypertonia (9/9) and axial hypotonia (4/9), progressing to opisthotonus (6/9), dystonic posturing (5/9), nystagmoid ocular movements (6/9)"
Hypertonia in 9 of 9 and axial hypotonia in 4 of 9 patients.
PMID:42195294 SUPPORT Human Clinical
"All patients presented with several clinical manifestations, including inspiratory laryngeal stridor, axial hypotonia, spastic quadriparesis, pseudobulbar syndrome, and microcephaly"
Axial hypotonia in all 17 patients of the largest cohort.
Opisthotonus FREQUENT HP:0002179 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Opisthotonus (HP:0002179). HP:0002179 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35189806 SUPPORT Human Clinical
"microcephaly (6/9), malnutrition (5/9), muscle hypertonia (9/9) and axial hypotonia (4/9), progressing to opisthotonus (6/9), dystonic posturing (5/9), nystagmoid ocular movements (6/9)"
Opisthotonus in 6 of 9 patients.
Nervous System 13
CNS Hypomyelination VERY_FREQUENT HP:0003429 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is CNS hypomyelination (HP:0003429). HP:0003429 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28931644 SUPPORT Human Clinical
"(1) hypomyelination, defined as a mildly elevated T2 signal intensity of most cerebral white matter in combination with mild T1 hypointensity, T1 isointensity, or mild T1 hyperintensity relative to the cortex"
Hypomyelination was an inclusion criterion met by all 16 patients.
PMID:39470296 SUPPORT Human Clinical
"However, P12 with HLD14 presented only with diffuse cerebral hypomyelination on neuroimaging"
An Indian patient with HLD14 had diffuse hypomyelination without the other H-ABC features, suggesting hypomyelination may occur even when the basal ganglia and cerebellum are spared (a single patient).
Very Small or Absent Putamen VERY_FREQUENT Abnormal putamen morphology HP:0031982 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Very small or absent putamen, annotated with Abnormal putamen morphology (HP:0031982). HP:0031982 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28931644 SUPPORT Human Clinical
"None of the patients showed a normal putamen and in all patients the caudate nucleus was small."
Putamen abnormality in every patient in the index series.
Small Caudate Nucleus VERY_FREQUENT Caudate atrophy HP:0002340 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Small caudate nucleus, annotated with Caudate atrophy (HP:0002340). HP:0002340 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28931644 SUPPORT Human Clinical
"None of the patients showed a normal putamen and in all patients the caudate nucleus was small."
Small caudate nucleus in every patient in the index series.
Cerebellar Atrophy FREQUENT HP:0001272 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar atrophy (HP:0001272), qualified as course progressive. HP:0001272 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:28931644 SUPPORT Human Clinical
"On the first MRI, 56% of patients had mild cerebellar atrophy, restricted to the vermis."
Gives the frequency on first imaging.
PMID:28931644 SUPPORT Human Clinical
"In 4 patients who initially lacked cerebellar atrophy, follow-up MRIs revealed cerebellar atrophy after 3-15 months."
Shows the atrophy is progressive.
Cerebral Atrophy FREQUENT HP:0002059 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral atrophy (HP:0002059). HP:0002059 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35189806 SUPPORT Human Clinical
"Brain imaging revealed cortical atrophy (7/9), atrophic ventricular dilatation (4/9), macrocisterna magna (5/9), reduced myelination (6/6), corpus callosum atrophy (3/6) and abnormal putamen and caput nuclei caudati."
Cortical atrophy in 7 of 9 patients.
Corpus Callosum Atrophy FREQUENT HP:0007371 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Corpus callosum atrophy (HP:0007371). HP:0007371 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35189806 SUPPORT Human Clinical
"Brain imaging revealed cortical atrophy (7/9), atrophic ventricular dilatation (4/9), macrocisterna magna (5/9), reduced myelination (6/6), corpus callosum atrophy (3/6) and abnormal putamen and caput nuclei caudati."
Corpus callosum atrophy in 3 of 6 patients with imaging.
Profound Global Developmental Delay VERY_FREQUENT HP:0012736 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Profound global developmental delay (HP:0012736). HP:0012736 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28931644 SUPPORT Human Clinical
"Sixteen patients from 14 families from different countries fulfilling the MRI criteria for H-ABC exhibited a similar, severe clinical phenotype, including lack of development and a severe epileptic encephalopathy."
Lack of development across the index series.
PMID:34573312 SUPPORT BACKGROUND Human Clinical
"It is characterized by hypotonia, an almost complete lack of motor or cognitive skills, absent language development, spasticity, and intractable seizures."
Summary of the HLD14 phenotype in the paper's introduction.
Developmental Regression VERY_FREQUENT HP:0002376 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Developmental regression (HP:0002376). HP:0002376 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35189806 SUPPORT Human Clinical
"Neurodevelopment was absent or minimal with subsequent regression after 2-5 mo."
Regression after early infancy in the Bulgarian series.
Drug-Resistant Epilepsy FREQUENT Epileptic encephalopathy HP:0200134 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epileptic encephalopathy (HP:0200134). HP:0200134 is a phenotype from the Human Phenotype Ontology.
Show evidence (4 references)
PMID:28931644 SUPPORT Human Clinical
"Seizures were frequent and present in all patients 18 months and older."
Seizures become universal among older survivors.
PMID:28931644 SUPPORT Human Clinical
"The epilepsy was often severe and drug-resistant, including West syndrome."
Drug resistance and West syndrome.
PMID:28931644 SUPPORT Human Clinical
"exhibited a similar, severe clinical phenotype, including lack of development and a severe epileptic encephalopathy"
The index series characterizes the epilepsy as an epileptic encephalopathy.
+ 1 more reference
Context-specific annotations (1)
Onset: INFANTILE
Infantile Spasms HP:0012469 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Infantile spasms (HP:0012469). HP:0012469 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28931644 SUPPORT Human Clinical
"The epilepsy was often severe and drug-resistant, including West syndrome."
West syndrome is defined by infantile spasms.
Dystonia VERY_FREQUENT HP:0001332 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dystonia (HP:0001332). HP:0001332 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28931644 SUPPORT Human Clinical
"Almost all patients exhibited spasticity and extrapyramidal movement abnormalities, mostly dystonia."
Dystonia as the main extrapyramidal sign.
Pseudobulbar Signs VERY_FREQUENT HP:0002200 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pseudobulbar signs (HP:0002200). HP:0002200 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42195294 SUPPORT Human Clinical
"All patients presented with several clinical manifestations, including inspiratory laryngeal stridor, axial hypotonia, spastic quadriparesis, pseudobulbar syndrome, and microcephaly"
Pseudobulbar syndrome in all 17 patients.
Caudate Head Signal Abnormality VERY_FREQUENT Abnormal basal ganglia MRI signal intensity HP:0012751 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal basal ganglia MRI signal intensity (HP:0012751). HP:0012751 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28931644 SUPPORT Human Clinical
"they consistently have an additional feature: signal abnormality of the lateral part of the head of the caudate nucleus suggestive of local apoptosis"
Consistent caudate head signal change in the index series.
PMID:28931644 SUPPORT Human Clinical
"This feature has not been observed in TUBB4A-related H-ABC and may be pathognomonic for UFM1-related H-ABC."
Proposed as distinguishing UFM1- from TUBB4A-related H-ABC.
Respiratory 3
Inspiratory Stridor VERY_FREQUENT HP:0005348 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Inspiratory stridor (HP:0005348). HP:0005348 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35189806 SUPPORT Human Clinical
"Dysphagia (7/9), inspiratory stridor (9/9), dyspnea (5/9), bradypnea (5/9), apnea (2/9) were major signs."
Stridor in all 9 patients.
PMID:42195294 SUPPORT Human Clinical
"The disorder is severe, with most patients dying before one year of age, and is characterized by inspiratory stridor, axial hypotonia, spastic quadriparesis, pseudobulbar signs, and microcephaly."
Stridor is characteristic in the largest cohort.
Context-specific annotations (1)
Onset: INFANTILE
Bradypnea and Apnea FREQUENT HP:0046507 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bradypnea (HP:0046507). HP:0046507 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35189806 SUPPORT Human Clinical
"Dysphagia (7/9), inspiratory stridor (9/9), dyspnea (5/9), bradypnea (5/9), apnea (2/9) were major signs."
Bradypnea in 5 of 9 and apnea in 2 of 9 patients.
Respiratory Insufficiency HP:0002093 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Respiratory insufficiency (HP:0002093). HP:0002093 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28931644 SUPPORT Human Clinical
"Nine patients died at ages between 7 months and 7 years, most often due to respiratory insufficiency."
Respiratory insufficiency as the usual cause of death.
PMID:28931644 SUPPORT Human Clinical
"Six patients underwent tracheostomy between 6 and 17 months, 4 of whom were on intermittent or permanent ventilation."
Respiratory failure severe enough to need tracheostomy in 6 of 16 patients.
Growth 2
Failure to Thrive FREQUENT HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35189806 SUPPORT Human Clinical
"microcephaly (6/9), malnutrition (5/9), muscle hypertonia (9/9) and axial hypotonia (4/9), progressing to opisthotonus (6/9), dystonic posturing (5/9), nystagmoid ocular movements (6/9)"
Malnutrition in 5 of 9 patients.
PMID:34573312 SUPPORT BACKGROUND Human Clinical
"Mutations in the UFM1 gene are associated with Hypomyelinating leukodystrophy type 14, presenting with global developmental delay, failure to thrive, progressive microcephaly, refractive epilepsy, and hypomyelination, with atrophy of the basal ganglia and cerebellum phenotypes."
Lists failure to thrive among the core HLD14 features.
Short Stature FREQUENT HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28931644 SUPPORT Human Clinical
"Stunted growth was frequent and all patients had microcephaly."
Stunted growth is frequent in the index series.
🧬

Genetic Associations

1
UFM1 (Biallelic hypomorphic UFM1 variants cause HLD14. Most patients are homozygous for a Roma founder promoter deletion on a shared haplotype; the homozygous p.Arg81Cys missense variant causes a related early-onset encephalopathy with progressive microcephaly, in which none of four patients had basal ganglia abnormalities.)
Gene: UFM1 hgnc:20597 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is UFM1 (hgnc:20597). hgnc:20597 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (3 references)
PMID:28931644 SUPPORT Human Clinical
"This study, focused on identifying the mutated gene in patients with H-ABC without TUBB4A mutations, revealed a homozygous 3-bp deletion in the UFM1 promoter area, which perfectly segregates with the disease."
Gene discovery by homozygosity mapping and exome sequencing, with segregation.
PMID:28931644 SUPPORT Human Clinical
"All patients shared a common haplotype, indicative of a founder effect."
Founder origin of the recurrent allele.
PMID:29868776 SUPPORT Human Clinical
"Here, we establish a locus for severe early-onset encephalopathy with progressive microcephaly based on two families, and map the phenotype to a novel homozygous UFM1 mutation."
Independent UFM1 missense allele in two further families.
🔬

Variants

2
UFM1 c.-273_-271delTCA
A 3-bp deletion in the UFM1 promoter, the Roma founder allele. The same deletion is written c.-155_-153delTCA in reports that number it against a different transcript.
Show evidence (3 references)
PMID:35189806 SUPPORT Human Clinical
"Retrospective analysis of all 9 cases with H-ABC due to c.-273_-271delTCA mutation in UFM1"
Names the variant in the c.-273_-271 numbering.
PMID:34573312 SUPPORT Human Clinical
"The c.-155_-153delTCA deletion in the promoter region of UFM1 is considered to be a founding mutation in the Roma population."
Names the same founder deletion in the c.-155_-153 numbering.
PMID:34573312 SUPPORT Human Clinical
"were the first to describe the homozygous UFM1:c.-155_-153delTCA founder mutation (reported as NM_001286704.1: c.-273_-271delTCA)"
Confirms the two numberings describe one variant.
UFM1 p.Arg81Cys
A homozygous missense variant at a conserved residue in the UFM1 C-terminal tail that contacts UBA5, reducing thioester formation with UBA5 and UFC1.
Show evidence (1 reference)
PMID:29868776 SUPPORT In Vitro
"Taken together, our data show that UFM1R81C has a hypomorphic effect on the UFM1-system and provide a plausible mechanistic explanation."
Functional characterization of the missense allele.
🗃️

External Assertions

2
OMIM hypomyelinating leukodystrophy 14 record
OMIM disease record OMIM:617899
OMIM phenotype identifier for hypomyelinating leukodystrophy 14, cited as "MIM # 617899" in PMID:34573312.
Orphanet hypomyelination with atrophy of basal ganglia and cerebellum record
Orphanet structured disease record ORPHA:139441
Orphanet's H-ABC record covers both the TUBB4A and UFM1 forms, so it is broader than HLD14 (a broad match, not an exact one).
💊

Medical Actions

5
Symptomatic and Supportive Care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
No disease-modifying therapy exists. Care is supportive and addresses seizures, feeding and swallowing failure, spasticity and dystonia, and respiratory complications.
Show evidence (1 reference)
PMID:42195294 SUPPORT Human Clinical
"Most rare diseases are genetic and carry high morbidity and mortality, with no targeted therapies currently available."
States that no targeted therapy is available for the founder disorders in this cohort, which include HLD14.
Tracheostomy and Ventilatory Support
Action: tracheostomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is tracheostomy, annotated with Tracheotomy (NCIT:C15341). NCIT:C15341 is a clinical intervention from the NCI Thesaurus. Ontology label: Tracheotomy NCIT:C15341
Laryngeal dysfunction with stridor and respiratory failure led to tracheostomy in many patients, some with intermittent or permanent ventilation.
Show evidence (2 references)
PMID:28931644 SUPPORT Human Clinical
"Six patients underwent tracheostomy between 6 and 17 months, 4 of whom were on intermittent or permanent ventilation."
Tracheostomy in 6 of 16 patients, 4 of them ventilated.
PMID:34573312 SUPPORT Human Clinical
"abnormal muscle tone not only affected skeletal muscles but apparently the laryngeal muscle, causing loud stridor, jugular retraction, and ineffective inhalation phase during breathing; therefore, most patients needed a tracheostomy"
Laryngeal dysfunction as the indication for tracheostomy.
Tube Feeding
Action: gastrostomy tube feedingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is gastrostomy tube feeding, annotated with Gastrostomy Tube Procedure (NCIT:C157864). NCIT:C157864 is a clinical intervention from the NCI Thesaurus. Ontology label: Gastrostomy Tube Procedure NCIT:C157864
Dysphagia requires nasogastric and later gastrostomy tube feeding.
Show evidence (1 reference)
PMID:34573312 SUPPORT Human Clinical
"Dysphagia necessitated feeding via nasogastric tube and later via gastrotube."
Nasogastric then gastrostomy feeding in a patient with HLD14.
Antiseizure Medication
Action: anticonvulsant therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is anticonvulsant therapy (NCIT:C64172). NCIT:C64172 is a clinical intervention from the NCI Thesaurus. Ontology label: Anticonvulsant Therapy NCIT:C64172
Seizures are treated with standard antiseizure drugs (carbamazepine in one reported patient) but are often drug-resistant.
Show evidence (1 reference)
PMID:34573312 SUPPORT Human Clinical
"revealed interictal epileptic spikes over the right hemisphere; therefore carbamazepine was introduced"
Carbamazepine started for focal epileptiform activity in a patient with HLD14.
Genetic Counseling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Counselling of families, carrier testing in high-frequency Roma communities and prenatal testing.
Show evidence (1 reference)
PMID:42195294 SUPPORT Human Clinical
"Prenatal and newborn screening, along with voluntary carrier testing for couples, is essential for proactive health management."
Recommends carrier and prenatal testing for these founder disorders.
🔬

Diagnosis

2
MRI pattern recognition with targeted UFM1 founder testing
The H-ABC MRI pattern (hypomyelination with a very small or absent putamen and cerebellar atrophy) in a child without a TUBB4A variant, or severe infantile encephalopathy with stridor and hypomyelination in a child of Roma descent, should prompt targeted testing for the UFM1 promoter deletion. Because the variant lies in the promoter, analysis must include that region; exome capture that covers only coding exons can miss it.
Show evidence (3 references)
PMID:35189806 SUPPORT Human Clinical
"Roma patients with severe encephalopathy in early infancy with stridor, opisthotonus, bradypnea, severe hearing and visual impairment should be tested for the Roma founder mutation of H-ABC in UFM1."
Clinical clues for targeted testing.
PMID:34573312 SUPPORT Human Clinical
"This mutation may be more common in the Roma population than previously estimated, and the targeted testing of the UFM1:c.-155_-153delTCA mutation may have an indication in cases of hypomyelination and neurodegenerative clinical course in pediatric patients of Roma descent."
Recommends targeted founder testing.
PMID:34573312 SUPPORT Human Clinical
"As the coverage of the promoter region of the UFM1 gene is generally poor in the case of exome sequencing data, and in many cases only the coding region of the genes are analyzed, this pathogenic founder variant could be easily missed"
Explains why exome sequencing can miss the promoter variant.
Carrier and prenatal testing in high-frequency communities
Knowing the founder allele allows carrier testing where its frequency is high, and prenatal testing.
Show evidence (1 reference)
PMID:28931644 SUPPORT Human Clinical
"The identification of the disease-causing variant enables better clinical and genetic counseling, the possibility of prenatal testing, and the option of carrier testing in populations with a high carrier frequency."
States the counselling and testing uses of the founder allele.
📈

Progression

1
Early death, usually from respiratory insufficiency
Age: 7 months to 7 years; median about 1-2 years depending on cohort
Most children homozygous for the founder deletion die in infancy or early childhood, most often of respiratory insufficiency. Curated under progression rather than phenotypes because HP:0001522 Death in infancy is in the HPO mortality branch and not in the PhenotypeTerm enum.
Show evidence (6 references)
PMID:28931644 SUPPORT Human Clinical
"Nine patients died at ages between 7 months and 7 years, most often due to respiratory insufficiency."
Age range and cause of death in the index series.
PMID:35189806 SUPPORT Human Clinical
"The age at death was between 8 and 18 mo."
Death in infancy in the Bulgarian series.
PMID:34573312 SUPPORT Human Clinical
"The median survival of the patients was 28 months, not counting the youngest who is still alive at 17 months of age."
Longer median survival in the Hungarian series than in the Bulgarian and Romanian cohorts.
+ 3 more references
📊

Prevalence

1
European Roma communities (carrier frequency of the UFM1 founder deletion)
Carrier Frequency 3000.0–25000.0 per 100,000
Carrier rate of 3%-25% for c.-273_-271delTCA across 1,000 Roma controls from different European panels; the upper value comes from a single Eastern Slovak community (14 of 57 individuals), which was sampled because an affected child came from it and is endogamous, so it is ascertainment-biased. The pan-European figure from 670 Roma controls was 4.5%. This is an allele-carrier figure in a founder population, not a disease prevalence.
Show evidence (3 references)
PMID:28931644 SUPPORT Human Clinical
"Screening of 1,000 controls from different European Roma panels demonstrated an overall carrier rate of the mutation of 3%-25%."
Population screening of Roma controls gives the founder-allele carrier rate.
PMID:28931644 SUPPORT Human Clinical
"Subsequent investigation of the carrier rate in the specific community where the homozygous individual came from revealed a carrier rate of approximately 25% (14 out of 57 individuals)."
Identifies the single community behind the 25% upper bound.
PMID:28931644 SUPPORT Human Clinical
"Screening of 670 Roma controls revealed 30 carriers with an overall carrier rate of 4.5% among different Roma communities across Europe"
Representative pan-European carrier rate.
🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Hypomyelinating Leukodystrophy 14:

Pelizaeus-Merzbacher Disease (HLD1, PLP1)
Overlapping Features The prototypic hypomyelinating leukodystrophy; X-linked, and without the basal ganglia atrophy of H-ABC.
🧫

Experimental Models

1
Cultured UFM1-deficient mouse neurons PRIMARY_CELL_CULTURE
Primary mouse neurons lacking UFM1, or lacking UFM1 and re-expressing either wild-type UFM1 or the pathogenic UFM1-R81C variant.
Organism
house mouse NCBITaxon:10090 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in house mouse, annotated with Mus musculus (NCBITaxon:10090). NCBITaxon:10090 is an organism from the NCBI Taxonomy.
Publication
PMID:41731076
Pathograph links
ER Stress and Unfolded Protein Response Activation recapitulates fidelity: moderate observes: cellular Shows ER stress and UPR activation after UFM1 loss, and a distinct response with UFM1-R81C.
Limitations: Mouse neurons in culture, not human cells and not oligodendrocytes. The model removes UFM1 or expresses the missense variant; it does not model the founder promoter deletion, which reduces UFM1 transcription rather than altering the protein.
Show evidence (1 reference)
PMID:41731076 SUPPORT In Vitro
"Mechanistically, UFM1 loss is associated with induction of ER stress, activation of the unfolded protein response (UPR) pathway, and reduced protein translation."
The model's principal mechanistic result.
Reduced Neuronal Protein Translation recapitulates fidelity: moderate observes: cellular Reduced protein translation after UFM1 loss, rescued by wild-type UFM1 and partly by UFM1-R81C.
Limitations: Mouse neurons in culture; the human relevance of the translation defect has not been measured in patient neurons.
Show evidence (1 reference)
PMID:41731076 SUPPORT In Vitro
"These defects are rescued by wild-type UFM1, but only partially by UFM1-R81C."
Rescue experiments in the model.
{ }

Source YAML

click to show 
name: Hypomyelinating Leukodystrophy 14
creation_date: "2026-09-25T20:45:00Z"
category: Mendelian
description: >-
  Hypomyelinating leukodystrophy 14 (HLD14) is an autosomal recessive
  leukodystrophy caused by biallelic variants in UFM1, which encodes ubiquitin
  fold modifier 1, the small ubiquitin-like protein conjugated to target
  proteins by the UBA5 (E1), UFC1 (E2) and UFL1-UFBP1 (E3) UFMylation cascade.
  Almost all reported patients are homozygous for a Roma founder 3-bp deletion
  in the UFM1 promoter (c.-273_-271delTCA; also written c.-155_-153delTCA
  against a different transcript), which lowers UFM1 transcription in neural
  cell lines. These children present in the first months of life with
  inspiratory stridor, feeding and swallowing failure, absent visual and
  auditory development, axial hypotonia with limb hypertonia, dystonia and
  opisthotonus, and later drug-resistant epilepsy and progressive
  microcephaly; most die in infancy or early childhood, often of respiratory
  insufficiency. MRI shows hypomyelination with a very small or absent putamen,
  small caudate and evolving cerebellar atrophy, the pattern of hypomyelination
  with atrophy of the basal ganglia and cerebellum (H-ABC) that is otherwise
  associated with dominant TUBB4A variants. A homozygous missense variant,
  p.Arg81Cys, found in two Sudanese families, causes a related early-onset
  encephalopathy with progressive microcephaly, delayed myelination and
  cerebellar hypoplasia but without the basal ganglia involvement of H-ABC.
  Mechanistically, UFMylation acts mainly at the
  endoplasmic reticulum, where modification of the ribosomal protein RPL26
  supports ER-associated ribosome quality control and ER-phagy; UFM1 loss in
  neurons induces ER stress and the unfolded protein response and reduces
  protein translation. How these neuronal defects relate to the failure of
  myelination is not established.
disease_term:
  preferred_term: Hypomyelinating leukodystrophy 14
  term:
    id: MONDO:0033486
    label: leukodystrophy, hypomyelinating, 14
synonyms:
- HLD14
- hypomyelinating leukodystrophy 14
- leukodystrophy, hypomyelinating, 14
- UFM1-related hypomyelinating leukodystrophy
- recessive H-ABC due to UFM1
parents:
- leukodystrophy
external_assertions:
- name: OMIM hypomyelinating leukodystrophy 14 record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:617899
  description: >-
    OMIM phenotype identifier for hypomyelinating leukodystrophy 14, cited as
    "MIM # 617899" in PMID:34573312.
- name: Orphanet hypomyelination with atrophy of basal ganglia and cerebellum record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:139441
  url: https://www.orpha.net/en/disease/detail/139441
  description: >-
    Orphanet's H-ABC record covers both the TUBB4A and UFM1 forms, so it is
    broader than HLD14 (a broad match, not an exact one).
inheritance:
- name: Autosomal Recessive
  description: >-
    Biallelic UFM1 variants are required. The Roma founder promoter deletion
    was homozygous in every affected child in the index series, while healthy
    Roma controls included heterozygous carriers but no homozygotes.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:34573312
    reference_title: "Four New Cases of Hypomyelinating Leukodystrophy Associated with the UFM1 c.-155_-153delTCA Founder Mutation in Pediatric Patients of Roma Descent in Hungary."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Hypomyelinating leukodystrophy type 14 (MIM # 617899) is caused by mutations in the UFM1 gene and is inherited in an autosomal recessive manner."
    explanation: >-
      States the recessive mode of inheritance for HLD14 in the paper's
      introduction.
  - reference: PMID:28931644
    reference_title: "UFM1 founder mutation in the Roma population causes recessive variant of H-ABC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sanger sequencing confirmed homozygosity for this variant in all 16 patients."
    explanation: >-
      Every affected child in the index series was homozygous for the founder
      deletion.
  - reference: PMID:28931644
    reference_title: "UFM1 founder mutation in the Roma population causes recessive variant of H-ABC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The Taqman screening assay confirmed a high carrier frequency and absence of homozygosity for the mutation among healthy Roma controls."
    explanation: >-
      Heterozygous carriers are unaffected, consistent with recessive
      inheritance.
prevalence:
- population: European Roma communities (carrier frequency of the UFM1 founder deletion)
  measure_type: CARRIER_FREQUENCY
  rate_low: 3000.0
  rate_high: 25000.0
  notes: >-
    Carrier rate of 3%-25% for c.-273_-271delTCA across 1,000 Roma controls
    from different European panels; the upper value comes from a single
    Eastern Slovak community (14 of 57 individuals), which was sampled because
    an affected child came from it and is endogamous, so it is
    ascertainment-biased. The pan-European figure from 670 Roma controls was
    4.5%. This is an allele-carrier figure in a founder population, not a
    disease prevalence.
  evidence:
  - reference: PMID:28931644
    reference_title: "UFM1 founder mutation in the Roma population causes recessive variant of H-ABC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Screening of 1,000 controls from different European Roma panels demonstrated an overall carrier rate of the mutation of 3%-25%."
    explanation: >-
      Population screening of Roma controls gives the founder-allele carrier
      rate.
  - reference: PMID:28931644
    reference_title: "UFM1 founder mutation in the Roma population causes recessive variant of H-ABC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subsequent investigation of the carrier rate in the specific community where the homozygous individual came from revealed a carrier rate of approximately 25% (14 out of 57 individuals)."
    explanation: >-
      Identifies the single community behind the 25% upper bound.
  - reference: PMID:28931644
    reference_title: "UFM1 founder mutation in the Roma population causes recessive variant of H-ABC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Screening of 670 Roma controls revealed 30 carriers with an overall carrier rate of 4.5% among different Roma communities across Europe"
    explanation: >-
      Representative pan-European carrier rate.
pathophysiology:
- name: Biallelic UFM1 Variants
  biological_scale: MOLECULAR
  description: >-
    Biallelic hypomorphic UFM1 variants. The predominant allele is a Roma
    founder 3-bp promoter deletion that lowers transcription; a rarer
    homozygous missense variant, p.Arg81Cys, alters the UFM1 C-terminal tail
    that binds UBA5. Complete loss is not observed: biallelic null alleles in
    UFMylation genes are depleted from human population databases, and
    knockout of the pathway is embryonic lethal in mice.
  genetic_context:
    gene:
      preferred_term: UFM1
      term:
        id: hgnc:20597
        label: UFM1
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
  downstream:
  - target: Reduced UFM1 Expression in Neural Cells
    causal_link_type: DIRECT
    description: >-
      Route taken by the Roma founder promoter deletion.
    evidence:
    - reference: PMID:28931644
      reference_title: "UFM1 founder mutation in the Roma population causes recessive variant of H-ABC."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The deletion significantly reduced promoter activity in SY-5Y and U373 but not in HeLa and HOG-F2 cell lines"
      explanation: >-
        Reporter assays show the promoter deletion reduces UFM1 transcription
        in neuroblastoma and astroglioma cells.
  - target: Impaired UFM1 Thioester Formation with UBA5 and UFC1
    causal_link_type: DIRECT
    description: >-
      Route taken by the p.Arg81Cys missense variant.
    evidence:
    - reference: PMID:29868776
      reference_title: "Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain development."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Accordingly, an in vitro pull-down assay revealed that the mutant has a lower binding affinity to UBA5 than wild-type UFM1"
      explanation: >-
        Pull-down assay showing the missense variant weakens UFM1 binding to
        UBA5.
  evidence:
  - reference: PMID:28931644
    reference_title: "UFM1 founder mutation in the Roma population causes recessive variant of H-ABC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "WES in 2 patients revealed a homozygous deletion in the promoter region of UFM1."
    explanation: >-
      Identifies the founder promoter deletion as the disease allele.
  - reference: PMID:29868776
    reference_title: "Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the conspicuous depletion of biallelic null mutations in the components of this pathway in human genome databases suggest that it is necessary for embryonic survival, which is consistent with the embryonic lethal nature of knockout models for the orthologous genes"
    explanation: >-
      Population-database depletion of null alleles and embryonic lethality
      of knockout models support describing disease alleles as hypomorphic
      rather than null.
  - reference: PMID:29868776
    reference_title: "Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain development."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our results show a reduction rather than abrogation of ufmylation with the activity of UFM1 and UFC1 mutants at 60-75% of their wild-type counterparts."
    explanation: >-
      Quantifies residual activity of the mutant proteins.
- name: Reduced UFM1 Expression in Neural Cells
  biological_scale: MOLECULAR
  description: >-
    The founder promoter deletion reduces UFM1 promoter activity in
    neuroblastoma (SH-SY5Y) and astroglioma (U373) cells but not in HeLa or
    oligodendroglioma-derived HOG cells, suggesting a cell-type-selective fall
    in UFM1 supply. That the oligodendroglial line was spared is notable given
    the hypomyelinating phenotype, although a single reporter assay in
    transformed cell lines is a weak guide to oligodendrocytes in vivo.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  downstream:
  - target: Impaired Protein UFMylation
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:28931644
    reference_title: "UFM1 founder mutation in the Roma population causes recessive variant of H-ABC."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Transfection assays showed that the deletion significantly reduced expression in specific CNS cell lines."
    explanation: >-
      Reporter-level evidence that the deletion lowers UFM1 expression in a
      CNS-cell-selective way.
- name: Impaired UFM1 Thioester Formation with UBA5 and UFC1
  biological_scale: MOLECULAR
  description: >-
    UFM1 p.Arg81Cys forms thioester intermediates with the E1 UBA5 and the E2
    UFC1 less efficiently than wild-type UFM1, reducing the amount of
    activated UFM1 available for conjugation. The molecular function below is
    UBA5's; the defect lies in the UFM1 substrate, so the annotation stands
    for reduced flux through the E1 step rather than a defective enzyme.
  molecular_functions:
  - preferred_term: UFM1 activating enzyme activity
    term:
      id: GO:0071566
      label: UFM1 activating enzyme activity
    modifier: DECREASED
  downstream:
  - target: Impaired Protein UFMylation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29868776
      reference_title: "Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain development."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "This mutation has a significantly diminished capacity to form thioester intermediates with UBA5 and with UFC1 (the E2-like enzyme for ufmylation), with resulting impaired ufmylation of cellular proteins."
      explanation: >-
        States both the thioester defect and its consequence for cellular
        UFMylation.
  evidence:
  - reference: PMID:29868776
    reference_title: "Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain development."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Taken together, our data show that UFM1R81C has a hypomorphic effect on the UFM1-system and provide a plausible mechanistic explanation."
    explanation: >-
      Characterizes the missense variant as hypomorphic.
- name: Impaired Protein UFMylation
  biological_scale: MOLECULAR
  description: >-
    Reduced covalent conjugation of UFM1 to cellular substrates. Two
    substrates tie UFMylation to the endoplasmic reticulum: the 60S ribosomal
    protein RPL26, the principal UFMylation target, and the ER membrane
    reductase CYB5R3, whose UFMylation triggers ER-phagy. The molecular function
    below is UFM1's own: it is the covalent tag, so reduced UFM1 availability
    reduces the tagging activity itself rather than an enzyme acting on it.
  genes:
  - preferred_term: UFM1
    term:
      id: hgnc:20597
      label: UFM1
  molecular_functions:
  - preferred_term: UFM1 protein tag activity
    term:
      id: GO:0031386
      label: protein tag activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: protein ufmylation
    term:
      id: GO:0071569
      label: protein ufmylation
    modifier: DECREASED
  downstream:
  - target: Defective ER-Associated Ribosome Quality Control
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40315331
      reference_title: "UFMylation orchestrates spatiotemporal coordination of RQC at the ER."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "Degradation of arrest peptides from endoplasmic reticulum (ER) translocon-bound 60S ribosomal subunits via the ribosome-associated quality control (ER-RQC) pathway requires covalent modification of RPL26/uL24 on 60S ribosomal subunits with UFM1."
      explanation: >-
        Establishes that ER-RQC requires RPL26 UFMylation. Indirect for HLD14
        because it is shown in cell-free and cell systems, not in patient
        cells.
  - target: Impaired ER-Phagy
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36543799
      reference_title: "The UFM1 system regulates ER-phagy through the ufmylation of CYB5R3."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "Our results indicate that CYB5R3 ufmylation induces ER-phagy, which is indispensable for brain development."
      explanation: >-
        Identifies CYB5R3 UFMylation as a trigger for ER-phagy. Indirect
        because it is not shown in HLD14 patient cells.
  evidence:
  - reference: PMID:30626644
    reference_title: "Ribosomal protein RPL26 is the principal target of UFMylation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here, we show that a largely uncharacterized ribosomal protein, RPL26, is the principal target of UFM1 conjugation."
    explanation: >-
      Identifies the dominant substrate of the process the disease impairs.
  - reference: PMID:29868776
    reference_title: "Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain development."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We also found that the level of two UFM1-conjugates with cellular proteins in patient-derived lymphoblasts was significantly reduced compared to control lymphoblasts"
    explanation: >-
      Reduced UFM1 conjugates measured in lymphoblasts from a patient
      homozygous for UFM1 p.Arg81Cys.
- name: Defective ER-Associated Ribosome Quality Control
  biological_scale: CELLULAR
  description: >-
    UFMylated RPL26 is enriched on ER membrane-bound ribosomes near the SEC61
    translocon, and its modification is needed to release and degrade arrested
    nascent chains on translocon-bound 60S subunits. Loss of this step is
    expected to compromise cotranslational protein biogenesis at the ER.
  biological_processes:
  - preferred_term: ribosome-associated quality control at the ER
    term:
      id: GO:0072344
      label: rescue of stalled cytosolic ribosome
    modifier: DECREASED
  downstream:
  - target: ER Stress and Unfolded Protein Response Activation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed link: ER protein-biogenesis failure is the natural source of the
      ER stress seen in UFM1-deficient neurons, but no study has shown the
      ribosome-quality-control defect itself drives the stress response in a
      disease model.
  evidence:
  - reference: PMID:30626644
    reference_title: "Ribosomal protein RPL26 is the principal target of UFMylation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These data suggest that UFMylation is a ribosomal modification specialized to facilitate metazoan-specific protein biogenesis at the ER."
    explanation: >-
      Places RPL26 UFMylation in ER-coupled protein biogenesis.
- name: Impaired ER-Phagy
  biological_scale: CELLULAR
  description: >-
    UFMylation of CYB5R3 on the ER membrane marks it for lysosomal turnover
    through ER-phagy. Mice carrying a UFMylation-resistant Cyb5r3 develop
    microcephaly, linking this branch to brain growth.
  biological_processes:
  - preferred_term: reticulophagy
    term:
      id: GO:0061709
      label: reticulophagy
    modifier: DECREASED
  downstream:
  - target: Neuronal Death and Impaired Brain Growth
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36543799
      reference_title: "The UFM1 system regulates ER-phagy through the ufmylation of CYB5R3."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "ufmylation-defective Cyb5r3 knock-in mice exhibit microcephaly"
      explanation: >-
        Blocking CYB5R3 UFMylation alone is enough to reduce brain size in
        mice. Indirect because the mice carry a substrate mutation, not a UFM1
        variant.
  evidence:
  - reference: PMID:36543799
    reference_title: "The UFM1 system regulates ER-phagy through the ufmylation of CYB5R3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Ufmylated CYB5R3 is degraded in lysosomes, which depends on the autophagy-related protein Atg7- and the autophagy-adaptor protein CDK5RAP3."
    explanation: >-
      Describes the ER-phagy pathway that depends on CYB5R3 UFMylation.
- name: ER Stress and Unfolded Protein Response Activation
  biological_scale: CELLULAR
  description: >-
    UFM1-deficient mouse neurons show ER stress and activation of the PERK
    arm of the unfolded protein response; ATF6 and IRE1alpha were also
    measured and did not rise. Neurons expressing UFM1 p.Arg81Cys respond to ER stress
    differently from UFM1-null neurons, so the missense allele is not simply a
    weaker version of loss.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: PERK-mediated unfolded protein response
    term:
      id: GO:0036499
      label: PERK-mediated unfolded protein response
    modifier: INCREASED
  downstream:
  - target: Reduced Neuronal Protein Translation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Supported for UFM1-R81C neurons only. The UPR inhibitor trazodone
      restored translation in R81C neurons but not in UFM1-null neurons, so
      the UPR does not account for the translation loss after complete UFM1
      loss, and the change in phosphorylated eIF2alpha downstream of PERK did
      not reach significance.
    evidence:
    - reference: PMID:41731076
      reference_title: "Encephalopathy-linked UFM1 variants impede neuronal protein translation, development, and function."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "Exploring therapeutic options, we show that Trazodone, an inhibitor of the UPR, restores protein translation solely in UFM1-R81C-expressing neurons"
      explanation: >-
        Pharmacologically inhibiting the UPR restores translation in
        UFM1-R81C neurons, which places the UPR upstream of the translation
        defect for that variant. Indirect because it is inferred from a drug
        rescue, and it did not hold for UFM1-null neurons.
  evidence:
  - reference: PMID:41731076
    reference_title: "Encephalopathy-linked UFM1 variants impede neuronal protein translation, development, and function."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Mechanistically, UFM1 loss is associated with induction of ER stress, activation of the unfolded protein response (UPR) pathway, and reduced protein translation."
    explanation: >-
      Direct observation of ER stress and UPR activation in UFM1-deficient
      cultured mouse neurons.
  - reference: PMID:41731076
    reference_title: "Encephalopathy-linked UFM1 variants impede neuronal protein translation, development, and function."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "UFM1-deficient and UFM1-R81C-expressing neurons display distinct responses to ER stress, indicating that UFM1-R81C is not merely a loss-of-function variant."
    explanation: >-
      Shows the missense and null states diverge at this node.
  - reference: PMID:29868776
    reference_title: "Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain development."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "Neither did we note appreciable difference in endoplasmic reticulum stress-induced apoptosis in cells expressing UFM1 wild-type or UFM1 p.R81C, after 48 h incubation in tunicamycin at various concentrations."
    explanation: >-
      In a non-neuronal overexpression system, p.Arg81Cys did not change ER
      stress-induced apoptosis, so the ER stress phenotype may be
      neuron-specific or depend on the model.
- name: Reduced Neuronal Protein Translation
  biological_scale: CELLULAR
  description: >-
    UFM1 loss reduces global protein synthesis in neurons. Wild-type UFM1
    restores it; UFM1 p.Arg81Cys restores it only partly.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: translation
    term:
      id: GO:0006412
      label: translation
    modifier: DECREASED
  downstream:
  - target: Impaired Neuronal Development and Synapse Function
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:41731076
    reference_title: "Encephalopathy-linked UFM1 variants impede neuronal protein translation, development, and function."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These defects are rescued by wild-type UFM1, but only partially by UFM1-R81C."
    explanation: >-
      Rescue experiments tie the translation defect to UFM1 and show the
      missense variant is hypomorphic.
- name: Impaired Neuronal Development and Synapse Function
  biological_scale: CELLULAR
  description: >-
    UFM1-deficient mouse neurons develop abnormally and have impaired synapse
    function; trazodone increases synapse numbers in both UFM1-null and
    UFM1-R81C neurons.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  downstream:
  - target: Profound Global Developmental Delay
  - target: Drug-Resistant Epilepsy
  evidence:
  - reference: PMID:41731076
    reference_title: "Encephalopathy-linked UFM1 variants impede neuronal protein translation, development, and function."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We found that UFM1-deficiency confounds neuron development and synapse function."
    explanation: >-
      Direct observation in cultured UFM1-deficient neurons.
- name: Neuronal Death and Impaired Brain Growth
  biological_scale: TISSUE
  description: >-
    Loss of UFMylation in the developing mouse nervous system causes neuronal
    apoptosis and microcephaly, matching the progressive microcephaly and brain
    atrophy seen in patients.
  biological_processes:
  - preferred_term: neuron apoptotic process
    term:
      id: GO:0051402
      label: neuron apoptotic process
    modifier: INCREASED
  downstream:
  - target: Progressive Microcephaly
  - target: Cerebral Atrophy
  - target: Cerebellar Atrophy
  - target: Very Small or Absent Putamen
  - target: Small Caudate Nucleus
    evidence:
    - reference: PMID:28931644
      reference_title: "UFM1 founder mutation in the Roma population causes recessive variant of H-ABC."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "they consistently have an additional feature: signal abnormality of the lateral part of the head of the caudate nucleus suggestive of local apoptosis"
      explanation: >-
        The authors read the caudate signal change on MRI as local cell
        death. Indirect because it is an imaging interpretation, not
        neuropathology.
  - target: Caudate Head Signal Abnormality
    evidence:
    - reference: PMID:28931644
      reference_title: "UFM1 founder mutation in the Roma population causes recessive variant of H-ABC."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "they consistently have an additional feature: signal abnormality of the lateral part of the head of the caudate nucleus suggestive of local apoptosis"
      explanation: >-
        The authors attribute the caudate head signal change to local cell
        death. Indirect because it is an imaging interpretation.
  - target: Corpus Callosum Atrophy
  - target: Enlarged Cisterna Magna
  - target: Developmental Regression
  evidence:
  - reference: PMID:28931644
    reference_title: "UFM1 founder mutation in the Roma population causes recessive variant of H-ABC."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: "CNS-specific knockout of Ufm1 in mice caused neonatal death with microcephaly and apoptosis of neurons in specific brain regions."
    explanation: >-
      Summarizes the CNS-specific Ufm1 knockout mouse, cited in the discussion
      of the human gene-discovery paper.
- name: Deficient CNS Myelination
  biological_scale: TISSUE
  description: >-
    Permanent hypomyelination of the cerebral white matter, the defining MRI
    feature. The step from reduced UFMylation to failed myelination has not
    been studied in UFM1-deficient oligodendrocytes, so this node has no
    sourced upstream edge.
  biological_processes:
  - preferred_term: central nervous system myelination
    term:
      id: GO:0022010
      label: central nervous system myelination
    modifier: DECREASED
  cell_types:
  - preferred_term: oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  downstream:
  - target: CNS Hypomyelination
  evidence:
  - reference: PMID:35189806
    reference_title: "Hypomyelination with Atrophy of Basal Ganglia and Cerebellum (HABC) Due to UFM1 Mutation in Roma Patients - Severe Early Encephalopathy with Stridor and Severe Hearing and Visual Impairment. A Single Center Experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain imaging revealed cortical atrophy (7/9), atrophic ventricular dilatation (4/9), macrocisterna magna (5/9), reduced myelination (6/6), corpus callosum atrophy (3/6) and abnormal putamen and caput nuclei caudati."
    explanation: >-
      Reduced myelination in every patient imaged in this series.
phenotypes:
- category: Neurological
  name: CNS Hypomyelination
  description: >-
    Diffuse hypomyelination of the cerebral white matter on MRI, defined in the
    index series as mildly raised T2 signal in most cerebral white matter with
    mild T1 changes.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: CNS hypomyelination
    term:
      id: HP:0003429
      label: CNS hypomyelination
  evidence:
  - reference: PMID:28931644
    reference_title: "UFM1 founder mutation in the Roma population causes recessive variant of H-ABC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "(1) hypomyelination, defined as a mildly elevated T2 signal intensity of most cerebral white matter in combination with mild T1 hypointensity, T1 isointensity, or mild T1 hyperintensity relative to the cortex"
    explanation: >-
      Hypomyelination was an inclusion criterion met by all 16 patients.
  - reference: PMID:39470296
    reference_title: "Neuroimaging to Genotype: Delineating the Spectrum of Disorders With Deficient Myelination in the Indian Population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, P12 with HLD14 presented only with diffuse cerebral hypomyelination on neuroimaging"
    explanation: >-
      An Indian patient with HLD14 had diffuse hypomyelination without the
      other H-ABC features, suggesting hypomyelination may occur even when
      the basal ganglia and cerebellum are spared (a single patient).
- category: Neurological
  name: Very Small or Absent Putamen
  description: >-
    A very small or absent putamen without signal change indicating a lesion,
    one of the two MRI criteria for H-ABC.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Very small or absent putamen
    term:
      id: HP:0031982
      label: Abnormal putamen morphology
  evidence:
  - reference: PMID:28931644
    reference_title: "UFM1 founder mutation in the Roma population causes recessive variant of H-ABC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "None of the patients showed a normal putamen and in all patients the caudate nucleus was small."
    explanation: >-
      Putamen abnormality in every patient in the index series.
- category: Neurological
  name: Small Caudate Nucleus
  description: >-
    A small caudate nucleus, part of the basal ganglia atrophy of H-ABC.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Small caudate nucleus
    term:
      id: HP:0002340
      label: Caudate atrophy
  evidence:
  - reference: PMID:28931644
    reference_title: "UFM1 founder mutation in the Roma population causes recessive variant of H-ABC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "None of the patients showed a normal putamen and in all patients the caudate nucleus was small."
    explanation: >-
      Small caudate nucleus in every patient in the index series.
- category: Neurological
  name: Cerebellar Atrophy
  description: >-
    Mild cerebellar atrophy, initially restricted to the vermis, present on
    first MRI in about half of patients and developing on follow-up in others.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:28931644
    reference_title: "UFM1 founder mutation in the Roma population causes recessive variant of H-ABC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On the first MRI, 56% of patients had mild cerebellar atrophy, restricted to the vermis."
    explanation: >-
      Gives the frequency on first imaging.
  - reference: PMID:28931644
    reference_title: "UFM1 founder mutation in the Roma population causes recessive variant of H-ABC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 4 patients who initially lacked cerebellar atrophy, follow-up MRIs revealed cerebellar atrophy after 3-15 months."
    explanation: >-
      Shows the atrophy is progressive.
- category: Neurological
  name: Cerebral Atrophy
  description: >-
    Cortical atrophy with atrophic ventricular dilatation.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
  evidence:
  - reference: PMID:35189806
    reference_title: "Hypomyelination with Atrophy of Basal Ganglia and Cerebellum (HABC) Due to UFM1 Mutation in Roma Patients - Severe Early Encephalopathy with Stridor and Severe Hearing and Visual Impairment. A Single Center Experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain imaging revealed cortical atrophy (7/9), atrophic ventricular dilatation (4/9), macrocisterna magna (5/9), reduced myelination (6/6), corpus callosum atrophy (3/6) and abnormal putamen and caput nuclei caudati."
    explanation: >-
      Cortical atrophy in 7 of 9 patients.
- category: Neurological
  name: Enlarged Cisterna Magna
  description: >-
    An enlarged cisterna magna on imaging.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Enlarged cisterna magna
    term:
      id: HP:0002280
      label: Enlarged cisterna magna
  evidence:
  - reference: PMID:35189806
    reference_title: "Hypomyelination with Atrophy of Basal Ganglia and Cerebellum (HABC) Due to UFM1 Mutation in Roma Patients - Severe Early Encephalopathy with Stridor and Severe Hearing and Visual Impairment. A Single Center Experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain imaging revealed cortical atrophy (7/9), atrophic ventricular dilatation (4/9), macrocisterna magna (5/9), reduced myelination (6/6), corpus callosum atrophy (3/6) and abnormal putamen and caput nuclei caudati."
    explanation: >-
      Enlarged cisterna magna in 5 of 9 patients.
- category: Neurological
  name: Corpus Callosum Atrophy
  description: >-
    Atrophy of the corpus callosum.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Corpus callosum atrophy
    term:
      id: HP:0007371
      label: Corpus callosum atrophy
  evidence:
  - reference: PMID:35189806
    reference_title: "Hypomyelination with Atrophy of Basal Ganglia and Cerebellum (HABC) Due to UFM1 Mutation in Roma Patients - Severe Early Encephalopathy with Stridor and Severe Hearing and Visual Impairment. A Single Center Experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain imaging revealed cortical atrophy (7/9), atrophic ventricular dilatation (4/9), macrocisterna magna (5/9), reduced myelination (6/6), corpus callosum atrophy (3/6) and abnormal putamen and caput nuclei caudati."
    explanation: >-
      Corpus callosum atrophy in 3 of 6 patients with imaging.
- category: Neurological
  name: Progressive Microcephaly
  description: >-
    Postnatal microcephaly that worsens with age; present in every patient of
    the index series and in the p.Arg81Cys families.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Progressive microcephaly
    term:
      id: HP:0000253
      label: Progressive microcephaly
  evidence:
  - reference: PMID:28931644
    reference_title: "UFM1 founder mutation in the Roma population causes recessive variant of H-ABC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Stunted growth was frequent and all patients had microcephaly."
    explanation: >-
      Microcephaly in all 16 patients.
  - reference: PMID:29868776
    reference_title: "Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we establish a locus for severe early-onset encephalopathy with progressive microcephaly based on two families, and map the phenotype to a novel homozygous UFM1 mutation."
    explanation: >-
      Progressive microcephaly with the homozygous p.Arg81Cys variant.
- category: Neurological
  name: Profound Global Developmental Delay
  description: >-
    Development is absent or minimal, with almost no motor or cognitive
    skills and no language.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Profound global developmental delay
    term:
      id: HP:0012736
      label: Profound global developmental delay
  evidence:
  - reference: PMID:28931644
    reference_title: "UFM1 founder mutation in the Roma population causes recessive variant of H-ABC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sixteen patients from 14 families from different countries fulfilling the MRI criteria for H-ABC exhibited a similar, severe clinical phenotype, including lack of development and a severe epileptic encephalopathy."
    explanation: >-
      Lack of development across the index series.
  - reference: PMID:34573312
    reference_title: "Four New Cases of Hypomyelinating Leukodystrophy Associated with the UFM1 c.-155_-153delTCA Founder Mutation in Pediatric Patients of Roma Descent in Hungary."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "It is characterized by hypotonia, an almost complete lack of motor or cognitive skills, absent language development, spasticity, and intractable seizures."
    explanation: >-
      Summary of the HLD14 phenotype in the paper's introduction.
- category: Neurological
  name: Developmental Regression
  description: >-
    Any early development is lost after 2-5 months.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:35189806
    reference_title: "Hypomyelination with Atrophy of Basal Ganglia and Cerebellum (HABC) Due to UFM1 Mutation in Roma Patients - Severe Early Encephalopathy with Stridor and Severe Hearing and Visual Impairment. A Single Center Experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurodevelopment was absent or minimal with subsequent regression after 2-5 mo."
    explanation: >-
      Regression after early infancy in the Bulgarian series.
- category: Neurological
  name: Drug-Resistant Epilepsy
  description: >-
    Seizures develop in all patients who survive past 18 months and are often
    severe and drug-resistant, including West syndrome.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Epileptic encephalopathy
    term:
      id: HP:0200134
      label: Epileptic encephalopathy
  phenotype_contexts:
  - onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:28931644
    reference_title: "UFM1 founder mutation in the Roma population causes recessive variant of H-ABC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seizures were frequent and present in all patients 18 months and older."
    explanation: >-
      Seizures become universal among older survivors.
  - reference: PMID:28931644
    reference_title: "UFM1 founder mutation in the Roma population causes recessive variant of H-ABC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The epilepsy was often severe and drug-resistant, including West syndrome."
    explanation: >-
      Drug resistance and West syndrome.
  - reference: PMID:28931644
    reference_title: "UFM1 founder mutation in the Roma population causes recessive variant of H-ABC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "exhibited a similar, severe clinical phenotype, including lack of development and a severe epileptic encephalopathy"
    explanation: >-
      The index series characterizes the epilepsy as an epileptic
      encephalopathy.
  - reference: PMID:35189806
    reference_title: "Hypomyelination with Atrophy of Basal Ganglia and Cerebellum (HABC) Due to UFM1 Mutation in Roma Patients - Severe Early Encephalopathy with Stridor and Severe Hearing and Visual Impairment. A Single Center Experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "epileptic seizures (4/9), non-epileptic spells (3/9)"
    explanation: >-
      In a series where most children died before 18 months, seizures were
      seen in 4 of 9, which fits seizures becoming more common with age.
- category: Neurological
  name: Infantile Spasms
  description: >-
    West syndrome is among the reported epilepsy types.
  phenotype_term:
    preferred_term: Infantile spasms
    term:
      id: HP:0012469
      label: Infantile spasms
  evidence:
  - reference: PMID:28931644
    reference_title: "UFM1 founder mutation in the Roma population causes recessive variant of H-ABC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The epilepsy was often severe and drug-resistant, including West syndrome."
    explanation: >-
      West syndrome is defined by infantile spasms.
- category: Neurological
  name: Spasticity
  description: >-
    Spasticity, progressing to spastic quadriparesis.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:28931644
    reference_title: "UFM1 founder mutation in the Roma population causes recessive variant of H-ABC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Almost all patients exhibited spasticity and extrapyramidal movement abnormalities, mostly dystonia."
    explanation: >-
      Spasticity in almost all patients.
  - reference: PMID:42195294
    reference_title: "Rare Genetic Diseases with Founder Effect in Roma Children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disorder is severe, with most patients dying before one year of age, and is characterized by inspiratory stridor, axial hypotonia, spastic quadriparesis, pseudobulbar signs, and microcephaly."
    explanation: >-
      Spastic quadriparesis in the largest HLD14 cohort (17 patients).
- category: Neurological
  name: Dystonia
  description: >-
    Extrapyramidal movement abnormalities, mostly dystonic posturing.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:28931644
    reference_title: "UFM1 founder mutation in the Roma population causes recessive variant of H-ABC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Almost all patients exhibited spasticity and extrapyramidal movement abnormalities, mostly dystonia."
    explanation: >-
      Dystonia as the main extrapyramidal sign.
- category: Neurological
  name: Axial Hypotonia with Limb Hypertonia
  description: >-
    Axial hypotonia with limb hypertonia, progressing to opisthotonus. Axial
    hypotonia was reported in all 17 Romanian patients but in 4 of 9
    Bulgarian patients, where limb hypertonia was universal.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Axial hypotonia
    term:
      id: HP:0008936
      label: Axial hypotonia
  evidence:
  - reference: PMID:35189806
    reference_title: "Hypomyelination with Atrophy of Basal Ganglia and Cerebellum (HABC) Due to UFM1 Mutation in Roma Patients - Severe Early Encephalopathy with Stridor and Severe Hearing and Visual Impairment. A Single Center Experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "microcephaly (6/9), malnutrition (5/9), muscle hypertonia (9/9) and axial hypotonia (4/9), progressing to opisthotonus (6/9), dystonic posturing (5/9), nystagmoid ocular movements (6/9)"
    explanation: >-
      Hypertonia in 9 of 9 and axial hypotonia in 4 of 9 patients.
  - reference: PMID:42195294
    reference_title: "Rare Genetic Diseases with Founder Effect in Roma Children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients presented with several clinical manifestations, including inspiratory laryngeal stridor, axial hypotonia, spastic quadriparesis, pseudobulbar syndrome, and microcephaly"
    explanation: >-
      Axial hypotonia in all 17 patients of the largest cohort.
- category: Neurological
  name: Opisthotonus
  description: >-
    Opisthotonic posturing develops by about 10 months.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Opisthotonus
    term:
      id: HP:0002179
      label: Opisthotonus
  evidence:
  - reference: PMID:35189806
    reference_title: "Hypomyelination with Atrophy of Basal Ganglia and Cerebellum (HABC) Due to UFM1 Mutation in Roma Patients - Severe Early Encephalopathy with Stridor and Severe Hearing and Visual Impairment. A Single Center Experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "microcephaly (6/9), malnutrition (5/9), muscle hypertonia (9/9) and axial hypotonia (4/9), progressing to opisthotonus (6/9), dystonic posturing (5/9), nystagmoid ocular movements (6/9)"
    explanation: >-
      Opisthotonus in 6 of 9 patients.
- category: Ophthalmological
  name: Nystagmoid Eye Movements
  description: >-
    Nystagmus-like ocular movements.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Nystagmoid ocular movements
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:35189806
    reference_title: "Hypomyelination with Atrophy of Basal Ganglia and Cerebellum (HABC) Due to UFM1 Mutation in Roma Patients - Severe Early Encephalopathy with Stridor and Severe Hearing and Visual Impairment. A Single Center Experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "microcephaly (6/9), malnutrition (5/9), muscle hypertonia (9/9) and axial hypotonia (4/9), progressing to opisthotonus (6/9), dystonic posturing (5/9), nystagmoid ocular movements (6/9)"
    explanation: >-
      Nystagmoid movements in 6 of 9 patients.
- category: Respiratory
  name: Inspiratory Stridor
  description: >-
    Inspiratory stridor from the first two months of life, a presenting sign
    and one of the clinical clues to the diagnosis.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Inspiratory stridor
    term:
      id: HP:0005348
      label: Inspiratory stridor
  phenotype_contexts:
  - onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:35189806
    reference_title: "Hypomyelination with Atrophy of Basal Ganglia and Cerebellum (HABC) Due to UFM1 Mutation in Roma Patients - Severe Early Encephalopathy with Stridor and Severe Hearing and Visual Impairment. A Single Center Experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dysphagia (7/9), inspiratory stridor (9/9), dyspnea (5/9), bradypnea (5/9), apnea (2/9) were major signs."
    explanation: >-
      Stridor in all 9 patients.
  - reference: PMID:42195294
    reference_title: "Rare Genetic Diseases with Founder Effect in Roma Children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disorder is severe, with most patients dying before one year of age, and is characterized by inspiratory stridor, axial hypotonia, spastic quadriparesis, pseudobulbar signs, and microcephaly."
    explanation: >-
      Stridor is characteristic in the largest cohort.
- category: Respiratory
  name: Bradypnea and Apnea
  description: >-
    Slow breathing in about half of patients and apneas in some.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Bradypnea
    term:
      id: HP:0046507
      label: Bradypnea
  evidence:
  - reference: PMID:35189806
    reference_title: "Hypomyelination with Atrophy of Basal Ganglia and Cerebellum (HABC) Due to UFM1 Mutation in Roma Patients - Severe Early Encephalopathy with Stridor and Severe Hearing and Visual Impairment. A Single Center Experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dysphagia (7/9), inspiratory stridor (9/9), dyspnea (5/9), bradypnea (5/9), apnea (2/9) were major signs."
    explanation: >-
      Bradypnea in 5 of 9 and apnea in 2 of 9 patients.
- category: Digestive
  name: Dysphagia
  description: >-
    Impaired sucking and swallowing from early infancy, with pseudobulbar signs.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:35189806
    reference_title: "Hypomyelination with Atrophy of Basal Ganglia and Cerebellum (HABC) Due to UFM1 Mutation in Roma Patients - Severe Early Encephalopathy with Stridor and Severe Hearing and Visual Impairment. A Single Center Experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Presentation is no later than 2 months with inspiratory stridor, impaired sucking, swallowing, vision and hearing, and reduced active movements."
    explanation: >-
      Impaired sucking and swallowing are presenting features.
  - reference: PMID:35189806
    reference_title: "Hypomyelination with Atrophy of Basal Ganglia and Cerebellum (HABC) Due to UFM1 Mutation in Roma Patients - Severe Early Encephalopathy with Stridor and Severe Hearing and Visual Impairment. A Single Center Experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dysphagia (7/9), inspiratory stridor (9/9), dyspnea (5/9), bradypnea (5/9), apnea (2/9) were major signs."
    explanation: >-
      Dysphagia in 7 of 9 patients.
- category: Ophthalmological
  name: Visual Impairment
  description: >-
    Vision is never acquired or is lost by 4-8 months.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
  evidence:
  - reference: PMID:35189806
    reference_title: "Hypomyelination with Atrophy of Basal Ganglia and Cerebellum (HABC) Due to UFM1 Mutation in Roma Patients - Severe Early Encephalopathy with Stridor and Severe Hearing and Visual Impairment. A Single Center Experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vision and hearing were never achieved or lost by 4-8 mo."
    explanation: >-
      Severe visual impairment in the Bulgarian series.
- category: Ear
  name: Hearing Impairment
  description: >-
    Hearing is never acquired or is lost by 4-8 months.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:35189806
    reference_title: "Hypomyelination with Atrophy of Basal Ganglia and Cerebellum (HABC) Due to UFM1 Mutation in Roma Patients - Severe Early Encephalopathy with Stridor and Severe Hearing and Visual Impairment. A Single Center Experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vision and hearing were never achieved or lost by 4-8 mo."
    explanation: >-
      Severe hearing impairment in the Bulgarian series.
- category: Growth
  name: Failure to Thrive
  description: >-
    Malnutrition and stunted growth; the p.Arg81Cys families were also short
    and underweight.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:35189806
    reference_title: "Hypomyelination with Atrophy of Basal Ganglia and Cerebellum (HABC) Due to UFM1 Mutation in Roma Patients - Severe Early Encephalopathy with Stridor and Severe Hearing and Visual Impairment. A Single Center Experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "microcephaly (6/9), malnutrition (5/9), muscle hypertonia (9/9) and axial hypotonia (4/9), progressing to opisthotonus (6/9), dystonic posturing (5/9), nystagmoid ocular movements (6/9)"
    explanation: >-
      Malnutrition in 5 of 9 patients.
  - reference: PMID:34573312
    reference_title: "Four New Cases of Hypomyelinating Leukodystrophy Associated with the UFM1 c.-155_-153delTCA Founder Mutation in Pediatric Patients of Roma Descent in Hungary."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Mutations in the UFM1 gene are associated with Hypomyelinating leukodystrophy type 14, presenting with global developmental delay, failure to thrive, progressive microcephaly, refractive epilepsy, and hypomyelination, with atrophy of the basal ganglia and cerebellum phenotypes."
    explanation: >-
      Lists failure to thrive among the core HLD14 features.
- category: Growth
  name: Short Stature
  description: >-
    Stunted growth is frequent.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:28931644
    reference_title: "UFM1 founder mutation in the Roma population causes recessive variant of H-ABC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Stunted growth was frequent and all patients had microcephaly."
    explanation: >-
      Stunted growth is frequent in the index series.
- category: Neurological
  name: Pseudobulbar Signs
  description: >-
    Pseudobulbar syndrome, reported in all patients of the largest cohort and
    contributing to the swallowing and airway problems.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Pseudobulbar signs
    term:
      id: HP:0002200
      label: Pseudobulbar signs
  evidence:
  - reference: PMID:42195294
    reference_title: "Rare Genetic Diseases with Founder Effect in Roma Children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients presented with several clinical manifestations, including inspiratory laryngeal stridor, axial hypotonia, spastic quadriparesis, pseudobulbar syndrome, and microcephaly"
    explanation: >-
      Pseudobulbar syndrome in all 17 patients.
- category: Neurological
  name: Caudate Head Signal Abnormality
  description: >-
    Abnormal T2 signal in the lateral part of the head of the caudate nucleus,
    seen consistently in UFM1-related H-ABC and proposed as pathognomonic for
    it; not seen in TUBB4A-related H-ABC.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Abnormal basal ganglia MRI signal intensity
    term:
      id: HP:0012751
      label: Abnormal basal ganglia MRI signal intensity
  evidence:
  - reference: PMID:28931644
    reference_title: "UFM1 founder mutation in the Roma population causes recessive variant of H-ABC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "they consistently have an additional feature: signal abnormality of the lateral part of the head of the caudate nucleus suggestive of local apoptosis"
    explanation: >-
      Consistent caudate head signal change in the index series.
  - reference: PMID:28931644
    reference_title: "UFM1 founder mutation in the Roma population causes recessive variant of H-ABC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This feature has not been observed in TUBB4A-related H-ABC and may be pathognomonic for UFM1-related H-ABC."
    explanation: >-
      Proposed as distinguishing UFM1- from TUBB4A-related H-ABC.
- category: Respiratory
  name: Respiratory Insufficiency
  description: >-
    The most common cause of death.
  phenotype_term:
    preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  evidence:
  - reference: PMID:28931644
    reference_title: "UFM1 founder mutation in the Roma population causes recessive variant of H-ABC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nine patients died at ages between 7 months and 7 years, most often due to respiratory insufficiency."
    explanation: >-
      Respiratory insufficiency as the usual cause of death.
  - reference: PMID:28931644
    reference_title: "UFM1 founder mutation in the Roma population causes recessive variant of H-ABC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Six patients underwent tracheostomy between 6 and 17 months, 4 of whom were on intermittent or permanent ventilation."
    explanation: >-
      Respiratory failure severe enough to need tracheostomy in 6 of 16 patients.
progression:
- phase: Early death, usually from respiratory insufficiency
  age_range: 7 months to 7 years; median about 1-2 years depending on cohort
  notes: >-
    Most children homozygous for the founder deletion die in infancy or early
    childhood, most often of respiratory insufficiency. Curated under
    progression rather than phenotypes because HP:0001522 Death in infancy is
    in the HPO mortality branch and not in the PhenotypeTerm enum.
  evidence:
  - reference: PMID:28931644
    reference_title: "UFM1 founder mutation in the Roma population causes recessive variant of H-ABC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nine patients died at ages between 7 months and 7 years, most often due to respiratory insufficiency."
    explanation: >-
      Age range and cause of death in the index series.
  - reference: PMID:35189806
    reference_title: "Hypomyelination with Atrophy of Basal Ganglia and Cerebellum (HABC) Due to UFM1 Mutation in Roma Patients - Severe Early Encephalopathy with Stridor and Severe Hearing and Visual Impairment. A Single Center Experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The age at death was between 8 and 18 mo."
    explanation: >-
      Death in infancy in the Bulgarian series.
  - reference: PMID:34573312
    reference_title: "Four New Cases of Hypomyelinating Leukodystrophy Associated with the UFM1 c.-155_-153delTCA Founder Mutation in Pediatric Patients of Roma Descent in Hungary."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The median survival of the patients was 28 months, not counting the youngest who is still alive at 17 months of age."
    explanation: >-
      Longer median survival in the Hungarian series than in the Bulgarian
      and Romanian cohorts.
  - reference: PMID:28931644
    reference_title: "UFM1 founder mutation in the Roma population causes recessive variant of H-ABC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Median survival was 2 years."
    explanation: >-
      Median survival in the index series.
  - reference: PMID:42195294
    reference_title: "Rare Genetic Diseases with Founder Effect in Roma Children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The average age at death was 11.8 months, and the longest-surviving patient lived to be 30 months old."
    explanation: >-
      Mean age at death in the largest cohort.
  - reference: PMID:42195294
    reference_title: "Rare Genetic Diseases with Founder Effect in Roma Children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disorder is severe, with most patients dying before one year of age, and is characterized by inspiratory stridor, axial hypotonia, spastic quadriparesis, pseudobulbar signs, and microcephaly."
    explanation: >-
      Most patients in the largest cohort died before one year.
genetic:
- name: UFM1
  gene_term:
    preferred_term: UFM1
    term:
      id: hgnc:20597
      label: UFM1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: >-
    Biallelic hypomorphic UFM1 variants cause HLD14. Most patients are
    homozygous for a Roma founder promoter deletion on a shared haplotype; the
    homozygous p.Arg81Cys missense variant causes a related early-onset
    encephalopathy with progressive microcephaly, in which none of four
    patients had basal ganglia abnormalities.
  evidence:
  - reference: PMID:28931644
    reference_title: "UFM1 founder mutation in the Roma population causes recessive variant of H-ABC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study, focused on identifying the mutated gene in patients with H-ABC without TUBB4A mutations, revealed a homozygous 3-bp deletion in the UFM1 promoter area, which perfectly segregates with the disease."
    explanation: >-
      Gene discovery by homozygosity mapping and exome sequencing, with
      segregation.
  - reference: PMID:28931644
    reference_title: "UFM1 founder mutation in the Roma population causes recessive variant of H-ABC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients shared a common haplotype, indicative of a founder effect."
    explanation: >-
      Founder origin of the recurrent allele.
  - reference: PMID:29868776
    reference_title: "Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we establish a locus for severe early-onset encephalopathy with progressive microcephaly based on two families, and map the phenotype to a novel homozygous UFM1 mutation."
    explanation: >-
      Independent UFM1 missense allele in two further families.
variants:
- name: UFM1 c.-273_-271delTCA
  description: >-
    A 3-bp deletion in the UFM1 promoter, the Roma founder allele. The same
    deletion is written c.-155_-153delTCA in reports that number it against a
    different transcript.
  evidence:
  - reference: PMID:35189806
    reference_title: "Hypomyelination with Atrophy of Basal Ganglia and Cerebellum (HABC) Due to UFM1 Mutation in Roma Patients - Severe Early Encephalopathy with Stridor and Severe Hearing and Visual Impairment. A Single Center Experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Retrospective analysis of all 9 cases with H-ABC due to c.-273_-271delTCA mutation in UFM1"
    explanation: >-
      Names the variant in the c.-273_-271 numbering.
  - reference: PMID:34573312
    reference_title: "Four New Cases of Hypomyelinating Leukodystrophy Associated with the UFM1 c.-155_-153delTCA Founder Mutation in Pediatric Patients of Roma Descent in Hungary."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The c.-155_-153delTCA deletion in the promoter region of UFM1 is considered to be a founding mutation in the Roma population."
    explanation: >-
      Names the same founder deletion in the c.-155_-153 numbering.
  - reference: PMID:34573312
    reference_title: "Four New Cases of Hypomyelinating Leukodystrophy Associated with the UFM1 c.-155_-153delTCA Founder Mutation in Pediatric Patients of Roma Descent in Hungary."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "were the first to describe the homozygous UFM1:c.-155_-153delTCA founder mutation (reported as NM_001286704.1: c.-273_-271delTCA)"
    explanation: >-
      Confirms the two numberings describe one variant.
- name: UFM1 p.Arg81Cys
  description: >-
    A homozygous missense variant at a conserved residue in the UFM1
    C-terminal tail that contacts UBA5, reducing thioester formation with UBA5
    and UFC1.
  evidence:
  - reference: PMID:29868776
    reference_title: "Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain development."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Taken together, our data show that UFM1R81C has a hypomorphic effect on the UFM1-system and provide a plausible mechanistic explanation."
    explanation: >-
      Functional characterization of the missense allele.
differential_diagnoses:
- name: TUBB4A-related H-ABC (Hypomyelinating Leukodystrophy 6)
  description: >-
    The classic cause of the H-ABC MRI pattern, due to dominant de novo TUBB4A
    variants. UFM1 was found by studying H-ABC patients without TUBB4A
    variants, and HLD14 is its recessive, more severe counterpart. Abnormal
    T2 signal in the lateral head of the caudate nucleus has been seen in
    UFM1-related but not TUBB4A-related H-ABC.
  evidence:
  - reference: PMID:28931644
    reference_title: "UFM1 founder mutation in the Roma population causes recessive variant of H-ABC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "OBJECTIVE: To identify the gene defect in patients with hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) who are negative for TUBB4A mutations."
    explanation: >-
      Frames HLD14 against TUBB4A-related H-ABC.
  - reference: PMID:28931644
    reference_title: "UFM1 founder mutation in the Roma population causes recessive variant of H-ABC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This feature has not been observed in TUBB4A-related H-ABC and may be pathognomonic for UFM1-related H-ABC."
    explanation: >-
      The caudate head signal change distinguishes UFM1- from TUBB4A-related
      H-ABC.
- name: UBA5-Related Developmental and Epileptic Encephalopathy
  description: >-
    Biallelic variants in UBA5, the UFM1 E1 enzyme, cause an overlapping
    infantile encephalopathy with epilepsy, dystonia and microcephaly; some
    UBA5 patients also have hypomyelination. Curated separately as
    UBA5-Related_Developmental_and_Epileptic_Encephalopathy.
- name: UFC1-related neurodevelopmental disorder
  description: >-
    Biallelic UFC1 variants, affecting the UFM1 E2 enzyme, cause a severe
    early-onset encephalopathy with progressive microcephaly that is
    clinically and biochemically very similar to the UFM1 p.Arg81Cys disorder.
  evidence:
  - reference: PMID:29868776
    reference_title: "Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Remarkably, in four additional families where eight children have severe early-onset encephalopathy with progressive microcephaly, we identified two biallelic UFC1 mutations, which impair UFM1-UFC1 intermediate formation with resulting widespread reduction of cellular ufmylation, a pattern similar to that observed with UFM1 mutation."
    explanation: >-
      Shows the UFC1 disorder converges on the same biochemical defect.
- name: Pelizaeus-Merzbacher Disease (HLD1, PLP1)
  description: >-
    The prototypic hypomyelinating leukodystrophy; X-linked, and without the
    basal ganglia atrophy of H-ABC.
diagnosis:
- name: MRI pattern recognition with targeted UFM1 founder testing
  description: >-
    The H-ABC MRI pattern (hypomyelination with a very small or absent putamen
    and cerebellar atrophy) in a child without a TUBB4A variant, or severe
    infantile encephalopathy with stridor and hypomyelination in a child of
    Roma descent, should prompt targeted testing for the UFM1 promoter
    deletion. Because the variant lies in the promoter, analysis must include
    that region; exome capture that covers only coding exons can miss it.
  evidence:
  - reference: PMID:35189806
    reference_title: "Hypomyelination with Atrophy of Basal Ganglia and Cerebellum (HABC) Due to UFM1 Mutation in Roma Patients - Severe Early Encephalopathy with Stridor and Severe Hearing and Visual Impairment. A Single Center Experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Roma patients with severe encephalopathy in early infancy with stridor, opisthotonus, bradypnea, severe hearing and visual impairment should be tested for the Roma founder mutation of H-ABC in UFM1."
    explanation: >-
      Clinical clues for targeted testing.
  - reference: PMID:34573312
    reference_title: "Four New Cases of Hypomyelinating Leukodystrophy Associated with the UFM1 c.-155_-153delTCA Founder Mutation in Pediatric Patients of Roma Descent in Hungary."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This mutation may be more common in the Roma population than previously estimated, and the targeted testing of the UFM1:c.-155_-153delTCA mutation may have an indication in cases of hypomyelination and neurodegenerative clinical course in pediatric patients of Roma descent."
    explanation: >-
      Recommends targeted founder testing.
  - reference: PMID:34573312
    reference_title: "Four New Cases of Hypomyelinating Leukodystrophy Associated with the UFM1 c.-155_-153delTCA Founder Mutation in Pediatric Patients of Roma Descent in Hungary."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As the coverage of the promoter region of the UFM1 gene is generally poor in the case of exome sequencing data, and in many cases only the coding region of the genes are analyzed, this pathogenic founder variant could be easily missed"
    explanation: >-
      Explains why exome sequencing can miss the promoter variant.
- name: Carrier and prenatal testing in high-frequency communities
  description: >-
    Knowing the founder allele allows carrier testing where its frequency is
    high, and prenatal testing.
  evidence:
  - reference: PMID:28931644
    reference_title: "UFM1 founder mutation in the Roma population causes recessive variant of H-ABC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The identification of the disease-causing variant enables better clinical and genetic counseling, the possibility of prenatal testing, and the option of carrier testing in populations with a high carrier frequency."
    explanation: >-
      States the counselling and testing uses of the founder allele.
treatments:
- name: Symptomatic and Supportive Care
  description: >-
    No disease-modifying therapy exists. Care is supportive and addresses
    seizures, feeding and swallowing failure, spasticity and dystonia, and
    respiratory complications.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:42195294
    reference_title: "Rare Genetic Diseases with Founder Effect in Roma Children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most rare diseases are genetic and carry high morbidity and mortality, with no targeted therapies currently available."
    explanation: >-
      States that no targeted therapy is available for the founder disorders
      in this cohort, which include HLD14.
- name: Tracheostomy and Ventilatory Support
  description: >-
    Laryngeal dysfunction with stridor and respiratory failure led to
    tracheostomy in many patients, some with intermittent or permanent
    ventilation.
  treatment_term:
    preferred_term: tracheostomy
    term:
      id: NCIT:C15341
      label: Tracheotomy
  evidence:
  - reference: PMID:28931644
    reference_title: "UFM1 founder mutation in the Roma population causes recessive variant of H-ABC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Six patients underwent tracheostomy between 6 and 17 months, 4 of whom were on intermittent or permanent ventilation."
    explanation: >-
      Tracheostomy in 6 of 16 patients, 4 of them ventilated.
  - reference: PMID:34573312
    reference_title: "Four New Cases of Hypomyelinating Leukodystrophy Associated with the UFM1 c.-155_-153delTCA Founder Mutation in Pediatric Patients of Roma Descent in Hungary."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "abnormal muscle tone not only affected skeletal muscles but apparently the laryngeal muscle, causing loud stridor, jugular retraction, and ineffective inhalation phase during breathing; therefore, most patients needed a tracheostomy"
    explanation: >-
      Laryngeal dysfunction as the indication for tracheostomy.
- name: Tube Feeding
  description: >-
    Dysphagia requires nasogastric and later gastrostomy tube feeding.
  treatment_term:
    preferred_term: gastrostomy tube feeding
    term:
      id: NCIT:C157864
      label: Gastrostomy Tube Procedure
  evidence:
  - reference: PMID:34573312
    reference_title: "Four New Cases of Hypomyelinating Leukodystrophy Associated with the UFM1 c.-155_-153delTCA Founder Mutation in Pediatric Patients of Roma Descent in Hungary."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dysphagia necessitated feeding via nasogastric tube and later via gastrotube."
    explanation: >-
      Nasogastric then gastrostomy feeding in a patient with HLD14.
- name: Antiseizure Medication
  description: >-
    Seizures are treated with standard antiseizure drugs (carbamazepine in one
    reported patient) but are often drug-resistant.
  treatment_term:
    preferred_term: anticonvulsant therapy
    term:
      id: NCIT:C64172
      label: Anticonvulsant Therapy
  evidence:
  - reference: PMID:34573312
    reference_title: "Four New Cases of Hypomyelinating Leukodystrophy Associated with the UFM1 c.-155_-153delTCA Founder Mutation in Pediatric Patients of Roma Descent in Hungary."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "revealed interictal epileptic spikes over the right hemisphere; therefore carbamazepine was introduced"
    explanation: >-
      Carbamazepine started for focal epileptiform activity in a patient
      with HLD14.
- name: Genetic Counseling
  description: >-
    Counselling of families, carrier testing in high-frequency Roma
    communities and prenatal testing.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:42195294
    reference_title: "Rare Genetic Diseases with Founder Effect in Roma Children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prenatal and newborn screening, along with voluntary carrier testing for couples, is essential for proactive health management."
    explanation: >-
      Recommends carrier and prenatal testing for these founder disorders.
experimental_models:
- name: Cultured UFM1-deficient mouse neurons
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    Primary mouse neurons lacking UFM1, or lacking UFM1 and re-expressing
    either wild-type UFM1 or the pathogenic UFM1-R81C variant.
  publication: PMID:41731076
  organism:
    preferred_term: house mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  modeled_mechanisms:
  - target: ER Stress and Unfolded Protein Response Activation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Shows ER stress and UPR activation after UFM1 loss, and a distinct
      response with UFM1-R81C.
    limitations: >-
      Mouse neurons in culture, not human cells and not oligodendrocytes. The
      model removes UFM1 or expresses the missense variant; it does not model
      the founder promoter deletion, which reduces UFM1 transcription rather
      than altering the protein.
    evidence:
    - reference: PMID:41731076
      reference_title: "Encephalopathy-linked UFM1 variants impede neuronal protein translation, development, and function."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Mechanistically, UFM1 loss is associated with induction of ER stress, activation of the unfolded protein response (UPR) pathway, and reduced protein translation."
      explanation: >-
        The model's principal mechanistic result.
  - target: Reduced Neuronal Protein Translation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Reduced protein translation after UFM1 loss, rescued by wild-type UFM1
      and partly by UFM1-R81C.
    limitations: >-
      Mouse neurons in culture; the human relevance of the translation defect
      has not been measured in patient neurons.
    evidence:
    - reference: PMID:41731076
      reference_title: "Encephalopathy-linked UFM1 variants impede neuronal protein translation, development, and function."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "These defects are rescued by wild-type UFM1, but only partially by UFM1-R81C."
      explanation: >-
        Rescue experiments in the model.
discussions:
- discussion_id: hld14_ufmylation_to_hypomyelination
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Deficient CNS Myelination
  prompt: >-
    How does reduced UFMylation cause hypomyelination: through a defect in
    oligodendrocytes themselves, or secondarily to neuronal loss and failed
    brain growth?
  rationale: >-
    Hypomyelination defines the disease, but every mechanistic study of UFM1
    loss so far has looked at neurons or non-neural cells. The founder promoter
    deletion lowered reporter expression in neuroblastoma and astroglioma cells
    but not in an oligodendroglioma-derived line, which, if it holds in real
    oligodendrocytes, would argue for a secondary rather than a
    cell-autonomous myelin defect. Oligodendrocyte-specific Ufm1 loss in mice,
    or patient-derived oligodendrocytes, would settle it.
- discussion_id: hld14_missense_not_simple_loss
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#ER Stress and Unfolded Protein Response Activation
  prompt: >-
    Is UFM1 p.Arg81Cys a partial loss-of-function allele, or does it have
    additional effects that make it behave differently from reduced UFM1
    supply?
  rationale: >-
    The Arg81Cys protein is hypomorphic in thioester assays, yet
    UFM1-R81C neurons respond to ER stress differently from UFM1-null neurons,
    and the UPR inhibitor trazodone restored translation only in R81C neurons.
    If the two allele classes act differently, a treatment that helps one may
    not help the other.
- discussion_id: hld14_no_disease_modifying_treatment
  kind: KNOWLEDGE_GAP
  attaches_to:
  - treatments#
  prompt: >-
    Is there any disease-modifying treatment for HLD14?
  rationale: >-
    Only supportive care and genetic counselling are curated. Trazodone
    increased synapse numbers in cultured UFM1-deficient mouse neurons, but
    that is a cell-culture result, not a clinical treatment, and it is not
    curated as a treatment here.
notes: >-
  The entry name follows the dismech convention used for the other
  Hypomyelinating_Leukodystrophy_N entries rather than the MONDO label
  ordering ("leukodystrophy, hypomyelinating, 14"); the MONDO label is used
  verbatim in disease_term and kept as a synonym.

  No GeneReviews chapter covers HLD14 or UFM1; a PubMed search for UFM1 and
  for hypomyelinating leukodystrophy restricted to genereviews[book] returned
  no chapter.

  The founder deletion is reported under two numberings, c.-273_-271delTCA and
  c.-155_-153delTCA, which refer to the same 3-bp deletion described against
  different transcripts; the variants section keeps one record.

  PMID:39846712 describes a UFC1 missense variant (p.Arg23Gln) as
  "HLD14-related" in oligodendroglial FBD-102b cells. UFC1 is not an HLD14
  gene in MONDO or OMIM, so that paper is not used as evidence for this entry.

  Many clinical frequencies come from small single-centre series of children
  homozygous for the founder deletion (16 in PMID:28931644, 9 in
  PMID:35189806). The four p.Arg81Cys patients in PMID:29868776
  differ from the founder-deletion series on MRI: Table 2 of that paper reports
  basal ganglia abnormality in 0/4, delayed CNS myelination in 3/4 and
  cerebellar hypoplasia in 3/4, against 16/16, 16/16 and 13/16 for the
  founder deletion. They are kept in this entry because MONDO and OMIM name
  UFM1 as the HLD14 gene, but whether OMIM 617899 lists p.Arg81Cys was not
  confirmed during curation (ClinVar lists the variant as likely pathogenic
  with no named condition). If it does not, a subtype split would fit better.
  Frequencies here are drawn from the founder-deletion series.
📚

References & Deep Research

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 (1)

Create: Hypomyelinating_Leukodystrophy_14 · 2026-09-26T00:53:45Z · View source

New entry for HLD14 (MONDO:0033486, UFM1). Deep research was requested from falcon; no Edison key was configured, so the run used dr_fallback and the report was produced by claude_code (research/Hypomyelinating_Leukodystrophy_14-deep-research-claude_code.md; frontmatter records fell_back, requested_provider falcon). Report reference validation: 16/16 identifiers resolved, 26/27 quotes valid; the one unsupported quote is on PMID:27545674 (a UBA5 paper), which is not cited here. Term validation mislabels were paraphrases only. preflight-dr WARN on UFC1 mentions was reviewed: UFC1 appears only as a differential diagnosis, and PMID:39846712 (describes a UFC1 variant as 'HLD14-related') is deliberately not used as evidence. Evidence was taken from primary papers cached with just fetch-reference (PMIDs 28931644, 29868776, 34573312, 35189806, 42195294, 41731076, 30626644, 40315331, 36543799, 39470296). A lymphoblast snippet first drafted from PMID:29868776 turned out to describe UFC1 patients and was replaced with the R81C-specific sentence; an unsupported claim of longer survival with p.Arg81Cys was removed. Death in infancy is curated under progression because HP:0001522 is outside the PhenotypeTerm enum. No GeneReviews chapter (check-genereviews --online: NO_CHAPTER). Validation: just validate passes, count-verified-snippets 88/88, check-entity-refs, check-causal-targets, check-duplicate-keys all OK. Stub stubs/Leukodystrophy_Hypomyelinating_14.yaml deleted. A fresh-context red-team review before the PR (6 important, 8 minor, no critical findings) led to these changes: p.Arg81Cys scope corrected from PMID:29868776 Table 2 (basal ganglia 0/4, delayed myelination 3/4), with the unconfirmed OMIM 617899 status noted; corpus callosum atrophy rebound to HP:0007371; drug-resistant epilepsy rebound to HP:0200134; UPR node narrowed to GO:0036499 PERK-mediated UPR; the UPR-to-translation edge downgraded to INDIRECT_UNKNOWN_INTERMEDIATES (trazodone rescue only in R81C neurons; p-eIF2alpha not significant); pseudobulbar signs (HP:0002200) and caudate head signal abnormality (HP:0012751) phenotypes added; tracheostomy, gastrostomy feeding and anticonvulsant therapy treatments added; progression age range corrected to a median of about 1-2 years; the 4.5% pan-European carrier rate added, with the 25% community figure flagged as ascertainment-biased; Orphanet ORPHA:139441 recorded as a broader external record; and several evidence_source and explanation corrections. Revalidated: just validate 99/99 snippets, validate-disorders, check-entity-refs, check-causal-targets and check-duplicate-keys all OK.

Claude Code ▸
Hypomyelinating Leukodystrophy 14 (HLD14; UFM1-related H-ABC): research report
claude-haiku-4-5-20251001, claude-opus-5-5 11 citations 2026-09-25T20:44:11.523234

I've read the ten cached references for HLD14. Next I'm confirming identifiers and the mouse-model papers online, then I'll write the report.

Term lookups are done. Last, I'm checking the NCIT treatment and CHEBI drug IDs in the local caches before writing.

Hypomyelinating Leukodystrophy 14 (HLD14; UFM1-related H-ABC): research report

Prepared: 2026-09-25, for the dismech entry kb/disorders/Hypomyelinating_Leukodystrophy_14.yaml. Most quotes come from the cached references in references_cache/, which are PubMed abstracts or PMC full texts. The rest come from database pages, and those sources are named where used.

Sources. Ten PubMed/PMC items were read in full or as abstracts: PMID:28931644, 29868776, 34573312, 35189806, 39470296, 39846712, 41731076, 42195294, 30626644 and 40315331. Web lookups covered MONDO (via OLS), HGNC REST, Orphanet, ClinicalTrials.gov and PubMed.

How identifiers were checked. Every ontology CURIE below was read from a lookup, never written from memory. Most came from the repo caches (cache/hp, cl, go, uberon, ncit, chebi). UFM1 and UFC1 came from the HGNC REST API, and the MONDO cross-references from OLS. A term marked [lookup needed] had no cached match and has not been verified; it must be searched before it is bound.

Summary of evidence limits

  1. The oligodendrocyte defect is inferred. In the only functional test of the founder promoter deletion, the variant reduced promoter activity in neuroblastoma and astroglioma cells. It did not reduce it in the oligodendrocytoma line (PMID:28931644). No study has measured UFM1 or UFMylation in patient oligodendrocytes, or in patient cells carrying the promoter deletion.
  2. No human neuropathology exists for UFM1-related disease.
  3. Studies disagree on ER stress. Overexpressing UFM1 p.R81C in cell lines did not change ER-stress markers (PMID:29868776). UFM1-knockout mouse neurons do activate the PERK arm of the unfolded protein response (PMID:41731076).
  4. One paper assigns a UFC1 variant to "HLD14". PMID:39846712 describes UFC1 p.Arg23Gln as "HLD14-related". OMIM 617899 is the UFM1 disorder; the UFC1 disease is a separate entry. Treat that paper as evidence about the shared pathway, not as evidence on HLD14 itself.
  5. It is unconfirmed whether the R81C missense patients are HLD14. The p.Arg81Cys cases (PMID:29868776) had no basal-ganglia abnormality (0/4) but did have delayed myelination (3/4). Before merging them into the entry, check whether OMIM 617899 lists them. A has_subtypes split, or a note, may be the better fit.

1. Disease information

Overview. HLD14 is an autosomal recessive, infantile-onset hypomyelinating leukodystrophy caused by biallelic UFM1 variants. UFM1 is the ubiquitin-like modifier of the UFMylation pathway. Almost all reported patients are homozygous for a 3-bp deletion in the UFM1 promoter, a founder variant in the Roma population. On MRI the disease meets the criteria for hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC), and patients sit at the most severe end of that spectrum.

"Sixteen patients from 14 families from different countries fulfilling the MRI criteria for H-ABC exhibited a similar, severe clinical phenotype, including lack of development and a severe epileptic encephalopathy." (PMID:28931644)

"Hypomyelinating leukodystrophy type 14 (MIM # 617899) is caused by mutations in the UFM1 gene and is inherited in an autosomal recessive manner. It is characterized by hypotonia, an almost complete lack of motor or cognitive skills, absent language development, spasticity, and intractable seizures." (PMID:34573312)

Identifiers

Resource ID Source / note
MONDO MONDO:0033486 "leukodystrophy, hypomyelinating, 14" OLS
OMIM 617899 MONDO xref
DOID DOID:0080296 MONDO xref
UMLS / MedGen C4693535 / 1635255 MONDO xref
GARD 0016266 MONDO xref
Orphanet ORPHA:139441, Hypomyelination with atrophy of basal ganglia and cerebellum Covers both TUBB4A and UFM1 forms, so it is broader than HLD14. Map as skos:broadMatch, not exactMatch.
ICD-10/ICD-11, MeSH No disease-specific code found MeSH indexing uses "Hereditary Central Nervous System Demyelinating Diseases"
GeneReviews No UFM1 chapter Checked against the offline Bookshelf index (cache/bookshelf/genereviews.csv). The only related chapter is TUBB4A-Related Neurologic Disorders (NBK395611, PMID:27809427), which does not cover UFM1.

Synonyms: HLD14; UFM1-related H-ABC; recessive H-ABC (Hamilton et al. title: "recessive variant of H-ABC"); leukodystrophy, hypomyelinating, 14.

Data provenance: aggregated case series and cohorts. There are no EHR-derived data.

2. Etiology

  • Cause. Biallelic hypomorphic variants in UFM1 (hgnc:20597; 13q13.3; OMIM gene 610553). The disease is monogenic.
  • Genetic risk.
  • Roma ancestry, which carries the founder allele.
  • Parental consanguinity or endogamy: "Parental consanguinity was reported in 7 families and 2 families were related" (PMID:28931644).
  • Environmental risk factors: none described.
  • Protective factors: none described. No modifier genes have been reported.
  • Gene–environment interaction: none described.

3. Phenotypes

Onset is early infantile, with medical attention drawn between the neonatal period and about 6 months. Across all cohorts the course is progressive and usually fatal in infancy or early childhood.

Frequency sources. Hamilton 2017 (n=16; frequencies from Nahorski 2018 Table 2), Szűcs 2021 (n=4), Ivanov 2023 (n=9) and Drobňaková 2026 (n=17). Drobňaková states that "All patients presented with" its listed signs.

Phenotype HPO term (cache-verified) Frequency / notes Key PMID
Global developmental delay, profound HP:0012736 Profound global developmental delay (parent HP:0001263) 100% (16/16; 4/4). "typically without intentional movements and language development" 28931644, 34573312
Absent speech HP:0001344 Universal in Hamilton 28931644
CNS hypomyelination HP:0003429 CNS hypomyelination 16/16. Szűcs reports "Delayed/absent myelination" in 4/4; Ivanov reports "reduced myelination" in 6/6 28931644, 34573312, 35189806
Small or absent putamen HP:0031982 Abnormal putamen morphology MRI criterion: "None of the patients showed a normal putamen" 28931644
Caudate atrophy with high T2 signal in the lateral caudate head HP:0002340 Caudate atrophy 16/16. Proposed as "pathognomonic for UFM1-related H-ABC" 28931644
Cerebellar atrophy (vermis) HP:0001272 56% on the first MRI; 81% overall (13/16); 4/4 in Szűcs 28931644, 29868776, 34573312
Cerebral atrophy HP:0002059 Progressive; 7/9 in Ivanov (cortical); 4/4 in Szűcs 35189806, 34573312
Thin corpus callosum HP:0033725 Corpus callosum atrophy 3/6 35189806
Microcephaly, postnatal and progressive HP:0000253 Progressive microcephaly 16/16; 6/9; 3/4; most of 17. Head size is normal at birth 28931644, 35189806, 34573312, 42195294
Seizures / epilepsy HP:0001250; drug-resistant epilepsy [lookup needed] 75% (12/16), and in all patients ≥18 months; West syndrome reported. Lower elsewhere: 4/9 in Ivanov, 1/4 in Szűcs 28931644, 35189806, 34573312
Infantile spasms / hypsarrhythmia HP:0012469 / HP:0002521 West syndrome in Hamilton 28931644
Non-epileptic tonic spells; EEG abnormality HP:0002353 EEG abnormality 4/4 had diffuse cortical dysfunction on EEG 34573312
Inspiratory stridor (laryngeal) HP:0005348 Inspiratory stridor 9/9 in Ivanov; 3/4 in Szűcs; "All patients" in the 17-patient cohort. Attributed to impaired laryngeal innervation or tone 35189806, 34573312, 42195294
Axial hypotonia HP:0008936 4/9; 3/4; all 17 35189806, 34573312, 42195294
Spasticity / spastic tetraparesis HP:0001285 Spastic tetraparesis "Almost all" in Hamilton; 9/9 hypertonia in Ivanov; 4/4; all 17 28931644, 35189806, 42195294
Dystonia, extrapyramidal signs HP:0001332 "mostly dystonia"; dystonic posturing in 5/9 28931644, 35189806
Opisthotonus HP:0002179 6/9 35189806
Pseudobulbar signs HP:0002200 All 17 in Drobňaková 42195294
Dysphagia and feeding difficulty (tube feeding) HP:0002015 / HP:0011968 7/9; 3/4 35189806, 34573312
Bradypnea, apnea, abnormal breathing pattern bradypnea [lookup needed]; HP:0002104 Apnea; HP:0002793 Abnormal pattern of respiration Bradypnea 5/9 and 3/4; apnea 2/9 35189806, 34573312
Respiratory insufficiency HP:0002093 The most common cause of death; 6/16 needed tracheostomy 28931644
Visual impairment HP:0000505 "Vision and hearing were never achieved or lost by 4-8 mo"; hypoplastic optic nerves in one case 35189806, 34573312
Hearing impairment HP:0000365 (HP:0000407 if sensorineural is confirmed) Ivanov: severe. Szűcs: absent brainstem auditory evoked responses in one case 35189806, 34573312
Nystagmoid eye movements HP:0000639 Nystagmus 6/9; horizontal nystagmus in 3/17 35189806, 42195294
Failure to thrive HP:0001508 63% (10/16); 3/4 29868776, 34573312
Short stature HP:0004322 75% (12/16); 2/4 29868776, 34573312
Developmental regression HP:0002376 "absent or minimal with subsequent regression after 2-5 mo"; 4/4 35189806, 34573312
Death in infancy HP:0001522 See section 11 28931644, 42195294

Quality of life. No EQ-5D, SF-36 or PROMIS data have been published. Patients are totally dependent, many with a tracheostomy, gastrostomy or ventilation.

CSF. One Szűcs patient had low CSF protein (138 mg/L). This is a single observation and should not be curated as a phenotype.

4. Genetic and molecular information

Causal gene: UFM1 (hgnc:20597; Entrez 51569; ENSG00000120686; UniProt P61960). The protein is a 9.1-kDa type I ubiquitin-like modifier.

Pathogenic variants

Variant Type Zygosity / population Evidence
c.-273_-271delTCA (NM_001286704.1) = c.-155_-153delTCA (NM_016617.4); GRCh38 chr13:38349765–38349767 del; rs747359907; ClinVar VCV 495149; HGMD CD1715768 3-bp promoter (5′ regulatory) deletion; hypomorphic Homozygous; Roma founder haplotype. Also found in Pakistani and Indian patients PMID:28931644, 34573312, 39470296
c.241C>T p.(Arg81Cys) (NM_016617.3) Missense in the C-terminal tail that binds UBA5; hypomorphic Homozygous; two Sudanese families from one village sharing an ancestral haplotype PMID:29868776
  • The two transcript numberings name the same variant. Szűcs states that the NM_016617.4 c.-155_-153delTCA was "reported as NM_001286704.1: c.-273_-271delTCA" (PMID:34573312). Pick one form for the KB and give the other in notes.
  • Classification.
  • Szűcs 2021 called it likely pathogenic under ACMG.
  • Kaur 2025 classified it "P (PS3, PS4_M, PM2, PP5)" (PMID:39470296).
  • Drobňaková 2026 reports it as pathogenic in ClinVar. Confirm the current ClinVar status before citing.
  • Population frequency. Absent from gnomAD (PMID:34573312). Among Roma: "Screening of 670 Roma controls revealed 30 carriers with an overall carrier rate of 4.5% ... An additional panel of Eastern Slovak Roma samples revealed a carrier frequency of 3.3% (9 out of 273) ... a carrier rate of approximately 25% (14 out of 57 individuals)" in one endogamous community (PMID:28931644).
  • Linkage. "LOD score calculations for the UFM1 variant showed a maximum LOD score of 9.18" (PMID:28931644).
  • Functional consequence. Both variants are partial loss of function (hypomorphic).
  • "Our results show a reduction rather than abrogation of ufmylation with the activity of UFM1 and UFC1 mutants at 60–75% of their wild-type counterparts" (PMID:29868776).
  • R81C may also have non-loss-of-function effects: "UFM1-deficient and UFM1-R81C-expressing neurons display distinct responses to ER stress, indicating that UFM1-R81C is not merely a loss-of-function variant" (PMID:41731076).
  • Suggested functional_impact_category: PARTIAL_LOSS_OF_FUNCTION for both; variant_origin: GERMLINE; zygosity: homozygous.
  • Biallelic null variants are depleted. "the conspicuous depletion of biallelic null mutations in the components of this pathway in human genome databases suggest that it is necessary for embryonic survival" (PMID:29868776).
  • Modifier genes, epigenetics, chromosomal abnormalities: none reported.
  • Other genes in the same pathway (differential diagnosis, not HLD14): UBA5 (E1; hgnc:23230) and UFC1 (E2; hgnc:26941). They give overlapping encephalopathies (PMID:29868776). TUBB4A (hgnc:20774) causes dominant H-ABC, which is HLD6.

5. Environmental information

No environmental, lifestyle or infectious contributors are described. This section is not applicable.

6. Mechanism and pathophysiology

Causal chain

  1. A homozygous UFM1 promoter deletion (or the R81C missense variant) leads to reduced UFM1 function. The deletion reduces UFM1 transcription, measured in neural cell lines only: "The deletion significantly reduced promoter activity in SY-5Y and U373 but not in HeLa and HOG-F2 cell lines" (PMID:28931644). R81C instead weakens UFM1's binding to UBA5 and its thioester transfer to UFC1 (PMID:29868776).
  2. Caveat: HOG-F2 is the oligodendroglial line, so a neuron- or astrocyte-selective effect is what was shown. Reduced UFM1 in patient tissue has not been measured for the promoter variant.
  3. Reduced UFM1 results in reduced protein UFMylation (GO:0071569 protein ufmylation, DECREASED). This was shown for R81C in patient lymphoblasts: "the level of two UFM1-conjugates with cellular proteins in patient-derived lymphoblasts was significantly reduced" (PMID:29868776). For the promoter variant it is inferred.
  4. Reduced UFMylation leads to loss of ribosomal uL24/RPL26 UFMylation at the ER. This step is inferred from cell biology in non-neural cells. "a largely uncharacterized ribosomal protein, RPL26, is the principal target of UFM1 conjugation ... UFMylated RPL26 and the UFMylation machinery are in close proximity to the SEC61 translocon" (PMID:30626644; HEK/K562 cells). Branches:
  5. 3a. Failed ER ribosome-associated quality control (ER-RQC) at stalled translocon-bound 60S subunits: "ER-RQC differs from cytosolic RQC by requiring covalent conjugation of the ubiquitin-like protein UFM1 (UFMylation) to uL24" (PMID:40315331). Arrest peptides are then released into the ER lumen instead of being degraded: "In the absence of RQC or UFMylation machinery, ER-APs are not properly extracted into the cytosol for degradation but are instead released into the ER lumen" (PMID:40315331; HEK293). See also PMID:36945571 (PNAS 2023) and PMID:31595041 (Cell Res 2020); both were found by search and are not yet cached.
  6. 3b. ER stress with PERK-branch UPR activation and reduced global translation in neurons. This was demonstrated in mouse Ufm1-KO neurons: "UFM1 loss is associated with induction of ER stress, activation of the unfolded protein response (UPR) pathway, and reduced protein translation" (PMID:41731076). The paper shows PERK specifically, with ATF6 and IRE1α unchanged. Suggested GO terms: GO:0036499 PERK-mediated unfolded protein response (INCREASED); GO:0006412 translation (DECREASED).
    • Conflicting evidence: overexpressing R81C in HeLa or SH-SY5Y cells did not change CHOP/BiP or tunicamycin-induced apoptosis (PMID:29868776).
  7. Steps 3a/3b lead to impaired neuronal development and synapse formation, demonstrated in mouse. "UFM1-deficiency confounds neuron development and synapse function" (PMID:41731076). Dendrite complexity (GO:0016358) and synapse number (GO:0007416) were reduced, excitatory transmission was reduced, and R81C rescued these only partially.
  8. Selective neuron loss. This is demonstrated in mouse; in humans it is inferred from MRI. "CNS-specific knockout of Ufm1 in mice caused neonatal death with microcephaly and apoptosis of neurons in specific brain regions" (PMID:28931644, citing Muona 2016, PMID:27545674). GO:0051402 neuron apoptotic process (INCREASED).
  9. In patients this appears as progressive atrophy of the caudate, putamen, cerebellar vermis and cortex, and as postnatal progressive microcephaly.
  10. The authors infer apoptosis from imaging: "signal abnormality of the lateral part of the head of the caudate nucleus suggestive of local apoptosis" (PMID:28931644).
  11. Hypomyelination, the step with the weakest evidence. The mechanism is unresolved: it may be a primary oligodendrocyte defect or secondary to neuronal and axonal failure.
  12. The only oligodendroglial data come from a UFC1 R23Q variant in the mouse FBD-102b line. There, mutant UFC1 aggregated in lysosomes, Akt phosphorylation fell, and MBP/PLP1 expression and morphological differentiation were reduced (PMID:39846712; IN_VITRO, a different gene).
  13. Suggested GO terms: GO:0022010 central nervous system myelination (DECREASED); GO:0048709 oligodendrocyte differentiation (DECREASED, and label it hypothesis).
  14. Steps 4–6 result in the clinical picture:
  15. basal-ganglia and cortical failure → dystonia, opisthotonus, spastic tetraparesis;
  16. cortical dysfunction → epileptic encephalopathy and absent development;
  17. brainstem and bulbar involvement → inspiratory stridor, dysphagia, bradypnea and apnea, leading to respiratory insufficiency and death (clinical inference);
  18. sensory pathway failure → visual and hearing loss.

Branch-point summary

Step Evidence type Demonstrated in
Reduced promoter activity IN_VITRO Neuroblastoma and astroglioma cell lines
Reduced UFMylation IN_VITRO R81C patient lymphoblasts, HEK293T
RPL26 UFMylation / ER-RQC IN_VITRO HEK293, K562
PERK-UPR activation, reduced translation, fewer synapses MODEL_ORGANISM / IN_VITRO Mouse Ufm1-cKO primary neurons, in utero electroporation
Neuronal apoptosis, microcephaly MODEL_ORGANISM Ufm1^f/f;nestin-Cre mouse
Oligodendrocyte differentiation defect IN_VITRO, UFC1 not UFM1 FBD-102b
Hypomyelination, basal-ganglia and cerebellar atrophy HUMAN_CLINICAL (MRI) Patients

Cell types (CL, cache-verified): - neuron CL:0000540 - medium spiny neuron CL:1001474 (striatum; inferred from caudate/putamen atrophy) - oligodendrocyte CL:0000128 - oligodendrocyte precursor cell CL:0002453 - astrocyte CL:0000127 (the promoter effect was seen in the U373 astroglioma line) - Purkinje cell CL:0000121 and cerebellar granule cell CL:0001031 are possible but not demonstrated.

Other GO terms: GO:0071566 UFM1 activating enzyme activity (UBA5 step). Terms for ribosome-associated quality control, rescue of stalled ribosomes, and UFM1 conjugating/transferase activity are [lookup needed].

Omics. Bulk RNA-seq of Ufm1-KO mouse neurons found 539 differentially expressed genes. Synaptic genes went down, and translation and RNA-processing genes went up (PMID:41731076). There are no human transcriptomic, proteomic, metabolomic, single-cell or spatial data.

7. Anatomical structures affected

  • Primary organ: brain (UBERON:0000955) and CNS (UBERON:0001017).
  • Structures on imaging:
  • cerebral white matter (white matter UBERON:0002316)
  • putamen (UBERON:0001874)
  • caudate nucleus (UBERON:0001873)
  • basal ganglion (UBERON:0002420)
  • cerebellum, mainly the vermis (UBERON:0002037)
  • corpus callosum (UBERON:0002336)
  • cerebral cortex (UBERON:0000956)
  • medulla oblongata, thin in one case (UBERON:0001896)
  • optic nerves, hypoplastic in one case
  • Secondary: larynx (UBERON:0001737), through abnormal tone or innervation producing stridor (PMID:34573312); respiratory control; growth.
  • Subcellular: the endoplasmic reticulum membrane (cytosolic face) and ER-bound ribosomes / the 60S subunit at the SEC61 translocon (PMID:30626644, 40315331). GO CC terms: [lookup needed].
  • Lateralization: bilateral and symmetric.

8. Temporal development

  • Onset: neonatal to early infantile.
  • "Presentation is no later than 2 months" (PMID:35189806).
  • Median age at first symptoms is 2 months (Hamilton, as summarized in PMID:34573312).
  • Szűcs gives an average of 2.5 months (range 1 week–6 months).
  • Course: progressive and neurodegenerative. Minimal development is followed by regression at 2–5 months. MRI shows progressive cerebral atrophy and cerebellar atrophy developing over 3–15 months (PMID:28931644). Myelination stays severely deficient, with only slight gains in 3/5 patients on follow-up scans.
  • Remission: none.
  • Critical period: the prenatal and early postnatal window. Carrier testing and prenatal diagnosis are the only interventions that change outcome.

9. Inheritance and population

  • Inheritance: autosomal recessive. Penetrance was assumed complete in the linkage analysis, and segregation was "in perfect agreement".
  • Expressivity: fairly uniform and severe for the promoter variant.
  • Anticipation and germline mosaicism: not reported.
  • Founder effect: a Roma founder haplotype (PMID:28931644) and a separate Sudanese R81C founder haplotype (PMID:29868776).
  • Geography: Slovakia, Hungary, Bulgaria, and other European Roma communities. The promoter variant has also been reported in Pakistani and Indian patients (PMID:34573312, 39470296).
  • The shared South Asian ancestry of the Roma (PMID:42195294) may explain the Indian and Pakistani cases, but no haplotype study has shown this.
  • Carrier frequency: 4.5% across European Roma panels, 3.3% in Eastern Slovak Roma, and about 25% in one endogamous community.
  • Prevalence and incidence: no published estimate.
  • My own derivation, not a sourced figure: Hardy–Weinberg with 4.5% carriers (q ≈ 0.0225) gives an expected birth prevalence of about 5 per 10,000 among Roma if mating were random. Endogamy would raise it locally.
  • For the KB, use prevalence_class: NOT_YET_DOCUMENTED or RARE with measure_type: UNKNOWN, and record the carrier data as CARRIER_FREQUENCY (PMID:28931644).
  • Case count: Szűcs counted 23 published patients in 2021. Adding Ivanov's 9 (2023), Kaur's 2 (2025) and Drobňaková's 17 (2026) gives more than 50. That total is my own tally, and the cohorts may overlap.
  • Sex ratio: 11 males to 6 females in the Slovak cohort (PMID:42195294) and 1:1 in Szűcs. There is no evidence of a sex effect.

10. Diagnostics

  • MRI pattern recognition is the key clinical clue:
  • hypomyelination
  • a very small or absent putamen
  • a small caudate with high T2 signal in the lateral part of the caudate head (distinguishes it from TUBB4A H-ABC)
  • cerebellar vermis atrophy
  • progressive cerebral atrophy (PMID:28931644)
  • MR spectroscopy: "almost equally high peaks of choline, creatine, and N-acetyl-aspartate" in one advanced case (PMID:34573312).
  • EEG: diffuse cortical dysfunction and hypsarrhythmia.
  • Genetic testing:
  • Targeted Sanger testing of the founder variant is fast and suited to Roma infants with the phenotype (PMID:34573312). The Slovak center diagnosed most patients this way, with a mean of 5.7 months from symptom onset to diagnosis (PMID:42195294).
  • Exome sequencing can miss the variant: "As the coverage of the promoter region of the UFM1 gene is generally poor in the case of exome sequencing data, and in many cases only the coding region of the genes are analyzed, this pathogenic founder variant could be easily missed" (PMID:34573312). Solo exome sequencing did detect it in two Indian patients (PMID:39470296).
  • Genome sequencing covers the promoter.
  • Chromosomal microarray, karyotype, FISH, mtDNA and repeat testing are not relevant.
  • Clinical rule of thumb: "Roma patients with severe encephalopathy in early infancy with stridor, opisthotonus, bradypnea, severe hearing and visual impairment should be tested for the Roma founder mutation" (PMID:35189806).
  • Biomarkers: none validated. UFM1-conjugate immunoblots of lymphoblasts are research-only (PMID:29868776).
  • Differential diagnosis:
  • TUBB4A H-ABC / HLD6 (dominant, de novo; normal caudate signal)
  • UBA5- and UFC1-related encephalopathies (same pathway)
  • PCH1B (EXOSC3, also a Roma founder variant, also with stridor)
  • Pelizaeus–Merzbacher disease
  • POLR3-related leukodystrophy
  • other HLDs (PMID:39470296, 42195294)
  • Screening: there is no newborn screening. Carrier and cascade testing in Roma communities is recommended (PMID:28931644, 42195294).

11. Outcome and prognosis

Cohort Survival
Hamilton 2017 (n=16) "Median survival was 2 years. Nine patients died at ages between 7 months and 7 years, most often due to respiratory insufficiency."
Szűcs 2021 (n=4) Median survival 28 months
Ivanov 2023 (n=9) "The age at death was between 8 and 18 mo."
Drobňaková 2026 (n=17) "The average age at death was 11.8 months, and the longest-surviving patient lived to be 30 months old"; 1 alive
Nahorski 2018, R81C (n=4) 100% mortality in Table 2; two deaths are described in the text, at 9 months and 8.5 years
  • Causes of death: respiratory insufficiency, apnea, cardiopulmonary arrest.
  • Morbidity: total dependence; no motor or cognitive milestones; need for tracheostomy, tube feeding or ventilation.
  • Recovery potential: none.
  • Prognostic factors: none established. The later-surviving Hamilton patients (up to 7 years) suggest some variability.

12. Treatment

No disease-modifying therapy exists. A ClinicalTrials.gov search for "UFM1" (API query, 2026-09-25) returned zero studies.

Supportive care

Intervention NCIT (cache-verified) Evidence
Anticonvulsants, e.g. carbamazepine (CHEBI:3387); levetiracetam (CHEBI:6437) and vigabatrin (CHEBI:63638) are plausible for West syndrome but not documented in HLD14 NCIT:C15986 Pharmacotherapy + therapeutic_agent Carbamazepine given to one patient (PMID:34573312); epilepsy is often "drug-resistant" (PMID:28931644)
Baclofen for spasticity (CHEBI:2972) NCIT:C15986 One patient (PMID:34573312)
Gastrostomy / tube feeding NCIT:C52006 Gastrostomy; NCIT:C15433 Nutritional Support PMID:34573312
Tracheostomy [lookup needed] (no cached NCIT term) 6/16 tracheostomy (PMID:28931644)
Ventilatory support NCIT:C70909 Mechanical Ventilation "4 of whom were on intermittent or permanent ventilation" (PMID:28931644)
Supportive and palliative care NCIT:C15747 Supportive Care General
Physical therapy / rehabilitation NCIT:C15302 / NCIT:C15315 General; not documented in HLD14 sources
Genetic counseling NCIT:C15240 PMID:28931644, 42195294

Preclinical only (not for treatments; better as a discussion or hypothesis): - Trazodone (UPR/PERK inhibitor): "Trazodone, an inhibitor of the UPR, restores protein translation solely in UFM1-R81C-expressing neurons, and increases synapse numbers in both UFM1-KO and UFM1-R81C-expressing neurons" (PMID:41731076; mouse neurons). It did not rescue dendrite complexity. The trazodone CHEBI ID is [lookup needed]. - Hesperetin: restored oligodendroglial differentiation in UFC1-R23Q FBD-102b cells (PMID:39846712). It is a different gene, and the authors themselves call the effect "limited".

There is no gene therapy, ASO or cell therapy, and no pharmacogenomic data.

13. Prevention

  • Primary prevention: carrier screening and preconception or prenatal testing in at-risk Roma communities.
  • "The identification of the disease-causing variant enables better clinical and genetic counseling, the possibility of prenatal testing, and the option of carrier testing in populations with a high carrier frequency" (PMID:28931644).
  • "Prenatal and newborn screening, along with voluntary carrier testing for couples, is essential" (PMID:42195294).
  • Secondary prevention: early targeted testing of symptomatic Roma infants shortens the diagnostic delay.
  • Tertiary prevention: airway management, nutrition and seizure control.
  • Not applicable: immunization, behavioral interventions, prophylaxis.

14. Other species and natural disease

  • No naturally occurring UFM1 disease was found. OMIA was not searched directly.
  • UFM1 orthologs are conserved across metazoans: "each of its components having a corresponding orthologue in all multicellular organisms" (PMID:29868776). UFMylation is metazoan-specific (PMID:30626644).
  • Mouse and human UFM1 proteins are identical (PMID:41731076).
  • No zoonotic or transmission relevance.

15. Model organisms

Model Recapitulation Limitations Source
Ufm1^f/f;nestin-Cre mouse (CNS cKO) Microcephaly, neuronal apoptosis, neonatal death Complete loss rather than hypomorph; death within a day limits study of myelination Muona 2016, PMID:27545674 (not yet cached; described in PMID:28931644, 29868776)
Ufm1 whole-body KO mouse Embryonic lethal Cannot model postnatal disease Unpublished, cited in PMID:29868776
Ufm1-cKO primary hippocampal/striatal neurons ± WT or R81C rescue; in utero CRISPR KO Reduced dendrites and synapses, PERK-UPR activation, reduced translation; R81C only partially rescues Neurons only, no oligodendrocytes; mouse; no promoter-variant model PMID:41731076 (MODEL_ORGANISM / IN_VITRO)
Ufl1/Ufbp1 forebrain KO mouse Microcephaly, seizures, neuron loss E3 rather than UFM1 Zhang 2022, Mol Neurobiol, doi:10.1007/s12035-022-02979-0 (PMID not verified)
Drosophila Ufm1 knockdown Reduced motor activity, shortened lifespan (most severe of the pathway knockdowns) Invertebrate; no myelin Duan 2016, cited in PMID:28931644
UFM1/UFC1-KO HEK293T; patient lymphoblasts (R81C) Reduced UFMylation Non-neural PMID:29868776
FBD-102b oligodendroglial line expressing UFC1-R23Q Differentiation defect Different gene; overexpression PMID:39846712

Gaps in models: - No animal or iPSC model carries the founder promoter deletion. - No oligodendrocyte-specific Ufm1 model exists. - No model reproduces hypomyelination together with the basal-ganglia pattern.

In the KB, the modeled_mechanisms links for the mouse cKO should record model_scale and a limitations or SPECIES_MISMATCH/BOUNDARY_OMISSION divergence. Hypomyelination is outside every current model.

Curation notes for the entry

  • Mappings:
  • disease_term: MONDO:0033486
  • Orphanet ORPHA:139441 as skos:broadMatch (H-ABC includes TUBB4A)
  • The TUBB4A GeneReviews chapter is not a baseline for this entry
  • Gene: hgnc:20597 (UFM1). It is not yet in cache/hgnc/terms.csv, so run just validate-terms after binding it.
  • Before binding, look up: drug-resistant epilepsy, bradypnea, tracheostomy (NCIT), trazodone (CHEBI), ER-RQC and ER-membrane GO terms.
  • Fetch before citing: PMID:27545674 (Muona), PMID:36945571 and PMID:31595041 (RPL26 ER-RQC). None of the three is cached yet.
  • Evidence grading for PMID:34573312: its opening paragraph quoting Hamilton's statistics restates another paper, so mark it quote_role: BACKGROUND. The same applies to the Drobňaková discussion paragraphs that restate Hamilton.

Sources

Reference Validation

Checked with linkml-reference-validator 0.3.0rc1.

Outcome Count
References checked 16
Resolved 16
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 27
Quoted claims found in source 26
Quoted claims not found in source 1
References weighed for topical relevance 16
On topic 10
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

  • PMID:27545674 (abstract only): "CNS-specific knockout of Ufm1 in mice caused neonatal death with microcephaly and apoptosis of neurons in specific brain regions"
  • closest text in source: "Finally, we show that the CNS-specific knockout of Ufm1 in mice causes neonatal death accompanied by microcephaly and apoptosis in specific neurons, further suggesting that the UFM1 system is essential for CNS development and function"

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 75
Resolved 74
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 27
Terms named correctly 18
Terms named as a different term 4
Terms whose name is worth a second look 5

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • DOID:0080296 (1 mention) - the report calls it "DOID"; DOID calls it hypomyelinating leukodystrophy 14
  • HP:0001332 (1 mention) - the report calls it "Dystonia, extrapyramidal signs"; HP calls it Dystonia
  • CL:1001474 (1 mention) - the report calls it "striatum; inferred from caudate/putamen atrophy"; CL calls it medium spiny neuron
  • UBERON:0000955 (1 mention) - the report calls it "Primary organ: brain"; UBERON calls it brain**

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0001272 (1 mention) - the report calls it "Cerebellar atrophy (vermis)"; HP calls it Cerebellar atrophy
  • UBERON:0002037 (1 mention) - the report calls it "cerebellum, mainly the vermis"; UBERON calls it cerebellum
  • UBERON:0001896 (1 mention) - the report calls it "medulla oblongata, thin in one case"; UBERON calls it medulla oblongata
  • UBERON:0001737 (1 mention) - the report calls it "Secondary: larynx"; UBERON calls it larynx**
  • CHEBI:2972 (1 mention) - the report calls it "Baclofen for spasticity"; CHEBI calls it baclofen, and lists "baclofeno" among its other names

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.