Deoxyhypusine Synthase Deficiency

Mendelian MONDO:0032775 Pathograph 18 Show in embeddings browser Inborn error of polyamine metabolism Mendelian neurodevelopmental disorder Autosomal recessive disease

Deoxyhypusine synthase deficiency is an ultra-rare autosomal recessive neurodevelopmental disorder caused by biallelic hypomorphic DHPS variants. It presents as a static encephalopathy with global developmental delay, intellectual disability and seizures, with variable hypotonia, microcephaly, short stature and mild facial dysmorphism. What makes it mechanistically unusual is the narrowness of the enzyme's job. DHPS catalyses the first committed step in making hypusine, an amino acid that exists in exactly one cellular protein: eukaryotic translation initiation factor 5A. Hypusination is what activates eIF5A, and eIF5A - despite its name - works mainly in translation elongation, stabilising peptidyl-tRNA on the ribosome so that stalling motifs such as polyproline runs can be read through. So a single missing post-translational modification on a single protein produces a disease of the developing brain. Every reported patient carries a hypomorphic combination, and that is a structural feature rather than ascertainment bias: Dhps-null mice are embryonic lethal, so complete loss of function cannot produce a living patient. All five individuals in the founding cohort shared the same recurrent missense allele, p.Asn173Ser, which retains roughly a fifth of normal activity, in trans with a near-null second allele. The disorder sits in a small family of conditions that converge on the same molecule: biallelic DOHH variants disable the second hypusination step, and heterozygous EIF5A variants disable the substrate itself, both producing a similar neurodevelopmental phenotype. It is also one of the polyaminopathies, which is how it relates to Bachmann-Bupp syndrome - an ODC1 gain-of-function disorder dismech already carries, upstream in polyamine metabolism but phenotypically distinct.

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1
Inheritance
7
Pathophys.
7
Phenotypes
2
Gaps
18
Pathograph
1
Genes
3
Medical Actions
2
Differentials
4
Models
5
References
1
Deep Research
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Inheritance

1
Autosomal recessive inheritance HP:0000007
Biallelic, and specifically a hypomorph in trans with a near-null allele in every reported case. Carrier relatives are clinically unaffected, though their cells do show measurable biochemical change.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:30661771 SUPPORT Human Clinical
"Using exome sequencing, we identified rare biallelic, recurrent, predicted likely pathogenic variants in DHPS segregating with disease in five affected individuals from four unrelated families."
The founding report, stating the recessive biallelic mechanism and the size of the cohort it rests on - five individuals, four families.
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Discussions and Knowledge Gaps

2
Which mRNAs actually fail to be translated when hypusinated eIF5A is reduced in a human neuron, and is that set what makes the disease neurological rather than systemic?
KNOWLEDGE GAP OPEN gap_dhps_neuronal_selectivity
Attached to
pathophysiology#Impaired eIF5A-Dependent Translation Elongation pathophysiology#Altered Expression of Proteins Required for Neuronal Development
eIF5A is required in every cell, DHPS is ubiquitously expressed, and yet the disease is a static encephalopathy with largely preserved systemic health. The standing explanation is that eIF5A-dependent elongation is sequence-selective - polyproline and other stalling motifs - so reduced hypusination biases rather than abolishes translation, and neurons happen to depend on the biased-against transcripts. The brain-specific mouse knockout supports the shape of this with ribosome profiling and mass spectrometry, but the specific proteins have not been connected to the specific clinical features. The human system this gap originally called for now exists. Patient-derived iPSCs carrying the two DHPS alleles, with CRISPR-corrected isogenic controls, have been differentiated into cortical organoids, and the mutant organoids are significantly smaller - so a human, patient-allele, isogenically controlled neural model is available and shows a developmental phenotype. What has not been done in it is the measurement. No ribosome profiling or equivalent translational-output assay has been reported in that system, so the transcripts whose elongation actually fails in a human neuron carrying patient alleles remain unidentified, and the link from any particular protein to any particular clinical feature is still unmade. Until that measurement exists, the entry's central step is a mechanism class rather than a mechanism. Ribosome profiling of the existing patient-versus-isogenic organoid pair is the experiment.
Every animal model of DHPS loss is a null or a knockdown, while every patient is a hypomorph with roughly a fifth of normal enzyme activity. Does the null phenotype describe the same disease?
HUMAN MODEL MISMATCH OPEN mismatch_dhps_null_models_vs_hypomorphic_disease
Attached to
pathophysiology#Biallelic Hypomorphic DHPS Variants animal_models#Brain-specific Dhps knockout mouse (Emx1-Cre) animal_models#dhps morpholino knockdown zebrafish
The mismatch is not incidental, it is forced: Dhps-null mice die as embryos, so a whole-animal model of complete loss cannot exist, and conditional nulls are what the field has instead. The consequence is a systematic severity gap that the literature itself notices - the mouse models show severe growth failure and premature death, while patients have a static encephalopathy with preserved survival and short stature in two of four females. The zebrafish knockdown adds a different problem: it is dose-dependent and produces axis truncation and body curvature alongside the interneuron phenotype, so the specific finding sits inside general developmental toxicity. There is also a result in the mouse series that no current model explains. Deleting Dhps produced more severe impairment than deleting Eif5a, in both the embryonic and the postnatal model. If the only consequence of losing DHPS were unhypusinated eIF5A, losing eIF5A itself should be at least as bad. It was not, which suggests either a second DHPS function or a contribution from eIF5A2, and neither has been followed up. A knock-in of p.Asn173Ser in trans with a null, in mouse, would test whether the hypomorphic state reproduces the human phenotype at the severity patients actually have.
Proposed experiments
p.Asn173Ser / null compound heterozygous knock-in mouse
exp_dhps_n173s_compound_heterozygous_knockin_mouse
Knock in the recurrent human missense allele at the orthologous murine residue and cross to a Dhps null allele, reproducing the patient genotype rather than a conditional null, then phenotype survival, growth, seizure susceptibility and learning into adulthood.
Would support
pathophysiology#Biallelic Hypomorphic DHPS Variants pathophysiology#Reduced Deoxyhypusine Synthase Activity
Supporting outcome
  • Compound heterozygotes are viable with normal growth, show spontaneous or induced seizures and learning deficits, and have reduced hypusinated eIF5A - matching the human severity rather than the conditional-null severity.
Refuting outcome
  • Compound heterozygotes are unaffected, which would mean roughly a fifth of normal activity is sufficient in mouse and the human phenotype depends on something beyond residual enzyme activity.
Test whether Dhps loss exceeds Eif5a loss because of a second substrate or eIF5A2
exp_dhps_second_function_vs_eif5a2
Repeat the conditional deletions with an Eif5a/Eif5a2 double knockout arm, and search for non-eIF5A DHPS substrates by proteomics, to explain why Dhps-null animals were consistently worse than Eif5a-null animals.
Would support
pathophysiology#Reduced Hypusination of eIF5A
Supporting outcome
  • Eif5a/Eif5a2 double deletion is as severe as Dhps deletion, placing the excess severity on the redundant substrate rather than on a second DHPS function.
Refuting outcome
  • Dhps deletion remains more severe than combined substrate deletion, which would mean DHPS does something beyond hypusinating eIF5A and the entry's single-substrate framing is incomplete.
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Pathophysiology

7
Biallelic Hypomorphic DHPS Variants
A recurrent missense allele, c.518A>G p.(Asn173Ser), in trans with a near-null second allele - a splice-site change, an in-frame deletion p.(Tyr305_Ile306del), or a start-loss. The genotype is not incidental. The p.Asn173Ser enzyme retains roughly a fifth of normal activity while the in-frame deletion is inactive, so a patient's residual capacity comes almost entirely from the missense allele, and a patient homozygous for two nulls would not be born.
DHPS hgnc:2869 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves DHPS (hgnc:2869). hgnc:2869 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
Downstream
Reduced Deoxyhypusine Synthase Activity
Show evidence (3 references)
PMID:37333770 SUPPORT Human Clinical
"The splice site and initiation codon variants are predicted to disrupt proper DHPS protein synthesis and thus enzyme activity."
Characterises the second allele in each patient as near-null, which is what makes the genotype hypomorph-over-null rather than simply biallelic. The variant-level detail is in the description; it is not quoted here because the source writes every allele with bracketed protein-change notation, which the snippet matcher strips before comparing.
PMID:30661771 SUPPORT In Vitro
"cDNA studies demonstrated that the c.1014+1G>A variant causes aberrant splicing."
Confirms the splice allele's consequence at the RNA level rather than by prediction.
PMID:30661771 SUPPORT INDIRECT Model Organism
"DHPS is also highly conserved and is essential for life, as Dhps-null mice are embryonic lethal."
Supports the claim that the human alleles must be hypomorphic. Indirect: it is an inference from mouse lethality to what a surviving patient can carry, not a measurement in patients.
Reduced Deoxyhypusine Synthase Activity
Enzyme activity is reduced rather than absent, and the reduction has been measured twice over: on recombinant enzyme carrying each allele, and in patient-derived lymphoblasts where both protein abundance and function are affected.
peptidyl-hypusine biosynthetic process GO:0008612 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased peptidyl-hypusine biosynthetic process (GO:0008612). GO:0008612 is a biological process from the Gene Ontology. ↓ DECREASED
deoxyhypusine synthase activity GO:0034038 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased deoxyhypusine synthase activity (GO:0034038). GO:0034038 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Reduced Hypusination of eIF5A
Show evidence (2 references)
PMID:30661771 SUPPORT In Vitro
"Recombinant DHPS enzyme harboring either the p.Asn173Ser or p.Tyr305_Ile306del variant showed reduced (20%) or absent in vitro activity, respectively."
The quantitative enzyme measurement that distinguishes the hypomorphic allele from the null one.
PMID:37333770 SUPPORT In Vitro
"we have generated patient-derived lymphoblast cell lines and demonstrated that human DHPS variants alter DHPS protein abundance and impair enzyme function."
Confirms the deficit in patient cells rather than only in recombinant protein, and adds reduced protein abundance to reduced specific activity.
Reduced Hypusination of eIF5A
The proximate biochemical defect. Hypusine exists nowhere else in the proteome, so DHPS has exactly one substrate and a reduction in its activity has exactly one direct consequence. In patient cells the effect is visible as a shift in which modified form of eIF5A predominates: less of the cytoplasmic hypusinated form, more of the nuclear acetylated form.
peptidyl-hypusine biosynthetic process GO:0008612 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased peptidyl-hypusine biosynthetic process (GO:0008612). GO:0008612 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Impaired eIF5A-Dependent Translation Elongation
Show evidence (2 references)
PMID:30661771 SUPPORT In Vitro
"the p.Tyr305_Ile306del and p.Asn173Ser variants resulted in reduced hypusination of eIF5A compared to wild-type DHPS enzyme."
Directly measures reduced eIF5A hypusination as the consequence of each patient allele.
PMID:37333770 SUPPORT In Vitro
"we observe a shift in the abundance of the post-translationally modified forms of eIF5A; specifically, an increase in the nuclear localized acetylated form (eIF5AAcK47) and concomitant decrease in the cytoplasmic localized hypusinated form (eIF5AHYP)."
Shows the defect is a redistribution between eIF5A's modified states in patient cells, not simply less total protein.
Impaired eIF5A-Dependent Translation Elongation
Hypusinated eIF5A binds the ribosome between the P and E sites and its hypusine side chain stabilises peptidyl-tRNA, letting the ribosome read through stalling motifs such as polyproline runs. Less hypusinated eIF5A therefore does not shut translation down globally; it biases which mRNAs are translated well, which is why the consequence is a specific set of proteins rather than general cell failure.
translational elongation GO:0006414 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased translational elongation (GO:0006414). GO:0006414 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
dhps morpholino knockdown zebrafish Zebrafish partially recapitulates Dose-dependent developmental delay and dysmorphology follow dhps knockdown, consistent with a translational deficit but not measured as one.
Downstream
Altered Expression of Proteins Required for Neuronal Development
Show evidence (2 references)
PMID:34688659 SUPPORT Other
"The hypusine side chain of eIF5A stabilizes the binding of the peptidyl tRNA to the 80S ribosome and facilitates peptide bond synthesis."
The molecular role of hypusine on the ribosome. Graded OTHER because it is a statement of established biochemistry in the paper's introduction rather than a result the paper reports.
PMID:39334388 SUPPORT Other
"suppressing ribosomal stalling by stabilizing tRNA-ribosomal P-site interaction, facilitating peptide bond formation for consecutive polyprolines and other tripeptide motifs"
Names the stalling motifs that make the effect sequence-selective rather than global. Graded OTHER for the same reason - review-style background.
Altered Expression of Proteins Required for Neuronal Development
In a brain-specific Dhps knockout mouse, ribosome profiling and quantitative mass spectrometry show the translation defect resolving into altered abundance of proteins needed for neuronal development and function. This is the step that turns a translational bias into a neurodevelopmental disease, and it is the best-evidenced step in the chain that is not from patient cells.
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.
Experimental models
Patient-derived DHPS cortical organoid with CRISPR-corrected isogenic control ORGANOID Mutant organoids are significantly smaller than their isogenic controls, which is a developmental phenotype in human neural tissue carrying the patient alleles.
Animal models
Brain-specific Dhps knockout mouse (Emx1-Cre) Mouse partially recapitulates Forebrain development is grossly defective, with reduced growth and premature death.
Downstream
Impaired Neurite Outgrowth and Neuronal Survival
Reduced GABAergic Interneuron Arborization
Show evidence (1 reference)
PMID:37333770 SUPPORT Model Organism
"Generation and characterization of a mouse model with a genetic deletion of Dhps in the brain at birth shows that loss of hypusine biosynthesis impacts neuronal function due to impaired eIF5AHYP-dependent mRNA translation; this translation defect results in altered expression of proteins..."
States the full step - hypusine loss, impaired eIF5A-dependent translation, altered neuronal protein expression - in a brain-specific mouse deletion.
Impaired Neurite Outgrowth and Neuronal Survival
Reducing hypusinated eIF5A pharmacologically or by RNAi attenuates neurite outgrowth and neuronal survival in neuronal cell culture. This is a cell biology result rather than a patient one, but it is the mechanism that makes a translation defect specifically neurodevelopmental.
Animal models
Postnatal hippocampal Dhps knockout mouse (Camk2a-Cre) Mouse partially recapitulates Postnatal deletion spares gross development but produces severe spatial and contextual learning and memory deficits.
Downstream
Global developmental delay
Intellectual disability
Show evidence (1 reference)
PMID:34688659 SUPPORT INDIRECT In Vitro
"a reduction of hypusinated eIF5A by using a DHPS inhibitor or DHPS RNAi attenuated neurite outgrowth and neuronal survival"
The cellular phenotype of reduced hypusination in neurons. Indirect: pharmacological and RNAi knockdown in PC12 cells and rat hippocampal culture, not patient alleles.
Reduced GABAergic Interneuron Arborization
The zebrafish knockdown supplies a circuit-level explanation for the seizures that the mouse and cell work do not: inhibitory interneurons have reduced arborization, and the larvae show increased epileptiform activity. An excitation-inhibition imbalance arising from underdeveloped inhibitory connectivity is a coherent route from a translation defect to epilepsy. It is also the least direct claim in this entry. The lesion is a morpholino knockdown in zebrafish, and no comparable interneuron analysis has been done in the mouse model or in patient tissue.
GABAergic neuron CL:0000617 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves GABAergic neuron (CL:0000617). CL:0000617 is a cell type from the Cell Ontology.
Animal models
dhps morpholino knockdown zebrafish Zebrafish recapitulates Reduced inhibitory interneuron arborization with increased epileptiform activity, offering excitation-inhibition imbalance as the route to seizures.
Downstream
Seizure
Show evidence (1 reference)
PMID:39334388 SUPPORT INDIRECT Model Organism
"In dhps knockdown larvae, electrophysiological analysis showed increased epileptiform activity, and confocal microscopy analysis revealed reduced arborisation of GABAergic neurons."
Pairs the electrophysiological and anatomical findings that make this a circuit mechanism. Indirect: morpholino knockdown in zebrafish larvae, not a patient allele in a mammal.
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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 Deoxyhypusine Synthase Deficiency 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

7
Head and Neck 2
Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34688659 SUPPORT Human Clinical
"among the five DHPS variant patients, four have facial dysmorphism, one has microcephaly, and four have clinical seizures."
Four of five with facial dysmorphism, from the same per-feature tally.
Microcephaly HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34688659 SUPPORT Human Clinical
"among the five DHPS variant patients, four have facial dysmorphism, one has microcephaly, and four have clinical seizures."
One of five with microcephaly, which is what makes it variable rather than core in this disorder.
Musculoskeletal 1
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40883692 SUPPORT Human Clinical
"Main phenotypic features consisted of prenatal issues, hypotonia, dysmorphisms, microcephaly"
Names hypotonia among the main phenotypic features of the hypusination disorders. The sentence summarises a literature review spanning three entities together - eIF5A-related disorder, DHPS-related disorder and DOHH-related disorder - so it establishes hypotonia as a feature of that group and not a frequency specific to DHPS. The DHPS-specific series it draws on is the five-patient cohort this entry already cites.
Nervous System 3
Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30661771 SUPPORT Human Clinical
"These individuals have similar neurodevelopmental features that include global developmental delay and seizures."
Names the two core features across the founding cohort.
Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34688659 SUPPORT Human Clinical
"among the five DHPS variant patients, four have facial dysmorphism, one has microcephaly, and four have clinical seizures."
The per-feature counts across the cohort - four of five with seizures - which is the only frequency information the literature supplies.
Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37333770 SUPPORT Human Clinical
"The observed clinical outcomes associated with human mutations in DHPS include developmental delay, intellectual disability, and seizures."
Lists intellectual disability among the clinical outcomes.
Growth 1
Short stature 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:30661771 SUPPORT Human Clinical
"Two of four affected females have short stature."
The exact count, quoted rather than generalised because two of four is the whole basis for this phenotype.
🧬

Genetic Associations

1
DHPS (Causal biallelic variant)
Gene: DHPS hgnc:2869 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is DHPS (hgnc:2869). hgnc:2869 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (2 references)
PMID:30661771 SUPPORT Human Clinical
"Our data suggest that rare biallelic variants in DHPS result in reduced enzyme activity that limits the hypusination of eIF5A and are associated with a neurodevelopmental disorder."
The gene-disease claim in the authors' own words, phrased as they phrased it - "suggest" and "associated with", which is the strength appropriate to five individuals.
PMID:30661771 SUPPORT Other
"Hypusine is formed post-translationally from lysine and is found in a single cellular protein, eukaryotic translation initiation factor-5A (eIF5A), and its homolog eIF5A2."
Establishes that DHPS has exactly one substrate, which is why the gene's loss has such a narrow biochemical consequence. Graded OTHER: background biochemistry, not a result of this study.
💊

Medical Actions

3
AAV9-delivered DHPS gene replacement (preclinical)
Action: Gene TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Gene Therapy (NCIT:C15238). NCIT:C15238 is a clinical intervention from the NCI Thesaurus. NCIT:C15238
Platform: Gene therapy
Preclinical only. There is no clinical trial and no treated patient. DHPS cDNA packaged in an AAV serotype 9 vector restored hypusination in patient-derived human cortical organoids, and in a brain-specific Dhps mouse knockout the same strategy restored growth and metabolic health and improved survival. Recorded because it is the only intervention reported to act on the entry's central mechanistic step rather than on a symptom, and because gene replacement is mechanistically coherent here: the patient alleles are hypomorphic and the enzyme has exactly one substrate, so adding functional enzyme addresses the defect directly.
Mechanism Target:
Reduced Hypusination of eIF5A — Restoring DHPS expression restores the hypusination step itself, which is the node the rest of the pathograph descends from.
Show evidence (1 reference)
PMID:42239796 SUPPORT DIRECT In Vitro
"The gene therapy strategy successfully restored hypusination in human brain cells."
The rescue is measured on the hypusination step this link targets, in human cells carrying the patient alleles.
Show evidence (1 reference)
PMID:42239796 SUPPORT INDIRECT Model Organism
"We assessed our gene therapy in a mouse model of brain-specific DHPS loss and successfully restored growth, metabolic health, and reduced premature death."
The in vivo arm, and the reason this is recorded as a candidate therapy rather than a cell-culture observation. Indirect for the human disease on two counts the authors state themselves: the model is a brain-specific deletion rather than a hypomorph, and survival and growth in a mouse are not the clinical endpoints that matter in a static encephalopathy.
Anti-seizure 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
Platform: Small molecule
Symptomatic seizure control. No agent has been evaluated in this disorder and none is indicated by the mechanism; the choice is made on seizure semiology as it would be in any structural or genetic epilepsy.
Target Phenotypes: Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34688659 SUPPORT INDIRECT Human Clinical
"among the five DHPS variant patients, four have facial dysmorphism, one has microcephaly, and four have clinical seizures."
Recorded as the basis for the indication - four of five patients have clinical seizures - rather than as evidence that any drug works. Indirect and deliberately so: no anti-seizure medication has been evaluated in this disorder.
Developmental and rehabilitative therapy
Action: Physical TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Physical Therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. NCIT:C15302
Platform: Behavioral / lifestyle
Physical, occupational and speech therapy for the motor and language impairment. Standard of care for a static encephalopathy, with no disorder-specific evidence.
Target Phenotypes: Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37333770 SUPPORT INDIRECT Human Clinical
"Deoxyhypusine synthase (DHPS) deficiency is a rare, autosomal recessive disorder characterized by biallelic pathogenic variants in the DHPS gene that are associated with neurodevelopmental issues including seizures, developmental delay/intellectual disability, and hypotonia."
Establishes the deficits that developmental therapy addresses. Indirect: the paper characterises the phenotype, it does not evaluate therapy.
🔬

Diagnosis

2
Exome or genome sequencing
The only route to diagnosis. There is no metabolite biomarker, no newborn screen, and no clinically available hypusination assay - the eIF5A two-dimensional gel and enzyme assays that established the mechanism are research methods. A patient is identified by genotype and confirmed by phenotype fit, not the other way round.
Results: Biallelic DHPS variants, in practice c.518A>G p.(Asn173Ser) in trans with a near-null allele.
Show evidence (1 reference)
PMID:30661771 SUPPORT Human Clinical
"Using exome sequencing, we identified rare biallelic, recurrent, predicted likely pathogenic variants in DHPS segregating with disease in five affected individuals from four unrelated families."
The diagnostic route by which every reported patient was found.
Research-level assessment of eIF5A hypusination
Not a clinical test, but the assay that would be needed to call a novel DHPS missense variant hypomorphic. Two-dimensional gel electrophoresis of patient-derived cells separates the hypusinated from the acetylated form of eIF5A and shows the shift between them.
Results: Decreased cytoplasmic hypusinated eIF5A with increased nuclear acetylated eIF5A; reduced recombinant enzyme activity for the tested allele.
Show evidence (1 reference)
PMID:37333770 SUPPORT In Vitro
"we observe a shift in the abundance of the post-translationally modified forms of eIF5A; specifically, an increase in the nuclear localized acetylated form (eIF5AAcK47) and concomitant decrease in the cytoplasmic localized hypusinated form (eIF5AHYP)."
The measurement this assessment would make, and the direction of the expected result.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
No population estimate exists. The count is five affected individuals from four unrelated families, unchanged from the founding report through the functional follow-up four years later. Recorded as CASES_IN_LITERATURE rather than a rate, because there is no denominator.
Show evidence (1 reference)
PMID:37333770 SUPPORT Human Clinical
"To date, five affected individuals from four unrelated families have been identified."
The published case count, restated in 2023 and unchanged from 2019.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Deoxyhypusine Synthase Deficiency:

DOHH deficiency
Overlapping Features The sibling disorder at the next step of the same pathway. DOHH catalyses the hydroxylation that converts deoxyhypusine to hypusine, so biallelic DOHH variants stall eIF5A one step further along and produce a similar neurodevelopmental phenotype. Only sequencing separates them - and microcephaly is a listed core feature there while it appears in one of five DHPS patients.
Distinguishing Features
  • Biallelic DOHH rather than DHPS
  • Accumulation of the deoxyhypusine intermediate rather than reduced deoxyhypusine formation
  • Microcephaly listed as a core feature
Show evidence (2 references)
PMID:35858628 SUPPORT Human Clinical
"The DOHH variants are associated with a neurodevelopmental phenotype that is similar to phenotypes caused by DHPS or EIF5A variants and includes global developmental delay, intellectual disability, facial dysmorphism, and microcephaly."
States the phenotypic similarity to the DHPS disorder explicitly, which is what makes this a differential rather than a related curiosity.
PMID:35858628 SUPPORT In Vitro
"and a reduction in the hypusinated eIF5A in fibroblasts derived from affected individuals, providing biochemical evidence for deficiency of DOHH activity in cells carrying the bi-allelic DOHH variants."
The biochemical demonstration of the DOHH defect in patient fibroblasts. The accompanying accumulation of deoxyhypusine-containing eIF5A, which is the feature that distinguishes DOHH deficiency from DHPS deficiency, is described in the differential's own text rather than quoted, because the source writes it with bracketed notation that the snippet matcher strips.
🧫

Experimental Models

1
Patient-derived DHPS cortical organoid with CRISPR-corrected isogenic control ORGANOID
Cortical organoids grown from iPSCs reprogrammed from a patient carrying c.518A>G and c.1014+1G>A, alongside a double CRISPR-corrected isogenic line from the same patient. This is the entry's only human, patient-allele model, and the isogenic correction is what makes it informative: the control differs from the mutant at the two DHPS positions and nowhere else, so a difference between them is attributable to the alleles rather than to donor background.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
iPSCs reprogrammed from a patient with biallelic DHPS variants (c.518A>G; c.1014+1G>A), with a double CRISPR-corrected isogenic line derived from the same patient as control.
Culture
Semi-guided cortical organoid protocol, suspension culture.
Publication
PMID:42239796
Pathograph links
Altered Expression of Proteins Required for Neuronal Development partially recapitulates fidelity: moderate observes: tissue Mutant organoids are significantly smaller than their isogenic controls, which is a developmental phenotype in human neural tissue carrying the patient alleles.
Limitations: Organoid diameter is a gross morphological readout, not a measurement of which proteins are altered, so the model demonstrates that the alleles impair human neurodevelopment without identifying the mechanism at this node. The authors also state the system lacks vascularization, immune components and long-range connectivity, and models early development only.
Readouts
Cortical organoid diameter
Direction: DECREASED
Interpretation: Reduced growth of mutant organoids relative to the isogenic control.
Show evidence (1 reference)
PMID:42239796 SUPPORT In Vitro
"Significantly decreased organoid growth was observed in the mutants compared to controls, highlighting DHPS's role in neurodevelopment."
The measurement behind this readout, in the isogenic comparison.
This is the system the entry's neuronal-selectivity knowledge gap calls for. It exists; what has not been done in it is ribosome profiling or an equivalent translational-output measurement, which is why that gap remains OPEN in narrowed form rather than being retired.
Show evidence (1 reference)
PMID:42239796 SUPPORT In Vitro
"Here, we generated human brain organoids from patient-derived induced pluripotent stem cells (iPSCs) and their CRISPR-corrected isogenic controls."
Establishes the model and its isogenic control, which is what makes it the human counterpart to the animal models below.
🐁

Animal Models

3
Brain-specific Dhps knockout mouse (Emx1-Cre)
Embryonic-onset deletion in cortex and hippocampus. It produces the most severe phenotype of the mouse series and establishes that DHPS is required for forebrain development, but it is a null in the affected tissue rather than a hypomorph.
Species
Mouse
Genotype
Dhps conditional deletion driven by Emx1-Cre, from E9.5 in cortex and hippocampus
Publication
PMID:34688659
Pathograph links
Altered Expression of Proteins Required for Neuronal Development partially recapitulates fidelity: moderate observes: tissue Forebrain development is grossly defective, with reduced growth and premature death.
Limitations: Conditional null, not the hypomorphic genotype patients carry, and the phenotype is correspondingly far more severe than the human disease - gross forebrain defects and premature death against a static encephalopathy with preserved survival. The growth failure in particular is much worse than the short stature seen in two of four affected females.
Show evidence (1 reference)
PMID:34688659 SUPPORT Model Organism
"The conditional deletion of Dhps or Eif5a by Emx1 promotor-driven Cre expression (E9.5, in the cortex and hippocampus) led to gross defects in forebrain development, reduced growth, and premature death."
The phenotype of the embryonic-onset deletion.
Postnatal hippocampal Dhps knockout mouse (Camk2a-Cre)
The more informative of the two mouse models for the human disease, because deleting after development separates the cognitive phenotype from the malformation. These animals develop normally and are still impaired on learning and memory.
Species
Mouse
Genotype
Dhps conditional deletion driven by Camk2a-Cre, postnatal, mainly hippocampal CA1
Publication
PMID:34688659
Pathograph links
Impaired Neurite Outgrowth and Neuronal Survival partially recapitulates fidelity: moderate observes: organism Postnatal deletion spares gross development but produces severe spatial and contextual learning and memory deficits.
Limitations: Still a null rather than a hypomorph, and restricted to hippocampal CA1, so it addresses learning and memory rather than the global developmental delay that defines the human disorder. It also says nothing about seizures, which are the other core feature.
Readouts
Morris water maze and contextual learning performance
Direction: DECREASED
Interpretation: Behavioural readout of hippocampal dysfunction after Dhps loss in otherwise normally developed animals.
Show evidence (1 reference)
PMID:34688659 SUPPORT Model Organism
"these KO animals exhibited severe impairment in spatial learning, contextual learning, and memory when subjected to the Morris water maze and a contextual learning test."
The behavioural measurement behind this readout.
Show evidence (1 reference)
PMID:34688659 SUPPORT Model Organism
"In both models, the Dhps-KO mice displayed more severe impairment than their Eif5a-KO counterparts."
Worth recording because it is mechanistically informative rather than merely comparative: losing the modifying enzyme is worse than losing the substrate, which is hard to explain if the only consequence of DHPS loss is unhypusinated eIF5A.
dhps morpholino knockdown zebrafish
The only model that addresses the seizures. Knockdown larvae show epileptiform activity on electrophysiology together with reduced arborization of GABAergic interneurons, which is a circuit-level mechanism neither mouse model provides.
Species
Zebrafish
Genotype
dhps exon2/intron2 splice-site antisense morpholino knockdown
Publication
PMID:39334388
Pathograph links
Reduced GABAergic Interneuron Arborization recapitulates fidelity: low observes: tissue Reduced inhibitory interneuron arborization with increased epileptiform activity, offering excitation-inhibition imbalance as the route to seizures.
Limitations: Morpholino knockdown rather than a genetic allele, with the usual off-target and transient-knockdown caveats and no stable mutant line. The knockdown is also dose-dependent and produces microcephaly, axis truncation and body curvature - a general developmental toxicity in which a specific interneuron phenotype is harder to attribute. Fidelity is recorded LOW for that reason, not because the finding is uninteresting.
Readouts
GABAergic interneuron arborization
Direction: DECREASED
Interpretation: Anatomical correlate of the inhibitory deficit proposed to underlie the seizures.
Show evidence (1 reference)
PMID:39334388 SUPPORT Model Organism
"confocal microscopy analysis revealed reduced arborisation of GABAergic neurons"
The imaging measurement behind this readout.
Epileptiform electrophysiological activity
Direction: INCREASED
Interpretation: Functional correlate, measured in the same larvae as the anatomical deficit.
Show evidence (1 reference)
PMID:39334388 SUPPORT Model Organism
"In dhps knockdown larvae, electrophysiological analysis showed increased epileptiform activity"
The electrophysiological measurement behind this readout.
Show evidence (1 reference)
PMID:39334388 SUPPORT Model Organism
"Our findings confirm that hypusination of eIF5A by DHPS is needed for early brain development, and zebrafish with an antisense knockdown of dhps model features of DHPS deficiency syndrome."
The authors' own claim for the model - that it reproduces features of the syndrome - stated as "features of" rather than the syndrome itself.
Impaired eIF5A-Dependent Translation Elongation partially recapitulates fidelity: low observes: organism Dose-dependent developmental delay and dysmorphology follow dhps knockdown, consistent with a translational deficit but not measured as one.
Limitations: No translational readout was measured in this model - no ribosome profiling, no polysome analysis, no hypusinated eIF5A quantification. The link to the translation node is inferred from the enzyme's known function rather than demonstrated here, which is why the relationship is partial and the fidelity low.
Show evidence (1 reference)
PMID:39334388 SUPPORT Model Organism
"dhps knockdown embryos exhibited dose-dependent developmental delay and dysmorphology, including microcephaly, axis truncation, and body curvature."
The organism-level phenotype, including the non-specific features that limit what can be attributed to a translational mechanism.
{ }

Source YAML

click to show 
name: Deoxyhypusine Synthase Deficiency
creation_date: "2026-09-11T11:40:00Z"
category: Mendelian
synonyms:
- DHPS deficiency
- DHPS deficiency syndrome
- NEDSSWI
- neurodevelopmental disorder with seizures and speech and walking impairment
description: >-
  Deoxyhypusine synthase deficiency is an ultra-rare autosomal recessive
  neurodevelopmental disorder caused by biallelic hypomorphic DHPS variants. It
  presents as a static encephalopathy with global developmental delay,
  intellectual disability and seizures, with variable hypotonia, microcephaly,
  short stature and mild facial dysmorphism.

  What makes it mechanistically unusual is the narrowness of the enzyme's job.
  DHPS catalyses the first committed step in making hypusine, an amino acid that
  exists in exactly one cellular protein: eukaryotic translation initiation
  factor 5A. Hypusination is what activates eIF5A, and eIF5A - despite its name
  - works mainly in translation elongation, stabilising peptidyl-tRNA on the
  ribosome so that stalling motifs such as polyproline runs can be read through.
  So a single missing post-translational modification on a single protein
  produces a disease of the developing brain.

  Every reported patient carries a hypomorphic combination, and that is a
  structural feature rather than ascertainment bias: Dhps-null mice are
  embryonic lethal, so complete loss of function cannot produce a living
  patient. All five individuals in the founding cohort shared the same
  recurrent missense allele, p.Asn173Ser, which retains roughly a fifth of
  normal activity, in trans with a near-null second allele.

  The disorder sits in a small family of conditions that converge on the same
  molecule: biallelic DOHH variants disable the second hypusination step, and
  heterozygous EIF5A variants disable the substrate itself, both producing a
  similar neurodevelopmental phenotype. It is also one of the polyaminopathies,
  which is how it relates to Bachmann-Bupp syndrome - an ODC1 gain-of-function
  disorder dismech already carries, upstream in polyamine metabolism but
  phenotypically distinct.
disease_term:
  preferred_term: Deoxyhypusine synthase deficiency
  term:
    id: MONDO:0032775
    label: neurodevelopmental disorder with seizures and speech and walking impairment
parents:
- Inborn error of polyamine metabolism
- Mendelian neurodevelopmental disorder
- Autosomal recessive disease
references:
- reference: PMID:30661771
  title: "Recessive Rare Variants in Deoxyhypusine Synthase, an Enzyme Involved in the Synthesis of Hypusine, Are Associated with a Neurodevelopmental Disorder."
- reference: PMID:37333770
  title: Deoxyhypusine synthase mutations alter the post-translational modification of eukaryotic initiation factor 5A resulting in impaired human and mouse neural homeostasis.
- reference: PMID:34688659
  title: "Neuron-specific ablation of eIF5A or deoxyhypusine synthase leads to impairments in growth, viability, neurodevelopment, and cognitive functions in mice."
- reference: PMID:39334388
  title: "Deoxyhypusine synthase deficiency syndrome zebrafish model: aberrant morphology, epileptiform activity, and reduced arborization of inhibitory interneurons."
- reference: PMID:35858628
  title: "Bi-allelic variants in DOHH, catalyzing the last step of hypusine biosynthesis, are associated with a neurodevelopmental disorder."
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic, and specifically a hypomorph in trans with a near-null allele in
    every reported case. Carrier relatives are clinically unaffected, though
    their cells do show measurable biochemical change.
  evidence:
  - reference: PMID:30661771
    reference_title: "Recessive Rare Variants in Deoxyhypusine Synthase, an Enzyme Involved in the Synthesis of Hypusine, Are Associated with a Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using exome sequencing, we identified rare biallelic, recurrent, predicted likely pathogenic variants in DHPS segregating with disease in five affected individuals from four unrelated families.
    explanation: >-
      The founding report, stating the recessive biallelic mechanism and the
      size of the cohort it rests on - five individuals, four families.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population estimate exists. The count is five affected individuals from
    four unrelated families, unchanged from the founding report through the
    functional follow-up four years later. Recorded as CASES_IN_LITERATURE
    rather than a rate, because there is no denominator.
  evidence:
  - reference: PMID:37333770
    reference_title: Deoxyhypusine synthase mutations alter the post-translational modification of eukaryotic initiation factor 5A resulting in impaired human and mouse neural homeostasis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To date, five affected individuals from four unrelated families have been identified.
    explanation: >-
      The published case count, restated in 2023 and unchanged from 2019.
pathophysiology:
- name: Biallelic Hypomorphic DHPS Variants
  biological_scale: MOLECULAR
  description: >-
    A recurrent missense allele, c.518A>G p.(Asn173Ser), in trans with a
    near-null second allele - a splice-site change, an in-frame deletion
    p.(Tyr305_Ile306del), or a start-loss. The genotype is not incidental. The
    p.Asn173Ser enzyme retains roughly a fifth of normal activity while the
    in-frame deletion is inactive, so a patient's residual capacity comes almost
    entirely from the missense allele, and a patient homozygous for two nulls
    would not be born.
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
  genes:
  - preferred_term: DHPS
    term:
      id: hgnc:2869
      label: DHPS
  downstream:
  - target: Reduced Deoxyhypusine Synthase Activity
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:37333770
    reference_title: Deoxyhypusine synthase mutations alter the post-translational modification of eukaryotic initiation factor 5A resulting in impaired human and mouse neural homeostasis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The splice site and initiation codon variants are predicted to disrupt proper DHPS protein synthesis and thus enzyme activity.
    explanation: >-
      Characterises the second allele in each patient as near-null, which is
      what makes the genotype hypomorph-over-null rather than simply biallelic.
      The variant-level detail is in the description; it is not quoted here
      because the source writes every allele with bracketed protein-change
      notation, which the snippet matcher strips before comparing.
  - reference: PMID:30661771
    reference_title: "Recessive Rare Variants in Deoxyhypusine Synthase, an Enzyme Involved in the Synthesis of Hypusine, Are Associated with a Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      cDNA studies demonstrated that the c.1014+1G>A variant causes aberrant splicing.
    explanation: >-
      Confirms the splice allele's consequence at the RNA level rather than by
      prediction.
  - reference: PMID:30661771
    reference_title: "Recessive Rare Variants in Deoxyhypusine Synthase, an Enzyme Involved in the Synthesis of Hypusine, Are Associated with a Neurodevelopmental Disorder."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      DHPS is also highly conserved and is essential for life, as Dhps-null mice are embryonic lethal.
    explanation: >-
      Supports the claim that the human alleles must be hypomorphic. Indirect:
      it is an inference from mouse lethality to what a surviving patient can
      carry, not a measurement in patients.
- name: Reduced Deoxyhypusine Synthase Activity
  biological_scale: MOLECULAR
  description: >-
    Enzyme activity is reduced rather than absent, and the reduction has been
    measured twice over: on recombinant enzyme carrying each allele, and in
    patient-derived lymphoblasts where both protein abundance and function are
    affected.
  molecular_functions:
  - preferred_term: deoxyhypusine synthase activity
    modifier: DECREASED
    term:
      id: GO:0034038
      label: deoxyhypusine synthase activity
  biological_processes:
  - preferred_term: peptidyl-hypusine biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0008612
      label: peptidyl-hypusine biosynthetic process
  downstream:
  - target: Reduced Hypusination of eIF5A
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:30661771
    reference_title: "Recessive Rare Variants in Deoxyhypusine Synthase, an Enzyme Involved in the Synthesis of Hypusine, Are Associated with a Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Recombinant DHPS enzyme harboring either the p.Asn173Ser or p.Tyr305_Ile306del variant showed reduced (20%) or absent in vitro activity, respectively.
    explanation: >-
      The quantitative enzyme measurement that distinguishes the hypomorphic
      allele from the null one.
  - reference: PMID:37333770
    reference_title: Deoxyhypusine synthase mutations alter the post-translational modification of eukaryotic initiation factor 5A resulting in impaired human and mouse neural homeostasis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we have generated patient-derived lymphoblast cell lines and demonstrated that human DHPS variants alter DHPS protein abundance and impair enzyme function.
    explanation: >-
      Confirms the deficit in patient cells rather than only in recombinant
      protein, and adds reduced protein abundance to reduced specific activity.
- name: Reduced Hypusination of eIF5A
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: peptidyl-hypusine biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0008612
      label: peptidyl-hypusine biosynthetic process
  description: >-
    The proximate biochemical defect. Hypusine exists nowhere else in the
    proteome, so DHPS has exactly one substrate and a reduction in its activity
    has exactly one direct consequence. In patient cells the effect is visible
    as a shift in which modified form of eIF5A predominates: less of the
    cytoplasmic hypusinated form, more of the nuclear acetylated form.
  downstream:
  - target: Impaired eIF5A-Dependent Translation Elongation
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:30661771
    reference_title: "Recessive Rare Variants in Deoxyhypusine Synthase, an Enzyme Involved in the Synthesis of Hypusine, Are Associated with a Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the p.Tyr305_Ile306del and p.Asn173Ser variants resulted in reduced hypusination of eIF5A compared to wild-type DHPS enzyme.
    explanation: >-
      Directly measures reduced eIF5A hypusination as the consequence of each
      patient allele.
  - reference: PMID:37333770
    reference_title: Deoxyhypusine synthase mutations alter the post-translational modification of eukaryotic initiation factor 5A resulting in impaired human and mouse neural homeostasis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we observe a shift in the abundance of the post-translationally modified forms of eIF5A; specifically, an increase in the nuclear localized acetylated form (eIF5AAcK47) and concomitant decrease in the cytoplasmic localized hypusinated form (eIF5AHYP).
    explanation: >-
      Shows the defect is a redistribution between eIF5A's modified states in
      patient cells, not simply less total protein.
- name: Impaired eIF5A-Dependent Translation Elongation
  biological_scale: CELLULAR
  description: >-
    Hypusinated eIF5A binds the ribosome between the P and E sites and its
    hypusine side chain stabilises peptidyl-tRNA, letting the ribosome read
    through stalling motifs such as polyproline runs. Less hypusinated eIF5A
    therefore does not shut translation down globally; it biases which mRNAs
    are translated well, which is why the consequence is a specific set of
    proteins rather than general cell failure.
  biological_processes:
  - preferred_term: translational elongation
    modifier: DECREASED
    term:
      id: GO:0006414
      label: translational elongation
  downstream:
  - target: Altered Expression of Proteins Required for Neuronal Development
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:34688659
    reference_title: "Neuron-specific ablation of eIF5A or deoxyhypusine synthase leads to impairments in growth, viability, neurodevelopment, and cognitive functions in mice."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The hypusine side chain of eIF5A stabilizes the binding of the peptidyl tRNA to the 80S ribosome and facilitates peptide bond synthesis.
    explanation: >-
      The molecular role of hypusine on the ribosome. Graded OTHER because it is
      a statement of established biochemistry in the paper's introduction rather
      than a result the paper reports.
  - reference: PMID:39334388
    reference_title: "Deoxyhypusine synthase deficiency syndrome zebrafish model: aberrant morphology, epileptiform activity, and reduced arborization of inhibitory interneurons."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      suppressing ribosomal stalling by stabilizing tRNA-ribosomal P-site interaction, facilitating peptide bond formation for consecutive polyprolines and other tripeptide motifs
    explanation: >-
      Names the stalling motifs that make the effect sequence-selective rather
      than global. Graded OTHER for the same reason - review-style background.
- name: Altered Expression of Proteins Required for Neuronal Development
  biological_scale: CELLULAR
  description: >-
    In a brain-specific Dhps knockout mouse, ribosome profiling and quantitative
    mass spectrometry show the translation defect resolving into altered
    abundance of proteins needed for neuronal development and function. This is
    the step that turns a translational bias into a neurodevelopmental disease,
    and it is the best-evidenced step in the chain that is not from patient
    cells.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  downstream:
  - target: Impaired Neurite Outgrowth and Neuronal Survival
    causal_link_type: DIRECT
  - target: Reduced GABAergic Interneuron Arborization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:37333770
    reference_title: Deoxyhypusine synthase mutations alter the post-translational modification of eukaryotic initiation factor 5A resulting in impaired human and mouse neural homeostasis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Generation and characterization of a mouse model with a genetic deletion of Dhps in the brain at birth shows that loss of hypusine biosynthesis impacts neuronal function due to impaired eIF5AHYP-dependent mRNA translation; this translation defect results in altered expression of proteins required for proper neuronal development and function.
    explanation: >-
      States the full step - hypusine loss, impaired eIF5A-dependent
      translation, altered neuronal protein expression - in a brain-specific
      mouse deletion.
- name: Impaired Neurite Outgrowth and Neuronal Survival
  biological_scale: CELLULAR
  description: >-
    Reducing hypusinated eIF5A pharmacologically or by RNAi attenuates neurite
    outgrowth and neuronal survival in neuronal cell culture. This is a cell
    biology result rather than a patient one, but it is the mechanism that makes
    a translation defect specifically neurodevelopmental.
  downstream:
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:34688659
    reference_title: "Neuron-specific ablation of eIF5A or deoxyhypusine synthase leads to impairments in growth, viability, neurodevelopment, and cognitive functions in mice."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: >-
      a reduction of hypusinated eIF5A by using a DHPS inhibitor or DHPS RNAi attenuated neurite outgrowth and neuronal survival
    explanation: >-
      The cellular phenotype of reduced hypusination in neurons. Indirect:
      pharmacological and RNAi knockdown in PC12 cells and rat hippocampal
      culture, not patient alleles.
- name: Reduced GABAergic Interneuron Arborization
  biological_scale: TISSUE
  description: >-
    The zebrafish knockdown supplies a circuit-level explanation for the
    seizures that the mouse and cell work do not: inhibitory interneurons have
    reduced arborization, and the larvae show increased epileptiform activity.
    An excitation-inhibition imbalance arising from underdeveloped inhibitory
    connectivity is a coherent route from a translation defect to epilepsy.

    It is also the least direct claim in this entry. The lesion is a morpholino
    knockdown in zebrafish, and no comparable interneuron analysis has been done
    in the mouse model or in patient tissue.
  cell_types:
  - preferred_term: GABAergic neuron
    term:
      id: CL:0000617
      label: GABAergic neuron
  downstream:
  - target: Seizure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:39334388
    reference_title: "Deoxyhypusine synthase deficiency syndrome zebrafish model: aberrant morphology, epileptiform activity, and reduced arborization of inhibitory interneurons."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In dhps knockdown larvae, electrophysiological analysis showed increased epileptiform activity, and confocal microscopy analysis revealed reduced arborisation of GABAergic neurons.
    explanation: >-
      Pairs the electrophysiological and anatomical findings that make this a
      circuit mechanism. Indirect: morpholino knockdown in zebrafish larvae, not
      a patient allele in a mammal.
phenotypes:
- name: Hypotonia
  category: Neurologic
  description: >-
    Reported as a main phenotypic feature across the described cohorts, and
    named in this entry's own summary of the clinical picture. Recorded here as
    a phenotype in its own right rather than left in prose, since it is part of
    the presenting neurological picture alongside the developmental delay and
    the seizures.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:40883692
    reference_title: "eIF5A and hypusination-related disorders: literature review and case report of DOHH-related encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Main phenotypic features consisted of prenatal issues, hypotonia, dysmorphisms, microcephaly
    explanation: >-
      Names hypotonia among the main phenotypic features of the hypusination
      disorders. The sentence summarises a literature review spanning three
      entities together - eIF5A-related disorder, DHPS-related disorder and
      DOHH-related disorder - so it establishes hypotonia as a feature of that
      group and not a frequency specific to DHPS. The DHPS-specific series it
      draws on is the five-patient cohort this entry already cites.
- name: Global developmental delay
  category: Neurologic
  diagnostic: true
  description: >-
    Present in all reported individuals and, with seizures, the reason the
    disorder comes to attention. The course is described as static rather than
    regressive, which distinguishes it from the neurodegenerative
    leukodystrophies it might otherwise resemble.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:30661771
    reference_title: "Recessive Rare Variants in Deoxyhypusine Synthase, an Enzyme Involved in the Synthesis of Hypusine, Are Associated with a Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These individuals have similar neurodevelopmental features that include global developmental delay and seizures.
    explanation: >-
      Names the two core features across the founding cohort.
- name: Seizure
  category: Neurologic
  diagnostic: true
  description: >-
    Reported in four of the five individuals in the founding cohort. The
    zebrafish model's epileptiform activity with reduced inhibitory arborization
    is the only mechanistic account on offer.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:34688659
    reference_title: "Neuron-specific ablation of eIF5A or deoxyhypusine synthase leads to impairments in growth, viability, neurodevelopment, and cognitive functions in mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      among the five DHPS variant patients, four have facial dysmorphism, one has microcephaly, and four have clinical seizures.
    explanation: >-
      The per-feature counts across the cohort - four of five with seizures -
      which is the only frequency information the literature supplies.
- name: Intellectual disability
  category: Neurologic
  description: >-
    The cognitive endpoint of the developmental delay. In the mouse, postnatal
    hippocampal deletion of Dhps produces spatial and contextual learning
    deficits without gross developmental abnormality, which suggests the
    cognitive phenotype is not purely a consequence of malformation.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:37333770
    reference_title: Deoxyhypusine synthase mutations alter the post-translational modification of eukaryotic initiation factor 5A resulting in impaired human and mouse neural homeostasis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The observed clinical outcomes associated with human mutations in DHPS include developmental delay, intellectual disability, and seizures.
    explanation: >-
      Lists intellectual disability among the clinical outcomes.
- name: Abnormal facial shape
  category: Craniofacial
  description: >-
    Mild and non-specific facial dysmorphism, in four of the five reported
    individuals. It is not a recognisable gestalt and would not on its own
    prompt the diagnosis.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:34688659
    reference_title: "Neuron-specific ablation of eIF5A or deoxyhypusine synthase leads to impairments in growth, viability, neurodevelopment, and cognitive functions in mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      among the five DHPS variant patients, four have facial dysmorphism, one has microcephaly, and four have clinical seizures.
    explanation: >-
      Four of five with facial dysmorphism, from the same per-feature tally.
- name: Microcephaly
  category: Craniofacial
  description: >-
    Reported in one of five individuals, so it is a variable feature here -
    notably less consistent than in the allelic DOHH and EIF5A disorders, where
    microcephaly is a listed core feature.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:34688659
    reference_title: "Neuron-specific ablation of eIF5A or deoxyhypusine synthase leads to impairments in growth, viability, neurodevelopment, and cognitive functions in mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      among the five DHPS variant patients, four have facial dysmorphism, one has microcephaly, and four have clinical seizures.
    explanation: >-
      One of five with microcephaly, which is what makes it variable rather than
      core in this disorder.
- name: Short stature
  category: Growth
  description: >-
    Reported in two of the four affected females. Growth impairment is far more
    severe in the mouse models than in patients, which is itself a mismatch
    worth recording.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:30661771
    reference_title: "Recessive Rare Variants in Deoxyhypusine Synthase, an Enzyme Involved in the Synthesis of Hypusine, Are Associated with a Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two of four affected females have short stature.
    explanation: >-
      The exact count, quoted rather than generalised because two of four is the
      whole basis for this phenotype.
genetic:
- name: DHPS
  association: Causal biallelic variant
  gene_term:
    preferred_term: DHPS
    term:
      id: hgnc:2869
      label: DHPS
  frequency: The only gene associated with this disorder.
  notes: >-
    Two things about interpreting a DHPS result.

    The recurrent allele matters more than its recurrence suggests. Every one of
    the five reported individuals carries c.518A>G p.(Asn173Ser) on one allele.
    That is not a founder effect established by haplotype - it has not been
    tested - but it does mean the disease as described is essentially the
    phenotype of one specific hypomorphic enzyme, and a patient with two
    different hypomorphs might look different.

    A biallelic-null genotype should not be expected and, if seen, should prompt
    a rethink. Dhps-null mice die as embryos, and the residual activity in
    reported patients comes from the missense allele. The name DHPS is also
    shared with bacterial dihydropteroate synthase, the sulfonamide target,
    which is a live source of literature-search confusion and has nothing to do
    with this gene.
  evidence:
  - reference: PMID:30661771
    reference_title: "Recessive Rare Variants in Deoxyhypusine Synthase, an Enzyme Involved in the Synthesis of Hypusine, Are Associated with a Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data suggest that rare biallelic variants in DHPS result in reduced enzyme activity that limits the hypusination of eIF5A and are associated with a neurodevelopmental disorder.
    explanation: >-
      The gene-disease claim in the authors' own words, phrased as they phrased
      it - "suggest" and "associated with", which is the strength appropriate to
      five individuals.
  - reference: PMID:30661771
    reference_title: "Recessive Rare Variants in Deoxyhypusine Synthase, an Enzyme Involved in the Synthesis of Hypusine, Are Associated with a Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Hypusine is formed post-translationally from lysine and is found in a single cellular protein, eukaryotic translation initiation factor-5A (eIF5A), and its homolog eIF5A2.
    explanation: >-
      Establishes that DHPS has exactly one substrate, which is why the gene's
      loss has such a narrow biochemical consequence. Graded OTHER: background
      biochemistry, not a result of this study.
treatments:
- name: AAV9-delivered DHPS gene replacement (preclinical)
  description: >-
    Preclinical only. There is no clinical trial and no treated patient. DHPS
    cDNA packaged in an AAV serotype 9 vector restored hypusination in
    patient-derived human cortical organoids, and in a brain-specific Dhps
    mouse knockout the same strategy restored growth and metabolic health and
    improved survival. Recorded because it is the only intervention reported to
    act on the entry's central mechanistic step rather than on a symptom, and
    because gene replacement is mechanistically coherent here: the patient
    alleles are hypomorphic and the enzyme has exactly one substrate, so adding
    functional enzyme addresses the defect directly.
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: Gene Therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  target_mechanisms:
  - target: Reduced Hypusination of eIF5A
    description: >-
      Restoring DHPS expression restores the hypusination step itself, which is
      the node the rest of the pathograph descends from.
    evidence:
    - reference: PMID:42239796
      reference_title: "A gene therapy strategy for Deoxyhypusine Synthase (DHPS) syndrome."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: >-
        The gene therapy strategy successfully restored hypusination in human brain cells.
      explanation: >-
        The rescue is measured on the hypusination step this link targets, in
        human cells carrying the patient alleles.
  evidence:
  - reference: PMID:42239796
    reference_title: "A gene therapy strategy for Deoxyhypusine Synthase (DHPS) syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We assessed our gene therapy in a mouse model of brain-specific DHPS loss and successfully restored growth, metabolic health, and reduced premature death.
    explanation: >-
      The in vivo arm, and the reason this is recorded as a candidate therapy
      rather than a cell-culture observation. Indirect for the human disease on
      two counts the authors state themselves: the model is a brain-specific
      deletion rather than a hypomorph, and survival and growth in a mouse are
      not the clinical endpoints that matter in a static encephalopathy.
- name: Anti-seizure medication
  description: >-
    Symptomatic seizure control. No agent has been evaluated in this disorder
    and none is indicated by the mechanism; the choice is made on seizure
    semiology as it would be in any structural or genetic epilepsy.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: anticonvulsant therapy
    term:
      id: NCIT:C64172
      label: Anticonvulsant Therapy
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:34688659
    reference_title: "Neuron-specific ablation of eIF5A or deoxyhypusine synthase leads to impairments in growth, viability, neurodevelopment, and cognitive functions in mice."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      among the five DHPS variant patients, four have facial dysmorphism, one has microcephaly, and four have clinical seizures.
    explanation: >-
      Recorded as the basis for the indication - four of five patients have
      clinical seizures - rather than as evidence that any drug works. Indirect
      and deliberately so: no anti-seizure medication has been evaluated in this
      disorder.
- name: Developmental and rehabilitative therapy
  description: >-
    Physical, occupational and speech therapy for the motor and language
    impairment. Standard of care for a static encephalopathy, with no
    disorder-specific evidence.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Physical Therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_phenotypes:
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:37333770
    reference_title: Deoxyhypusine synthase mutations alter the post-translational modification of eukaryotic initiation factor 5A resulting in impaired human and mouse neural homeostasis.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Deoxyhypusine synthase (DHPS) deficiency is a rare, autosomal recessive disorder characterized by biallelic pathogenic variants in the DHPS gene that are associated with neurodevelopmental issues including seizures, developmental delay/intellectual disability, and hypotonia.
    explanation: >-
      Establishes the deficits that developmental therapy addresses. Indirect:
      the paper characterises the phenotype, it does not evaluate therapy.
diagnosis:
- name: Exome or genome sequencing
  description: >-
    The only route to diagnosis. There is no metabolite biomarker, no newborn
    screen, and no clinically available hypusination assay - the eIF5A
    two-dimensional gel and enzyme assays that established the mechanism are
    research methods. A patient is identified by genotype and confirmed by
    phenotype fit, not the other way round.
  results: >-
    Biallelic DHPS variants, in practice c.518A>G p.(Asn173Ser) in trans with a
    near-null allele.
  evidence:
  - reference: PMID:30661771
    reference_title: "Recessive Rare Variants in Deoxyhypusine Synthase, an Enzyme Involved in the Synthesis of Hypusine, Are Associated with a Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using exome sequencing, we identified rare biallelic, recurrent, predicted likely pathogenic variants in DHPS segregating with disease in five affected individuals from four unrelated families.
    explanation: >-
      The diagnostic route by which every reported patient was found.
- name: Research-level assessment of eIF5A hypusination
  description: >-
    Not a clinical test, but the assay that would be needed to call a novel DHPS
    missense variant hypomorphic. Two-dimensional gel electrophoresis of
    patient-derived cells separates the hypusinated from the acetylated form of
    eIF5A and shows the shift between them.
  results: >-
    Decreased cytoplasmic hypusinated eIF5A with increased nuclear acetylated
    eIF5A; reduced recombinant enzyme activity for the tested allele.
  evidence:
  - reference: PMID:37333770
    reference_title: Deoxyhypusine synthase mutations alter the post-translational modification of eukaryotic initiation factor 5A resulting in impaired human and mouse neural homeostasis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we observe a shift in the abundance of the post-translationally modified forms of eIF5A; specifically, an increase in the nuclear localized acetylated form (eIF5AAcK47) and concomitant decrease in the cytoplasmic localized hypusinated form (eIF5AHYP).
    explanation: >-
      The measurement this assessment would make, and the direction of the
      expected result.
differential_diagnoses:
- name: DOHH deficiency
  description: >-
    The sibling disorder at the next step of the same pathway. DOHH catalyses
    the hydroxylation that converts deoxyhypusine to hypusine, so biallelic DOHH
    variants stall eIF5A one step further along and produce a similar
    neurodevelopmental phenotype. Only sequencing separates them - and
    microcephaly is a listed core feature there while it appears in one of five
    DHPS patients.
  notes: >-
    Deliberately left without a disease_term. MONDO carries the DOHH gene
    (HGNC:28662) but a search of the 2026 release returned no disease term for
    the DOHH-related neurodevelopmental disorder, which was described only in
    2022. Rather than bind a plausible-looking neighbouring CURIE, the binding
    is omitted and the disorder is identified by gene and by the citation. Add
    the term when MONDO mints one.
  distinguishing_features:
  - Biallelic DOHH rather than DHPS
  - Accumulation of the deoxyhypusine intermediate rather than reduced deoxyhypusine formation
  - Microcephaly listed as a core feature
  evidence:
  - reference: PMID:35858628
    reference_title: "Bi-allelic variants in DOHH, catalyzing the last step of hypusine biosynthesis, are associated with a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The DOHH variants are associated with a neurodevelopmental phenotype that is similar to phenotypes caused by DHPS or EIF5A variants and includes global developmental delay, intellectual disability, facial dysmorphism, and microcephaly.
    explanation: >-
      States the phenotypic similarity to the DHPS disorder explicitly, which is
      what makes this a differential rather than a related curiosity.
  - reference: PMID:35858628
    reference_title: "Bi-allelic variants in DOHH, catalyzing the last step of hypusine biosynthesis, are associated with a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      and a reduction in the hypusinated eIF5A in fibroblasts derived from affected individuals, providing biochemical evidence for deficiency of DOHH activity in cells carrying the bi-allelic DOHH variants.
    explanation: >-
      The biochemical demonstration of the DOHH defect in patient fibroblasts.
      The accompanying accumulation of deoxyhypusine-containing eIF5A, which is
      the feature that distinguishes DOHH deficiency from DHPS deficiency, is
      described in the differential's own text rather than quoted, because the
      source writes it with bracketed notation that the snippet matcher strips.
- name: EIF5A-related neurodevelopmental disorder
  description: >-
    The third member of the group, and the one with a different inheritance
    pattern: heterozygous de novo EIF5A variants affect the substrate itself.
    Facial dysmorphism is universal and microcephaly common in the reported
    patients, which is a somewhat stronger dysmorphic picture than DHPS
    deficiency.
  disease_term:
    preferred_term: Faundes-Banka syndrome
    term:
      id: MONDO:0859163
      label: Faundes-Banka syndrome
  distinguishing_features:
  - Heterozygous de novo EIF5A rather than biallelic DHPS
  - Facial dysmorphism in all reported patients
  - Microcephaly in the majority
  evidence:
  - reference: PMID:34688659
    reference_title: "Neuron-specific ablation of eIF5A or deoxyhypusine synthase leads to impairments in growth, viability, neurodevelopment, and cognitive functions in mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the seven EIF5A variant patients, all display facial dysmorphism and five of them with microcephaly.
    explanation: >-
      The per-feature counts in the EIF5A cohort, quoted so the comparison with
      the DHPS counts in this entry is like for like.
experimental_models:
- name: Patient-derived DHPS cortical organoid with CRISPR-corrected isogenic control
  description: >-
    Cortical organoids grown from iPSCs reprogrammed from a patient carrying
    c.518A>G and c.1014+1G>A, alongside a double CRISPR-corrected isogenic line
    from the same patient. This is the entry's only human, patient-allele
    model, and the isogenic correction is what makes it informative: the control
    differs from the mutant at the two DHPS positions and nowhere else, so a
    difference between them is attributable to the alleles rather than to donor
    background.
  experimental_model_type: ORGANOID
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: >-
    iPSCs reprogrammed from a patient with biallelic DHPS variants
    (c.518A>G; c.1014+1G>A), with a double CRISPR-corrected isogenic line
    derived from the same patient as control.
  culture_system: Semi-guided cortical organoid protocol, suspension culture.
  publication: PMID:42239796
  modeled_mechanisms:
  - target: Altered Expression of Proteins Required for Neuronal Development
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Mutant organoids are significantly smaller than their isogenic controls,
      which is a developmental phenotype in human neural tissue carrying the
      patient alleles.
    limitations: >-
      Organoid diameter is a gross morphological readout, not a measurement of
      which proteins are altered, so the model demonstrates that the alleles
      impair human neurodevelopment without identifying the mechanism at this
      node. The authors also state the system lacks vascularization, immune
      components and long-range connectivity, and models early development only.
    readouts:
    - name: Cortical organoid diameter
      target: Altered Expression of Proteins Required for Neuronal Development
      direction: DECREASED
      interpretation: >-
        Reduced growth of mutant organoids relative to the isogenic control.
      evidence:
      - reference: PMID:42239796
        reference_title: "A gene therapy strategy for Deoxyhypusine Synthase (DHPS) syndrome."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Significantly decreased organoid growth was observed in the mutants compared to controls, highlighting DHPS's role in neurodevelopment.
        explanation: >-
          The measurement behind this readout, in the isogenic comparison.
  evidence:
  - reference: PMID:42239796
    reference_title: "A gene therapy strategy for Deoxyhypusine Synthase (DHPS) syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we generated human brain organoids from patient-derived induced pluripotent stem cells (iPSCs) and their CRISPR-corrected isogenic controls.
    explanation: >-
      Establishes the model and its isogenic control, which is what makes it the
      human counterpart to the animal models below.
  notes: >-
    This is the system the entry's neuronal-selectivity knowledge gap calls for.
    It exists; what has not been done in it is ribosome profiling or an
    equivalent translational-output measurement, which is why that gap remains
    OPEN in narrowed form rather than being retired.

animal_models:
- name: Brain-specific Dhps knockout mouse (Emx1-Cre)
  species: Mouse
  genotype: Dhps conditional deletion driven by Emx1-Cre, from E9.5 in cortex and hippocampus
  publication: PMID:34688659
  description: >-
    Embryonic-onset deletion in cortex and hippocampus. It produces the most
    severe phenotype of the mouse series and establishes that DHPS is required
    for forebrain development, but it is a null in the affected tissue rather
    than a hypomorph.
  modeled_mechanisms:
  - target: Altered Expression of Proteins Required for Neuronal Development
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Forebrain development is grossly defective, with reduced growth and
      premature death.
    limitations: >-
      Conditional null, not the hypomorphic genotype patients carry, and the
      phenotype is correspondingly far more severe than the human disease -
      gross forebrain defects and premature death against a static encephalopathy
      with preserved survival. The growth failure in particular is much worse
      than the short stature seen in two of four affected females.
    evidence:
    - reference: PMID:34688659
      reference_title: "Neuron-specific ablation of eIF5A or deoxyhypusine synthase leads to impairments in growth, viability, neurodevelopment, and cognitive functions in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The conditional deletion of Dhps or Eif5a by Emx1 promotor-driven Cre expression (E9.5, in the cortex and hippocampus) led to gross defects in forebrain development, reduced growth, and premature death.
      explanation: >-
        The phenotype of the embryonic-onset deletion.
- name: Postnatal hippocampal Dhps knockout mouse (Camk2a-Cre)
  species: Mouse
  genotype: Dhps conditional deletion driven by Camk2a-Cre, postnatal, mainly hippocampal CA1
  publication: PMID:34688659
  description: >-
    The more informative of the two mouse models for the human disease, because
    deleting after development separates the cognitive phenotype from the
    malformation. These animals develop normally and are still impaired on
    learning and memory.
  modeled_mechanisms:
  - target: Impaired Neurite Outgrowth and Neuronal Survival
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Postnatal deletion spares gross development but produces severe spatial
      and contextual learning and memory deficits.
    limitations: >-
      Still a null rather than a hypomorph, and restricted to hippocampal CA1,
      so it addresses learning and memory rather than the global developmental
      delay that defines the human disorder. It also says nothing about seizures,
      which are the other core feature.
    readouts:
    - name: Morris water maze and contextual learning performance
      target: Impaired Neurite Outgrowth and Neuronal Survival
      direction: DECREASED
      interpretation: >-
        Behavioural readout of hippocampal dysfunction after Dhps loss in
        otherwise normally developed animals.
      evidence:
      - reference: PMID:34688659
        reference_title: "Neuron-specific ablation of eIF5A or deoxyhypusine synthase leads to impairments in growth, viability, neurodevelopment, and cognitive functions in mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          these KO animals exhibited severe impairment in spatial learning, contextual learning, and memory when subjected to the Morris water maze and a contextual learning test.
        explanation: >-
          The behavioural measurement behind this readout.
    evidence:
    - reference: PMID:34688659
      reference_title: "Neuron-specific ablation of eIF5A or deoxyhypusine synthase leads to impairments in growth, viability, neurodevelopment, and cognitive functions in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In both models, the Dhps-KO mice displayed more severe impairment than their Eif5a-KO counterparts.
      explanation: >-
        Worth recording because it is mechanistically informative rather than
        merely comparative: losing the modifying enzyme is worse than losing the
        substrate, which is hard to explain if the only consequence of DHPS loss
        is unhypusinated eIF5A.
- name: dhps morpholino knockdown zebrafish
  species: Zebrafish
  genotype: dhps exon2/intron2 splice-site antisense morpholino knockdown
  publication: PMID:39334388
  description: >-
    The only model that addresses the seizures. Knockdown larvae show
    epileptiform activity on electrophysiology together with reduced arborization
    of GABAergic interneurons, which is a circuit-level mechanism neither mouse
    model provides.
  modeled_mechanisms:
  - target: Reduced GABAergic Interneuron Arborization
    relationship: RECAPITULATES
    fidelity: LOW
    model_scale: TISSUE
    description: >-
      Reduced inhibitory interneuron arborization with increased epileptiform
      activity, offering excitation-inhibition imbalance as the route to
      seizures.
    limitations: >-
      Morpholino knockdown rather than a genetic allele, with the usual
      off-target and transient-knockdown caveats and no stable mutant line. The
      knockdown is also dose-dependent and produces microcephaly, axis truncation
      and body curvature - a general developmental toxicity in which a specific
      interneuron phenotype is harder to attribute. Fidelity is recorded LOW for
      that reason, not because the finding is uninteresting.
    readouts:
    - name: GABAergic interneuron arborization
      target: Reduced GABAergic Interneuron Arborization
      direction: DECREASED
      interpretation: >-
        Anatomical correlate of the inhibitory deficit proposed to underlie the
        seizures.
      evidence:
      - reference: PMID:39334388
        reference_title: "Deoxyhypusine synthase deficiency syndrome zebrafish model: aberrant morphology, epileptiform activity, and reduced arborization of inhibitory interneurons."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          confocal microscopy analysis revealed reduced arborisation of GABAergic neurons
        explanation: >-
          The imaging measurement behind this readout.
    - name: Epileptiform electrophysiological activity
      target: Reduced GABAergic Interneuron Arborization
      direction: INCREASED
      interpretation: >-
        Functional correlate, measured in the same larvae as the anatomical
        deficit.
      evidence:
      - reference: PMID:39334388
        reference_title: "Deoxyhypusine synthase deficiency syndrome zebrafish model: aberrant morphology, epileptiform activity, and reduced arborization of inhibitory interneurons."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          In dhps knockdown larvae, electrophysiological analysis showed increased epileptiform activity
        explanation: >-
          The electrophysiological measurement behind this readout.
    evidence:
    - reference: PMID:39334388
      reference_title: "Deoxyhypusine synthase deficiency syndrome zebrafish model: aberrant morphology, epileptiform activity, and reduced arborization of inhibitory interneurons."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our findings confirm that hypusination of eIF5A by DHPS is needed for early brain development, and zebrafish with an antisense knockdown of dhps model features of DHPS deficiency syndrome.
      explanation: >-
        The authors' own claim for the model - that it reproduces features of
        the syndrome - stated as "features of" rather than the syndrome itself.
  - target: Impaired eIF5A-Dependent Translation Elongation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      Dose-dependent developmental delay and dysmorphology follow dhps
      knockdown, consistent with a translational deficit but not measured as one.
    limitations: >-
      No translational readout was measured in this model - no ribosome
      profiling, no polysome analysis, no hypusinated eIF5A quantification.
      The link to the translation node is inferred from the enzyme's known
      function rather than demonstrated here, which is why the relationship is
      partial and the fidelity low.
    evidence:
    - reference: PMID:39334388
      reference_title: "Deoxyhypusine synthase deficiency syndrome zebrafish model: aberrant morphology, epileptiform activity, and reduced arborization of inhibitory interneurons."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        dhps knockdown embryos exhibited dose-dependent developmental delay and dysmorphology, including microcephaly, axis truncation, and body curvature.
      explanation: >-
        The organism-level phenotype, including the non-specific features that
        limit what can be attributed to a translational mechanism.
discussions:
- discussion_id: gap_dhps_neuronal_selectivity
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Which mRNAs actually fail to be translated when hypusinated eIF5A is
    reduced in a human neuron, and is that set what makes the disease
    neurological rather than systemic?
  attaches_to:
  - pathophysiology#Impaired eIF5A-Dependent Translation Elongation
  - pathophysiology#Altered Expression of Proteins Required for Neuronal Development
  rationale: >-
    eIF5A is required in every cell, DHPS is ubiquitously expressed, and yet the
    disease is a static encephalopathy with largely preserved systemic health.
    The standing explanation is that eIF5A-dependent elongation is
    sequence-selective - polyproline and other stalling motifs - so reduced
    hypusination biases rather than abolishes translation, and neurons happen to
    depend on the biased-against transcripts. The brain-specific mouse knockout
    supports the shape of this with ribosome profiling and mass spectrometry, but
    the specific proteins have not been connected to the specific clinical
    features.

    The human system this gap originally called for now exists. Patient-derived
    iPSCs carrying the two DHPS alleles, with CRISPR-corrected isogenic controls,
    have been differentiated into cortical organoids, and the mutant organoids
    are significantly smaller - so a human, patient-allele, isogenically
    controlled neural model is available and shows a developmental phenotype.
    What has not been done in it is the measurement. No ribosome profiling or
    equivalent translational-output assay has been reported in that system, so
    the transcripts whose elongation actually fails in a human neuron carrying
    patient alleles remain unidentified, and the link from any particular
    protein to any particular clinical feature is still unmade. Until that
    measurement exists, the entry's central step is a mechanism class rather
    than a mechanism. Ribosome profiling of the existing patient-versus-isogenic
    organoid pair is the experiment.
- discussion_id: mismatch_dhps_null_models_vs_hypomorphic_disease
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Every animal model of DHPS loss is a null or a knockdown, while every patient
    is a hypomorph with roughly a fifth of normal enzyme activity. Does the null
    phenotype describe the same disease?
  attaches_to:
  - pathophysiology#Biallelic Hypomorphic DHPS Variants
  - animal_models#Brain-specific Dhps knockout mouse (Emx1-Cre)
  - animal_models#dhps morpholino knockdown zebrafish
  rationale: >-
    The mismatch is not incidental, it is forced: Dhps-null mice die as embryos,
    so a whole-animal model of complete loss cannot exist, and conditional nulls
    are what the field has instead. The consequence is a systematic severity gap
    that the literature itself notices - the mouse models show severe growth
    failure and premature death, while patients have a static encephalopathy with
    preserved survival and short stature in two of four females. The zebrafish
    knockdown adds a different problem: it is dose-dependent and produces axis
    truncation and body curvature alongside the interneuron phenotype, so the
    specific finding sits inside general developmental toxicity.

    There is also a result in the mouse series that no current model explains.
    Deleting Dhps produced more severe impairment than deleting Eif5a, in both
    the embryonic and the postnatal model. If the only consequence of losing DHPS
    were unhypusinated eIF5A, losing eIF5A itself should be at least as bad. It
    was not, which suggests either a second DHPS function or a contribution from
    eIF5A2, and neither has been followed up.

    A knock-in of p.Asn173Ser in trans with a null, in mouse, would test whether
    the hypomorphic state reproduces the human phenotype at the severity
    patients actually have.
  proposed_experiments:
  - experiment_id: exp_dhps_n173s_compound_heterozygous_knockin_mouse
    name: p.Asn173Ser / null compound heterozygous knock-in mouse
    description: >-
      Knock in the recurrent human missense allele at the orthologous murine
      residue and cross to a Dhps null allele, reproducing the patient genotype
      rather than a conditional null, then phenotype survival, growth, seizure
      susceptibility and learning into adulthood.
    would_support:
    - pathophysiology#Biallelic Hypomorphic DHPS Variants
    - pathophysiology#Reduced Deoxyhypusine Synthase Activity
    supporting_outcome:
    - >-
      Compound heterozygotes are viable with normal growth, show spontaneous or
      induced seizures and learning deficits, and have reduced hypusinated eIF5A
      - matching the human severity rather than the conditional-null severity.
    refuting_outcome:
    - >-
      Compound heterozygotes are unaffected, which would mean roughly a fifth of
      normal activity is sufficient in mouse and the human phenotype depends on
      something beyond residual enzyme activity.
  - experiment_id: exp_dhps_second_function_vs_eif5a2
    name: Test whether Dhps loss exceeds Eif5a loss because of a second substrate or eIF5A2
    description: >-
      Repeat the conditional deletions with an Eif5a/Eif5a2 double knockout arm,
      and search for non-eIF5A DHPS substrates by proteomics, to explain why
      Dhps-null animals were consistently worse than Eif5a-null animals.
    would_support:
    - pathophysiology#Reduced Hypusination of eIF5A
    supporting_outcome:
    - >-
      Eif5a/Eif5a2 double deletion is as severe as Dhps deletion, placing the
      excess severity on the redundant substrate rather than on a second DHPS
      function.
    refuting_outcome:
    - >-
      Dhps deletion remains more severe than combined substrate deletion, which
      would mean DHPS does something beyond hypusinating eIF5A and the entry's
      single-substrate framing is incomplete.
notes: >-
  Three notes for anyone working on this entry.

  The name is ambiguous in a way that matters for literature searching. DHPS is
  the gene symbol for deoxyhypusine synthase, and it is also the standard
  abbreviation for bacterial dihydropteroate synthase, the sulfonamide target,
  which has its own substantial literature and its own dismech mechanism module
  (bacterial_folate_synthesis_inhibition). A keyword search on DHPS returns
  both. Every reference in this entry was checked to be about the human enzyme.

  The frequency statements are quoted rather than paraphrased on purpose. With
  five patients, "four of five have clinical seizures" and "two of four affected
  females have short stature" are the actual evidence, and rounding them to
  "frequent" or "variable" would discard the only quantitative information the
  literature has. Note that the per-feature tally is quoted from a 2021 review of
  the cohort rather than from the founding clinical report, which did not break
  the features down that way.

  The model evidence is systematically about a more severe lesion than the
  disease. Every model is a null or a knockdown; every patient is a hypomorph
  with roughly 20 percent residual activity. This is recorded as a
  HUMAN_MODEL_MISMATCH rather than absorbed into the fidelity ratings, because
  the severity gap is structural - Dhps-null mice die as embryos, so the
  matching model does not exist and cannot simply be built as a null.
📚

References & Deep Research

References

5
PMID:30661771
Recessive Rare Variants in Deoxyhypusine Synthase, an Enzyme Involved in the Synthesis of Hypusine, Are Associated with a Neurodevelopmental Disorder.
No top-level findings curated for this source.
PMID:37333770
Deoxyhypusine synthase mutations alter the post-translational modification of eukaryotic initiation factor 5A resulting in impaired human and mouse neural homeostasis.
No top-level findings curated for this source.
PMID:34688659
Neuron-specific ablation of eIF5A or deoxyhypusine synthase leads to impairments in growth, viability, neurodevelopment, and cognitive functions in mice.
No top-level findings curated for this source.
PMID:39334388
Deoxyhypusine synthase deficiency syndrome zebrafish model: aberrant morphology, epileptiform activity, and reduced arborization of inhibitory interneurons.
No top-level findings curated for this source.
PMID:35858628
Bi-allelic variants in DOHH, catalyzing the last step of hypusine biosynthesis, are associated with a neurodevelopmental disorder.
No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (1)

Create: Deoxyhypusine Synthase Deficiency · 2026-09-11T12:48:53Z · View source

De novo curation of DHPS deficiency (MONDO:0032775, DHPS) from one openscientist deep-research report (preflight-dr PASS) plus direct reading of every cited reference. Entry name is Deoxyhypusine_Synthase_Deficiency rather than the MONDO label, matching the preferred_term already used for this term in the Bachmann-Bupp_Syndrome differential block on main. Pathograph: biallelic hypomorphic DHPS variants -> reduced DHPS activity -> reduced eIF5A hypusination -> impaired eIF5A-dependent translation elongation -> altered neuronal protein expression, branching to impaired neurite outgrowth/survival and to reduced GABAergic interneuron arborization -> seizures. functional_impact_category PARTIAL_LOSS_OF_FUNCTION, because Dhps-null mice are embryonic lethal so no patient can carry complete loss. Evidence tiering: enzyme activity, hypusination and the eIF5A modified-form shift are measured in recombinant protein and patient lymphoblasts (IN_VITRO, no directness qualifier). The neurite-outgrowth, interneuron and circuit steps carry directness: INDIRECT because they come from RNAi/inhibitor work in cell lines and from a zebrafish morpholino knockdown. Frequency claims are quoted verbatim rather than paraphrased - four of five with seizures, one of five with microcephaly, two of four affected females with short stature - because with five patients those counts are the whole evidence. A HUMAN_MODEL_MISMATCH discussion records that every model is a null or knockdown while every patient is a hypomorph with ~20% residual activity, and that the mismatch is structural rather than an oversight. It also records an unexplained result: Dhps deletion was consistently more severe than Eif5a deletion in both mouse models, which is hard to explain if unhypusinated eIF5A is the only consequence of DHPS loss. Two proposed experiments address each. Errors caught during curation: two MONDO CURIEs written from memory for the differential diagnoses. MONDO:0859263 resolved to 'developmental delay, impaired speech, and behavioral abnormalities' rather than Faundes-Banka syndrome (the correct term, verified by runoak, is MONDO:0859163 / OMIM:619376). MONDO:0859280 resolved to 'developmental delay, hypotonia, and impaired language' rather than the DOHH disorder. A MONDO search of the 2026 release returned no disease term for the DOHH-related neurodevelopmental disorder, so that differential deliberately carries no disease_term and records why in its notes, per the ontology contract's instruction to omit rather than manufacture a binding. Two snippets initially failed exact-substring matching because the sources write allele and protein-change detail in square brackets, which the snippet matcher strips before comparing. Both were re-quoted from bracket-free spans of the same papers rather than adjusting literal_bracket_patterns, and the explanation fields record why the variant detail is in prose rather than in the quote. Validation: just validate-disorders clean with 36/36 snippets verified; schema, terms, duplicate-keys, entity-refs, causal-targets, qualifier-terms, enum-values, reference-titles and snippet-length all OK.

OpenScientist ▸
Deoxyhypusine Synthase (DHPS) Deficiency — Comprehensive Disease Characterization Report
openscientist-autonomous 9 citations 2026-09-11T12:29:44.180829

Deoxyhypusine Synthase (DHPS) Deficiency — Comprehensive Disease Characterization Report

MONDO ID: MONDO:0032775 | OMIM phenotype: #618480 | Category: Genetic (autosomal recessive neurodevelopmental disorder)

Summary

Deoxyhypusine synthase (DHPS) deficiency is an ultra-rare autosomal recessive neurodevelopmental disorder caused by biallelic hypomorphic (partial loss-of-function) variants in the DHPS gene on chromosome 19p13.13. It is one of five recognized "polyaminopathies" — inborn disorders of polyamine biosynthesis/utilization — and belongs to the subgroup of hypusination (eIF5A) disorders. DHPS catalyzes the first and committed step in the post-translational synthesis of the unique amino acid hypusine, which is present in only one cellular protein, eukaryotic translation initiation factor 5A (eIF5A) and its homolog eIF5A2. Hypusinated eIF5A is required for the efficient translation-elongation of mRNAs containing polyproline stretches and for general control of ribosomal elongation and termination. Because complete loss of DHPS is embryonic-lethal in mice, all surviving human patients carry partial-function allele combinations.

The disorder was first delineated by Ganapathi et al. in 2019 (American Journal of Human Genetics), who described five affected individuals from four unrelated families. Remarkably, all five shared a recurrent hypomorphic missense allele, c.518A>G (p.Asn173Ser), in trans with a near-null allele (a splice-site, in-frame deletion, or start-loss variant). The clinical picture is a static (non-progressive) encephalopathy dominated by global developmental delay/intellectual disability and seizures, with variable hypotonia, microcephaly, short stature, and mild facial dysmorphism. Model organisms — conditional/neuron-specific Dhps knockout mice and dhps mutant zebrafish — recapitulate the growth, cognitive, and epilepsy phenotypes, and the zebrafish model provides a circuit-level mechanism via reduced arborization of inhibitory (GABAergic) interneurons.

Diagnosis is molecular — via whole-exome or whole-genome sequencing — and no validated metabolite biomarker or newborn-screening assay exists. Management is currently supportive/symptomatic (anti-seizure medication, developmental therapies). A preclinical AAV-based gene therapy for DHPS syndrome was reported in 2026, representing the first disease-modifying strategy in development. Because only ~5 patients have been fully characterized, formal epidemiology, penetrance, expressivity, and natural-history data remain undefined, and much mechanistic understanding is extrapolated from model systems and the closely related aging/spermidine literature.

Key Findings

Finding 1 — DHPS deficiency is an autosomal recessive neurodevelopmental disorder caused by biallelic hypomorphic DHPS variants

Ganapathi et al. (2019) identified rare biallelic, recurrent, predicted likely-pathogenic DHPS variants segregating with disease in five affected individuals from four unrelated families. All five affected individuals share a recurrent missense variant, c.518A>G (p.Asn173Ser), in trans with a likely gene-disrupting variant (c.1014+1G>A splice-site; c.912_917delTTACAT [p.Tyr305_Ile306del] in-frame deletion; or c.1A>G [p.Met1?] start-loss). Functional testing of recombinant enzyme demonstrated that the p.Asn173Ser protein retained only ~20% of normal in vitro activity, while p.Tyr305_Ile306del had absent activity — consistent with a hypomorphic loss-of-function mechanism.

The genotype architecture is important: because constitutive Dhps-null mice are embryonic lethal, complete loss of DHPS function is presumed incompatible with human life. Surviving patients therefore invariably carry a partial-function (hypomorphic) allele — the relatively common p.Asn173Ser — that provides enough residual activity to permit development, paired in trans with a more severe (near-null) allele.

"we identified rare biallelic, recurrent, predicted likely pathogenic variants in DHPS segregating with disease in five affected individuals from four unrelated families. These individuals have similar neurodevelopmental features that include global developmental delay and seizures" — PMID: 30661771

"Recombinant DHPS enzyme harboring either the p.Asn173Ser or p.Tyr305_Ile306del variant showed reduced (20%) or absent in vitro activity" — PMID: 30661771

Evidence type: Human clinical + in vitro enzymology. Inheritance: Autosomal recessive.

Finding 2 — Mechanism: DHPS catalyzes the first step of hypusine synthesis on eIF5A, essential for translation of polyproline motifs

Hypusine [N-ε-(4-amino-2-hydroxybutyl)lysine] is a unique amino acid formed post-translationally from lysine and is found in a single cellular protein — eIF5A — and its homolog eIF5A2. Its biosynthesis is a two-step reaction: (1) DHPS transfers the aminobutyl moiety of the polyamine spermidine to a specific conserved lysine residue of eIF5A, forming the intermediate deoxyhypusine; then (2) deoxyhypusine hydroxylase (DOHH) hydroxylates deoxyhypusine to form mature hypusine. DHPS thus performs the committed, rate-defining first step.

Hypusinated eIF5A functions principally in translation ELONGATION: it facilitates the translation of peptide sequences containing polyproline stretches and exerts a broad regulatory effect on the elongation and termination phases of protein synthesis. DHPS is highly conserved and essential for eukaryotic life.

"Hypusine is formed post-translationally from lysine and is found in a single cellular protein, eukaryotic translation initiation factor-5A (eIF5A), and its homolog eIF5A2. Biosynthesis of hypusine is a two-step reaction involving the enzymes deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH)" — PMID: 30661771

"eIF5A facilitates the translation of peptide sequences containing polyproline stretches and exerts a universal regulatory effect on the elongation and termination phases of protein synthesis" — PMID: 39303786

Ontology suggestions: GO:0008612 (peptidyl-lysine modification to peptidyl-hypusine); GO:0006414 (translational elongation); CHEBI:16610 (spermidine); CHEBI:59905 (hypusine).

Finding 3 — Downstream mechanism: hypusinated eIF5A supports neuronal mitochondrial function and autophagy; spermidine is the substrate

Beyond bulk protein synthesis, independent studies show that eIF5A hypusination is required for mitochondrial respiratory competence and autophagy in neurons. Dietary spermidine — the aminobutyl donor for the DHPS reaction — crosses the blood-brain barrier in mice, increases hippocampal eIF5A hypusination and mitochondrial function, and improves cognition in aged animals (Schroeder et al., 2021). A parallel study demonstrated that spermidine-induced hypusination preserves mitochondrial and cognitive function during aging (Hofer et al., 2021), with effects dependent on autophagy/mitophagy machinery (Atg7, Pink1/Parkin).

While these studies were conducted in aging (not DHPS-deficiency) models, they establish the mechanistically relevant hypusination → mitochondrial function → cognition axis. In DHPS deficiency, reduced hypusination is inferred to compromise this axis in developing neurons, contributing to the neurodevelopmental phenotype. This downstream link is inferred by analogy rather than directly demonstrated in patient tissue.

"dietary spermidine passes the blood-brain barrier in mice and increases hippocampal eIF5A hypusination and mitochondrial function" — PMID: 33852843

"Spermidine-induced hypusination preserves mitochondrial and cognitive function during aging" — PMID: 34105442

Ontology suggestions: GO:0006914 (autophagy); GO:0045333 (cellular respiration); GO:0005739 (mitochondrion); CHEBI:16610 (spermidine).

Finding 4 — Clinical phenotype: global developmental delay, seizures, hypotonia, microcephaly, short stature, dysmorphism

The cardinal features in the founding cohort (5 patients / 4 families) were global developmental delay / intellectual disability (5/5, 100%) and seizures/epilepsy (present in the majority). Short stature was noted in 2 of 4 affected females. Broader reviews of the hypusination disorders (DHPS/DOHH/EIF5A) describe a shared spectrum comprising prenatal issues, hypotonia, dysmorphisms, microcephaly, moderate-to-severe neurodevelopmental disorder/intellectual disability, and behavioral disorders. The zebrafish-model summary characterizes the human syndrome as causing "epilepsy, cognitive and motor impairments, and mild facial dysmorphology."

Onset is congenital/infantile, and the course is chronic and non-progressive (a static encephalopathy) with lifelong disability.

Phenotype HPO term Frequency (founding cohort) Type
Global developmental delay HP:0001263 5/5 (100%) Neurodevelopmental
Intellectual disability HP:0001249 High (majority–all) Neurodevelopmental
Seizures / epilepsy HP:0001250 Majority Clinical sign / neurological
Hypotonia HP:0001252 Reported Clinical sign
Microcephaly HP:0000252 Reported Physical manifestation
Short stature HP:0004322 2/4 females Physical manifestation
Facial dysmorphism HP:0001999 Reported (mild) Physical manifestation
Behavioral abnormality HP:0000708 Reported Behavioral

"These individuals have similar neurodevelopmental features that include global developmental delay and seizures" — PMID: 30661771

"Two of four affected females have short stature" — PMID: 30661771

"Main phenotypic features consisted of prenatal issues, hypotonia, dysmorphisms, microcephaly, moderate-severe neurodevelopmental disorders/intellectual disability and behavioral disorders" — PMID: 40883692

Finding 5 — DHPS deficiency is one of five polyaminopathies; a hypusination/eIF5A disorder with emerging gene therapy

The polyaminopathies comprise five rare neurodevelopmental disorders that disrupt polyamine biosynthesis/utilization:

Disorder Gene Mechanism Inheritance First described
Snyder-Robinson syndrome SMS Loss of function X-linked 1969
Bachmann-Bupp syndrome ODC1 Gain of function AD (de novo) ~past 7 yr
Faundes-Banka syndrome EIF5A Loss of function AD ~past 7 yr
DHPS deficiency DHPS Biallelic hypomorphic LoF AR 2019
DOHH disorder DOHH Biallelic LoF AR ~past 7 yr

Four of the five (including DHPS deficiency) have been identified only within roughly the past seven years, underscoring their recency and rarity. Treatment is currently supportive/symptomatic (anti-seizure medications and developmental therapies). Notably, a preclinical AAV gene-therapy strategy for DHPS syndrome was reported in 2026 (Santo et al.), representing the first disease-modifying approach in development.

"DHPS (deoxyhypusine synthase) deficiency is an autosomal recessive disease and results from bi-allelic hypomorphic variants in the deoxyhypusine synthase (DHPS) gene, which results in reduced deoxyhypusine synthase enzyme activity" — PMID: 41410504

"Snyder-Robinson syndrome was first described in 1969, while the other four syndromes have only been identified in the past 7 years" — PMID: 41410504

"Deoxyhypusine synthase (DHPS) syndrome is a rare, autosomal recessive neurodevelopmental disorder caused by biallelic pathogenic variants" — PMID: 42239796

Ontology suggestion: NCIT — gene therapy / AAV vector-based gene transfer.

Finding 6 — Gene identifiers, locus, and allele frequency of the recurrent p.Asn173Ser hypomorphic variant

Gene identifiers: NCBI Gene ID 1725; HGNC:2869; OMIM gene 600944; UniProt P49366; Ensembl ENSG00000095059. Locus: chromosome 19p13.13 (GRCh38 chr19:12,673,411–12,681,901, minus strand). Disease phenotype: OMIM #618480.

Querying gnomAD v4, the recurrent hypomorphic missense c.518A>G (p.Asn173Ser) has an exome allele frequency of ≈9.9×10⁻⁵ and a genome AF of ≈5.3×10⁻⁵ — rare but recurrent, consistent with a tolerated partial-function allele carried heterozygously in the general population. Other codon-173 variants exist at low frequency (e.g., p.Asn173Lys, AF ≈4.9×10⁻⁵).

Variant classes documented in patients: missense (p.Asn173Ser), splice-site (c.1014+1G>A), in-frame deletion (p.Tyr305_Ile306del), and start-loss (c.1A>G, p.Met1?). All are germline; the functional consequence is partial loss of function (hypomorphic) — complete loss of function is embryonic-lethal.

"All five affected individuals share a recurrent missense variant (c.518A>G [p.Asn173Ser]) in trans with a likely gene disrupting variant (c.1014+1G>A, c.912_917delTTACAT [p.Tyr305_Ile306del], or c.1A>G [p.Met1?])" — PMID: 30661771

Ontology suggestions: SO:0001583 (missense variant); SO:0001574 (splice-acceptor/donor variant); SO:0001822 (inframe deletion); SO:0002012 (start-lost).

Finding 7 — Epidemiology, diagnosis, and prognosis: ultra-rare, molecularly diagnosed, static lifelong course

Epidemiology: Ultra-rare. The founding report described only 5 affected individuals from 4 families, and subsequent reviews note only ~5 individuals characterized to date. Formal prevalence and incidence are not established; Orphanet lists it among ultra-rare disorders. Inheritance is autosomal recessive with presumed complete penetrance in biallelic carriers; both sexes are affected. Consanguinity and founder effects are not established — recurrence is driven by the relatively common p.Asn173Ser hypomorphic allele rather than a founder haplotype.

Diagnosis: Molecular, via whole-exome or whole-genome sequencing (or DHPS single-gene / NDD-epilepsy panel testing). Confirmatory functional support comes from reduced recombinant DHPS enzyme activity and impaired eIF5A hypusination assays. There is no validated blood/urine metabolite biomarker or newborn-screening assay. Supportive workup: EEG (epileptiform activity), brain MRI, and developmental assessment.

Differential diagnosis: Other polyaminopathies (DOHH disorder, Faundes-Banka/EIF5A, Snyder-Robinson, Bachmann-Bupp) and other genetic developmental and epileptic encephalopathies.

Prognosis: Chronic, static (non-degenerative) encephalopathy with lifelong intellectual disability and epilepsy; no evidence of progressive neurodegeneration. Formal survival/mortality data are unavailable given the small cohort.

"we identified rare biallelic, recurrent, predicted likely pathogenic variants in DHPS segregating with disease in five affected individuals from four unrelated families" — PMID: 30661771

"one reporting 5 subjects with DHPS-related disorders (DHPS-D)" — PMID: 40883692

Finding 8 — Deep evolutionary conservation and validated model organisms

DHPS orthologs (HomoloGene 1453) span the eukaryotic tree, reflecting that hypusine/eIF5A modification is essential for eukaryotic life:

Species Gene NCBI Gene ID Database
Human (Homo sapiens) DHPS 1725 NCBI / HGNC
Mouse (Mus musculus) Dhps 330817 MGI
Rat (Rattus norvegicus) Dhps 288923 RGD
Zebrafish (Danio rerio) dhps 406329 ZFIN
Fruit fly (Drosophila melanogaster) Dhps 38917 FlyBase
Nematode (C. elegans) dhps-1 174840 WormBase
Budding yeast (S. cerevisiae) DYS1 856465 SGD

Validated disease models: - Mouse — constitutive Dhps knockout is embryonic lethal; conditional neuron/brain-specific Dhps (or Eif5a) deletion impairs growth, viability, neurodevelopment, and cognition (Kar et al., 2021), recapitulating the human developmental/cognitive deficits. - Zebrafish — the dhps mutant shows aberrant morphology, epileptiform activity, and reduced arborization of inhibitory interneurons (Shojaeinia et al., 2024), recapitulating the epilepsy phenotype and providing a circuit-level mechanism. - Cellular/in vitro — HEK293T co-transfection assays showed mutant DHPS reduces eIF5A hypusination (Ganapathi, 2019); iPSC/organoid and AAV gene-therapy models are emerging (Santo et al., 2026).

"Neuron-specific ablation of eIF5A or deoxyhypusine synthase leads to impairments in growth, viability, neurodevelopment, and cognitive functions in mice" — PMID: 34688659

"DHPS is also highly conserved and is essential for life, as Dhps-null mice are embryonic lethal" — PMID: 30661771

Finding 9 — Anatomical involvement: central nervous system (cortex and inhibitory interneuron circuits), with growth axis secondary

Although DHPS is ubiquitously expressed and hypusination occurs in all cells, the clinical phenotype is dominated by the central nervous system: global developmental delay, intellectual disability, and epilepsy. Zebrafish modeling localizes the dysfunction to inhibitory (GABAergic) interneurons — reduced arborization producing epileptiform activity — implicating cortical/forebrain inhibitory circuits. Microcephaly and dysmorphic facial features indicate effects on brain and craniofacial growth; short stature indicates a secondary effect on the somatic growth axis. Subcellularly, the primary defect is cytoplasmic (translation), with downstream impact on mitochondria and autophagy/lysosomal turnover.

"reduced arborization of inhibitory interneurons" — PMID: 39334388

Ontology suggestions: UBERON:0000955 (brain); UBERON:0000956 (cerebral cortex); CL:0000617 (GABAergic neuron / inhibitory interneuron); GO:0005737 (cytoplasm); GO:0005739 (mitochondrion).

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

  1. Biallelic hypomorphic DHPS variants (recurrent p.Asn173Ser in trans with a near-null allele) lead to reduced DHPS enzyme protein activity (~20% residual for p.Asn173Ser; near-absent for null alleles). [Demonstrated: in vitro enzymology, PMID 30661771]
  2. Reduced DHPS activity results in decreased transfer of the aminobutyl group from spermidine to eIF5A → reduced formation of deoxyhypusine, and consequently reduced mature hypusine on eIF5A. [Demonstrated: cellular hypusination assay, PMID 30661771]
  3. Hypomodified (hypusine-deficient) eIF5A leads to impaired translation elongation, particularly of mRNAs encoding polyproline motifs and other elongation-sensitive transcripts. [Demonstrated in general eIF5A biology; PMID 39303786 — inferred for patient tissue]
  4. Impaired translation results in downstream deficits in neuronal mitochondrial respiratory function and autophagy/mitophagy. [Inferred by analogy from spermidine/aging models, PMIDs 33852843, 34105442]
  5. Branch A (neuronal circuits): In developing brain, this leads to reduced arborization of inhibitory (GABAergic) interneurons → cortical excitation/inhibition imbalance → epileptiform activity and seizures. [Demonstrated: zebrafish, PMID 39334388]
  6. Branch B (neurodevelopment/cognition): Impaired neuronal protein synthesis and viability result in global developmental delay, intellectual disability, hypotonia, and microcephaly. [Demonstrated: conditional mouse, PMID 34688659; human, PMID 30661771]
  7. Branch C (somatic growth): Reduced systemic translation capacity contributes to short stature and facial dysmorphism (secondary growth-axis effects). [Inferred from human phenotype, PMID 30661771]
  8. Net clinical result: a static (non-progressive) encephalopathy with lifelong neurodevelopmental disability and epilepsy.
 DHPS variants (p.Asn173Ser / null)
    │  (partial loss of function; full LoF = embryonic lethal)
    ▼
   ↓ DHPS enzyme activity  ── substrate: spermidine (CHEBI:16610)
    ▼
   ↓ deoxyhypusine → ↓ hypusine on eIF5A
    ▼
   Impaired eIF5A-dependent translation ELONGATION
   (polyproline motifs; GO:0006414)
    │
   ┌────────┼──────────────────────┐
   ▼        ▼                       ▼
Mito/autophagy   GABAergic          Systemic translation
dysfunction      interneuron        capacity ↓
(neurons)        arborization ↓
   │                │                       │
   ▼                ▼                       ▼
Neurodevelopmental   Seizures /        Short stature,
delay, ID,           epilepsy          dysmorphism
hypotonia,           (E/I imbalance)   (growth axis)
microcephaly
    \        |        /
     ▼       ▼       ▼
      STATIC ENCEPHALOPATHY (lifelong)

Upstream vs downstream: The mutation → reduced enzyme activity → reduced eIF5A hypusination steps are upstream and directly demonstrated. The specific tissue-injury branches (interneuron, mitochondrial, growth) are downstream and rest partly on model-organism and analogy evidence. The convergence on the CNS despite ubiquitous expression likely reflects the exceptional dependence of post-mitotic neurons on efficient translation, mitochondrial output, and autophagy.

Evidence Base

PMID Title (abbrev.) Evidence type Supports finding(s)
30661771 Recessive rare DHPS variants associated with a neurodevelopmental disorder (Ganapathi et al., AJHG 2019) Human clinical + in vitro F1, F2, F4, F6, F7, F8 (founding/definitional)
39303786 Insights into eIF5A: role and mechanisms in protein synthesis Review (molecular biology) F2 (elongation/polyproline function)
34688659 Neuron-specific ablation of eIF5A or DHPS impairs growth/neurodevelopment/cognition in mice (Kar et al., 2021) Model organism (mouse) F3, F8 (phenotype recapitulation)
39334388 DHPS deficiency zebrafish model: epileptiform activity, reduced inhibitory interneuron arborization (Shojaeinia et al., 2024) Model organism (zebrafish) F3, F8, F9 (seizure circuit mechanism)
41410504 Genetic and phenotypic features of the five polyaminopathies (review) Narrative review F5 (classification)
42239796 A gene therapy strategy for DHPS syndrome (Santo et al., 2026) Preclinical therapeutic F5 (emerging treatment)
40883692 eIF5A and hypusination-related disorders: review + DOHH case Review + case F4, F7 (phenotype spectrum, rarity)
33852843 Dietary spermidine improves cognitive function (Schroeder et al., 2021) Model organism (mouse) F3 (hypusination–mitochondria–cognition axis)
34105442 Spermidine-induced hypusination preserves mitochondrial/cognitive function during aging (Hofer et al., 2021) Model organism F3 (downstream mechanism)
35858628 Bi-allelic DOHH variants associated with a neurodevelopmental disorder Human clinical Differential diagnosis / pathway context

How the evidence coheres: The founding paper (30661771) anchors every clinical and genetic claim and provides the direct in vitro proof of hypomorphic loss of function. General eIF5A biology (39303786) supplies the molecular function. Two model organisms (mouse 34688659; zebrafish 39334388) independently reproduce distinct arms of the human phenotype — growth/cognition and epilepsy respectively — strengthening causal inference. The spermidine/aging literature (33852843, 34105442) is supportive but indirect, informing the downstream mitochondrial/autophagy branch by analogy rather than in patient tissue. Reviews (41410504, 40883692) place the disorder within the polyaminopathy family and confirm ultra-rarity, and the 2026 gene-therapy report (42239796) marks the therapeutic frontier.

Section-by-Section Template Coverage

  • 1. Disease Information: AR neurodevelopmental hypusination disorder; MONDO:0032775, OMIM #618480 (phenotype), DHPS gene OMIM 600944; synonyms: "DHPS syndrome," "deoxyhypusine synthase deficiency," a polyaminopathy / hypusination disorder. Information is aggregated (case series + reviews), not EHR-derived.
  • 2. Etiology: Genetic — biallelic hypomorphic DHPS variants; the recurrent p.Asn173Ser hypomorph is the key recurring risk allele carried in trans with a near-null allele. No environmental cause; no established gene-environment interaction. Spermidine availability is a plausible modifier (mechanistic, unproven). No protective factors identified.
  • 3. Phenotypes: See Finding 4 table (HPO terms and frequencies). Onset congenital/infantile; severity moderate–severe; course static/non-progressive.
  • 4. Genetic/Molecular: DHPS (Gene 1725, HGNC:2869, UniProt P49366), 19p13.13; variant classes missense/splice/in-frame-deletion/start-loss; all germline; partial LoF; complete LoF embryonic-lethal. No modifier genes, epigenetic, or chromosomal abnormalities established.
  • 5. Environmental: None identified — purely monogenic; no infectious agents.
  • 6. Mechanism: See causal chain and diagram above.
  • 7. Anatomy: CNS (cortex, GABAergic interneurons; UBERON:0000955/0000956; CL:0000617); secondary somatic growth axis; cytoplasm/mitochondria subcellularly; bilateral CNS involvement.
  • 8. Temporal: Congenital/infantile onset; insidious; static, chronic, lifelong; non-progressive.
  • 9. Inheritance/Population: AR; ultra-rare (~5 cases); both sexes; presumed complete penetrance; no established founder effect/consanguinity requirement; recurrence via common hypomorphic allele.
  • 10. Diagnostics: WES/WGS; DHPS single-gene/NDD-epilepsy panels; functional enzyme/hypusination assays; EEG, brain MRI; no biomarker or newborn screen.
  • 11. Prognosis: Lifelong ID + epilepsy; static course; formal survival/mortality data lacking.
  • 12. Treatment: Supportive (anti-seizure medications, developmental/physical/occupational therapy); preclinical AAV gene therapy (PMID 42239796); spermidine supplementation is a mechanistic hypothesis only.
  • 13. Prevention: Genetic counseling, carrier/cascade testing, prenatal/PGT for known familial variants; no primary prevention or immunization applicable.
  • 14. Other Species: Deeply conserved orthologs (mouse Dhps, rat, zebrafish, fly, worm, yeast DYS1); no naturally occurring analogous animal disease reported; no zoonotic relevance.
  • 15. Model Organisms: Conditional/neuron-specific Dhps KO mouse (constitutive KO embryonic-lethal); dhps zebrafish; HEK293T assays; emerging iPSC/organoid and AAV models.

Limitations and Knowledge Gaps

  • Tiny evidence base: Only ~5 fully characterized patients from 4 families. Phenotype frequencies, penetrance, expressivity, sex effects, and natural history are therefore statistically fragile and may broaden as more cases are found.
  • No formal epidemiology: Prevalence and incidence are unquantified; there is no carrier-frequency estimate specific to the disorder, though the p.Asn173Ser allele frequency (~1×10⁻⁴) hints that biallelic hypomorphic combinations are exceptionally rare.
  • Downstream mechanism partly inferred: The mitochondrial/autophagy branch relies on aging/spermidine studies (33852843, 34105442), not on DHPS-patient tissue. Whether these mechanisms operate identically during neurodevelopment is unproven.
  • No biomarker or newborn screen: Diagnosis depends entirely on sequencing plus functional confirmation; there is no validated metabolite readout.
  • Genotype–phenotype correlation unresolved: With essentially one recurrent hypomorphic allele described, the relationship between residual enzyme activity and severity cannot yet be modeled across an allelic series.
  • Human neuropathology absent: No detailed brain imaging series, histopathology, or human single-cell/transcriptomic data are available; interneuron involvement rests on the zebrafish model.
  • Citation verification needed: Several supporting quotes (e.g., PMIDs 34105442, 34688659, 39334388) are paraphrased from abstracts/summaries and should be verified verbatim before database ingestion.

Proposed Follow-up Experiments / Actions

  1. Establish an international patient registry for DHPS deficiency (and the polyaminopathies broadly) to accumulate cases, define frequencies of each HPO feature, and build a natural-history dataset.
  2. Generate an allelic series in cellular models (patient iPSC-derived neurons/organoids and recombinant enzyme) spanning residual DHPS activity, and correlate with eIF5A hypusination levels and translational output to define a genotype–activity–phenotype curve.
  3. Directly test the mitochondrial/autophagy branch in DHPS-deficient neurons (patient iPSC or conditional-KO mouse neurons): measure respiration (Seahorse), mitophagy (Pink1/Parkin reporters), and rescue with spermidine supplementation.
  4. Ribosome profiling / proteomics in DHPS-deficient neurons to identify the specific polyproline-motif and elongation-sensitive transcripts whose translation fails — candidate effectors of the phenotype.
  5. Deep phenotyping of the zebrafish and conditional mouse models with EEG, behavior, and GABAergic circuit mapping to validate the excitation/inhibition-imbalance seizure mechanism and to serve as preclinical efficacy endpoints.
  6. Advance the AAV gene-therapy program (PMID 42239796): define the therapeutic window, dosing, and durability in models; explore substrate-based (spermidine) and small-molecule adjuncts.
  7. Biomarker discovery: evaluate blood/CSF eIF5A-hypusination ratios or polyamine metabolite panels as candidate diagnostic/pharmacodynamic markers.
  8. Verify all abstract quotes verbatim against source PMIDs before populating the knowledge base, particularly the citations flagged as paraphrased.

Report compiled from 10 confirmed findings across 5 investigation iterations and 10 reviewed papers. Evidence types are labeled throughout as human clinical, model organism, in vitro, or inferred/analogy.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 10
Resolved 10
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 10
On topic 8
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 25
Resolved 24
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 23
Terms named correctly 15
Terms named as a different term 1
Terms whose name is worth a second look 7

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:

  • GO:0008612 (1 mention) - the report calls it "peptidyl-lysine modification to peptidyl-hypusine"; GO calls it peptidyl-hypusine biosynthetic process

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:

  • CHEBI:59905 (1 mention) - the report calls it "hypusine"; CHEBI calls it dopaminium(1+), and lists "dopamine" among its other names
  • HP:0001250 (1 mention) - the report calls it "Seizures / epilepsy"; HP calls it Seizure, and lists "Seizures" among its other names
  • SO:0001583 (1 mention) - the report calls it "missense variant"; SO calls it missense_variant
  • SO:0001574 (1 mention) - the report calls it "splice-acceptor/donor variant"; SO calls it splice_acceptor_variant, and lists "splice acceptor variant" among its other names
  • SO:0001822 (1 mention) - the report calls it "inframe deletion"; SO calls it inframe_deletion, and lists "inframe deletion" among its other names
  • SO:0002012 (1 mention) - the report calls it "start-lost"; SO calls it start_lost
  • CL:0000617 (2 mentions) - the report calls it "GABAergic neuron / inhibitory interneuron"; CL calls it GABAergic neuron