UBA5-Related Developmental and Epileptic Encephalopathy

Mendelian MONDO:0014933 Pathograph 24 Show in embeddings browser Epilepsy Neurological Disease

UBA5-related developmental and epileptic encephalopathy (DEE44) is an autosomal recessive disorder caused by biallelic variants in UBA5, the E1 activating enzyme of the ubiquitin-fold modifier 1 (UFM1) conjugation cascade. UFMylation is a ubiquitin-like modification system distinct from canonical ubiquitination. Affected children present in the first weeks to months of life with severe irritability, dystonia and stagnation of development, followed by drug-resistant epilepsy, often including epileptic spasms - together with axial hypotonia, appendicular hypertonia, postnatal microcephaly and failure to thrive. Most reported individuals are compound heterozygous for a mild partial-function allele - often recurrent c.1111G>A (p.Ala371Thr) - and a more severe allele, although symptomatic partial-function plus partial-function combinations are also reported. Functional allelic strength appears to contribute substantially to severity, but does not by itself establish an exact clinical prognosis.

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1
Inheritance
10
Pathophys.
19
Phenotypes
4
Gaps
24
Pathograph
1
Genes
1
Variants
4
Medical Actions
2
Differentials
3
Models
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Deep Research
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Inheritance

1
Autosomal recessive HP:0000007
Biallelic UBA5 variants are required. Most reported symptomatic individuals carry a mild or intermediate partial-function allele in trans with a severe loss-of-function allele. Exceptions with two partial-function alleles are known, while homozygous p.Ala371Thr adults without an apparent neurologic phenotype show that this recurrent allele is not sufficient by itself to cause DEE44.
Autosomal recessive inheritance
Show evidence (3 references)
PMID:27545674 SUPPORT Human Clinical
"our data imply that the combination of a hypomorphic p.Ala371Thr variant in trans with a loss-of-function allele in UBA5 underlies a severe infantile-onset encephalopathy"
States the biallelic, compound-heterozygous architecture that defines the disorder.
PMID:28965491 SUPPORT Human Clinical
"we have identified three adult Icelanders homozygous for the p.Ala371Thr mutation who show no signs of neurological disease"
Shows that homozygosity for this very mild allele is not sufficient to cause the DEE44 phenotype in the three observed adults.
PMID:38079206 SUPPORT Human Clinical
"However, two individuals from a previous report (IA/II) and this study (IB/II) show that the disease is also associated with a combination of two partial LoF alleles"
Documents exceptions to the usual mild-plus-severe pairing.
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Discussions and Knowledge Gaps

4
Which downstream consequence of reduced UFMylation - ER stress, mitochondrial damage, or the GABAergic interneuron deficit - actually produces the seizures?
KNOWLEDGE GAP OPEN gap_which_downstream_arm_drives_the_seizures
Attached to
pathophysiology#Aberrant Neuronal Firing
Three downstream arms are established, each in a different model system: ER stress and UPR activation in patient fibroblasts and organoids, mitochondrial damage in zebrafish, and a GABAergic interneuron deficit in organoids. No source demonstrates that any one of them causes the abnormal network activity, and none is shown to be upstream of another. This entry therefore hangs the ER and mitochondrial arms off the conjugation node in parallel rather than in series. No causal edge is added from the GABAergic interneuron development deficit to aberrant firing; that relationship remains unresolved, consistent with the following firing-direction knowledge gap. Placing the findings in a chain would assert a precedence that has not been established.
Proposed experiments
Arm-specific rescue in patient-derived organoids
exp_arm_specific_rescue_in_organoids
Rescue each arm independently in the patient-derived organoid model - a chemical chaperone or UPR modulator for the ER arm, a mitophagy or mitochondrial-protective agent for the mitochondrial arm - and ask which, if either, normalizes the multi-electrode firing phenotype without correcting UBA5 abundance itself.
In which direction is network activity abnormal in UBA5 patient organoids, and does it match the hyperexcitability the clinical phenotype implies?
KNOWLEDGE GAP OPEN gap_direction_of_the_organoid_firing_abnormality
Attached to
pathophysiology#Aberrant Neuronal Firing
The pathophysiology node deliberately says "aberrant" rather than "increased". The accessible source text establishes that firing is abnormal but does not specify which parameters move which way. The same abstract reports a GABAergic-interneuron development defect, but does not describe loss of that population or show that the development finding causes the firing abnormality. Curating a direction or causal link that the quotable evidence does not state would manufacture that finding.
Proposed experiments
Directional reporting of organoid multi-electrode parameters
exp_report_directional_mea_parameters
Report, from the multi-electrode organoid data, the separate directions of mean firing rate, single-electrode burst frequency and network burst frequency, so that a concordance or divergence between cellular and network excitability can be curated explicitly.
Can a complete-null animal model inform a disease represented clinically by genotypes that retain partial UBA5 function?
HUMAN MODEL MISMATCH OPEN mismatch_null_mouse_models_a_different_lethal_mechanism
Attached to
pathophysiology#Biallelic UBA5 Variants Reducing E1 Enzyme Function
No biallelic-null affected individual is represented in the cited clinical series, while most functionally analysed affected individuals carry at least one mild or partial-function allele. A germline null therefore is not genotype matched to those documented cohorts. The CNS-specific Ufm1 knockout is informative in a different way - it causes neonatal death with microcephaly and neuronal apoptosis, establishing that the pathway is essential for CNS development - but essentiality of the pathway is a weaker claim than fidelity to the human hypomorphic disease. The zebrafish lines and humanized flies, which grade residual activity, are better-matched models.
Proposed experiments
Patient-genotype-matched hypomorphic mouse
exp_patient_matched_hypomorphic_mouse
Generate a mouse carrying the human-equivalent p.Ala371Thr allele in trans with a null, matching the actual patient genotype, and ask whether it reproduces the seizure and movement phenotype that the null cannot be used to test.
Is increasing UBA5 abundance a viable therapeutic strategy, and what dose and durability would be required?
KNOWLEDGE GAP OPEN controversy_can_modest_upregulation_be_therapeutic
Attached to
pathophysiology#Reduced Global UFM1 Conjugation
Asymptomatic adults homozygous for the mild p.Ala371Thr allele show that this genotype can be compatible with health, but they do not establish that modest upregulation is sufficient in affected compound genotypes. Two approaches that augment UBA5 protein abundance rescued phenotypes in cultured models. Durability, minimum effective dose, upper safe bound and in-vivo translation remain unknown; the absence of an overt phenotype after fly overexpression does not establish human safety.
Proposed experiments
UBA5 abundance dose-response and durability
exp_uba5_dose_response_window
Establish a dose-response relationship between UBA5 protein abundance and correction of the organoid electrophysiological and ER-stress phenotypes, identifying both the minimum effective and maximum tolerated increase, and measure the durability of correction beyond the intervals so far reported.
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Pathophysiology

10
Biallelic UBA5 Variants Reducing E1 Enzyme Function
The initiating lesion. Pathogenic UBA5 variants reduce the activity of the UFM1 E1 activating enzyme, by impairing catalysis, ATP binding, or protein stability depending on where the residue sits. This node is the genetic lesion only; the separate enzymatic steps it disrupts are curated as their own nodes below, because the sources measure them separately.
UBA5 hgnc:23230 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves UBA5 (hgnc:23230). hgnc:23230 is a gene from the HUGO Gene Nomenclature Committee.
UFM1 activating enzyme activity GO:0071566 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased UFM1 activating enzyme activity (GO:0071566). GO:0071566 is a molecular function from the Gene Ontology. ↓ DECREASED
Animal models
Humanized UBA5 allelic-series Drosophila Drosophila melanogaster measures Variant-dependent rescue of fly Uba5 loss provides an in-vivo allelic-strength measurement complementary to biochemical assays.
Downstream
Impaired UFM1 Adenylation and Thioester Formation Loss of enzyme function acts first on the two catalytic steps UBA5 performs.
Show evidence (1 reference)
PMID:27545681 SUPPORT In Vitro
"Biochemical studies of mutant UBA5 proteins and studies in fibroblasts from affected individuals revealed that UBA5 mutations impair the process of ufmylation"
Establishes that patient variants impair UFMylation, measured biochemically and in patient fibroblasts.
Impaired UFM1 Adenylation and Thioester Formation
UBA5 is a non-canonical E1 that carries its catalytic cysteine inside the adenylation domain rather than in a separate domain. It adenylates the UFM1 C-terminal glycine and then forms a thioester bond through Cys250. This node covers those two steps on the enzyme itself, and is kept separate from the handoff to UFC1 because the two are assayed independently and specific variants dissociate them - p.Tyr53Phe leaves E1 activity at 3.4% but transthiolation at 6.8% of wild type.
UFM1 adenylation and thioester bond formation at Cys250 GO:0071566 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased UFM1 adenylation and thioester bond formation at Cys250, annotated with UFM1 activating enzyme activity (GO:0071566). GO:0071566 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Impaired UFM1 Transfer to UFC1 A charged E1 is the substrate for the transthiolation handoff.
Show evidence (2 references)
PMID:28360427 SUPPORT In Vitro
"In the activation process UBA5 adenylates UFM1 C-terminal Gly and then forms a thioester bond with the UFM1 C-terminus via its active site Cys250"
Defines the two catalytic steps this node covers and names the catalytic residue.
PMID:28360427 SUPPORT In Vitro
"UBA5 is a non-canonical E1 activating enzyme that possesses an adenylation domain but lacks a distinct cysteine domain"
Explains why the catalytic cysteine sits inside the adenylation domain, which is why a single missense change can affect both steps.
Impaired UFM1 Transfer to UFC1
Transthiolation - transfer of activated UFM1 from the UBA5 active-site cysteine to the E2 enzyme UFC1. The recurrent hypomorphic p.Ala371Thr allele was characterised specifically at this step, showing attenuated rather than absent transfer, consistent with its classification as a very mild partial-function allele.
transthiolation transfer of UFM1 to the E2 enzyme UFC1 GO:0071566 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased transthiolation transfer of UFM1 to the E2 enzyme UFC1, annotated with UFM1 activating enzyme activity (GO:0071566). GO:0071566 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Reduced Global UFM1 Conjugation Failure of the handoff reduces activated UFM1 available for downstream substrates.
Show evidence (1 reference)
PMID:27545674 SUPPORT In Vitro
"we show that the p.Ala371Thr variant is hypomorphic with attenuated ability to transfer the activated UFM1 to UFC1"
Localises the recurrent hypomorphic allele's defect to this specific step, and records it as attenuated rather than abolished.
Reduced Global UFM1 Conjugation
The cell-level readout of the enzymatic defect - the pool of UFM1-conjugated substrates falls. Curated as its own node rather than merged with the enzymology because it is measured differently (conjugate levels on blot, in an intact animal). Free-Ufm1 results are assay-condition dependent and are not incorporated in this node.
protein ufmylation GO:0071569 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein ufmylation (GO:0071569). GO:0071569 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
uba5 mutant zebrafish Zebrafish recapitulates Directly measures the conjugation deficit that defines the biochemical lesion.
Downstream
Endoplasmic Reticulum Stress and Unfolded Protein Response Activation Loss of UFMylation is associated with ER abnormalities and an exaggerated unfolded protein response, but the intervening substrate-level route is not established here.
Mitochondrial Structural Damage Mitochondrial pathology is a separate downstream arm, reported in the same mutant animals but not shown to run through the ER arm.
Show evidence (1 reference)
PMID:38046095 SUPPORT Model Organism
"We found that Ufm1-conjugated proteins of ∼25 kDa were reduced in uba5−/− fish, indicating that ufmylation is impaired, at 6 dpf"
Directly records impaired UFM1 conjugation in an intact animal. The free-Ufm1 direction is omitted because the study reports different directions under reducing and non-reducing assay conditions.
Endoplasmic Reticulum Stress and Unfolded Protein Response Activation
Loss of UFMylation is associated with perturbed ER homeostasis and an exaggerated unfolded protein response. The findings have been shown in patient fibroblasts as abnormal ER structure and in patient-derived organoids and engineered cells as an exacerbated UPR.
response to endoplasmic reticulum stress GO:0034976 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased response to endoplasmic reticulum stress (GO:0034976). GO:0034976 is a biological process from the Gene Ontology. ↑ INCREASED response to unfolded protein GO:0006986 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased response to unfolded protein (GO:0006986). GO:0006986 is a biological process from the Gene Ontology. ↑ INCREASED
endoplasmic reticulum GO:0005783 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves endoplasmic reticulum (GO:0005783). GO:0005783 is a cellular component from the Gene Ontology.
Experimental models
Patient-derived cortical organoids (UBA5 compound heterozygous) ORGANOID Patient-genotype models show perturbed ER homeostasis and an exacerbated UPR.
Show evidence (2 references)
PMID:27545681 SUPPORT In Vitro
"UBA5 mutations impair the process of ufmylation, resulting in an abnormal endoplasmic reticulum structure"
Links the UFMylation defect to ER abnormality in cells from affected individuals.
PMID:40333994 SUPPORT In Vitro
"we showed that ER homeostasis is perturbed along with an exacerbated unfolded protein response pathway in engineered U87-MG cells and patient-derived organoids expressing UBA5 pathogenic variants"
Confirms the ER/UPR arm in a humanized neuronal model carrying patient genotypes.
Mitochondrial Structural Damage
Curated as a parallel arm because its relationship to the ER arm, and whether it is a direct or downstream effect of UBA5 deficiency, remain unresolved. Mutant animals show enlarged mitochondria with abnormal cristae, vacuolar degeneration, and double-membraned "onion-ring" profiles in cerebellar neurons, peripheral nerve terminals and skeletal muscle.
mitochondrion organization GO:0007005 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal mitochondrion organization (GO:0007005). GO:0007005 is a biological process from the Gene Ontology. ⚠ ABNORMAL
mitochondrion GO:0005739 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves mitochondrion (GO:0005739). GO:0005739 is a cellular component from the Gene Ontology.
Animal models
uba5 mutant zebrafish Zebrafish recapitulates Ultrastructural mitochondrial pathology across CNS, PNS and skeletal muscle.
Show evidence (2 references)
PMID:38046095 SUPPORT Model Organism
"we detected elongated mitochondria and ‘onion-ring’ double membranous structures at the peripheral nerve terminals, indicating mitochondrial degradation"
Direct ultrastructural evidence of mitochondrial degeneration in mutant peripheral nerve terminals.
PMID:38046095 SUPPORT Model Organism
"We found that there was an increase in full-length Pink1 isoform levels"
Adds the measured PINK1 damage-response readout. It does not establish increased mitophagic flux, so no separate mitophagy-activation node is asserted.
GABAergic Interneuron Development Deficit
Single-cell RNA sequencing of patient-derived cortical organoids identified defects in the development of GABAergic interneurons. The available abstract does not establish loss of the interneuron population, a direction of functional inhibition, or a causal relationship to the firing abnormality measured in the same model.
GABAergic interneuron CL:0000617 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves GABAergic interneuron, annotated with GABAergic neuron (CL:0000617). CL:0000617 is a cell type from the Cell Ontology.
Experimental models
Patient-derived cortical organoids (UBA5 compound heterozygous) ORGANOID Single-cell transcriptomics identified the interneuron-lineage defect.
Show evidence (1 reference)
PMID:40333994 SUPPORT In Vitro
"Single-cell RNA sequencing of 100-day organoids identified defects in GABAergic interneuron development"
Establishes the interneuron-lineage deficit in organoids carrying patient genotypes.
Aberrant Neuronal Firing
Patient-derived organoids show abnormal neuronal firing on multi-electrode recording. Curated at the level the source states it - "aberrant" - without asserting a direction, because the abstract that is available establishes that firing is abnormal but does not, in the text accessible here, specify which parameters rose and which fell. See the knowledge-gap discussion on this point.
Experimental models
Patient-derived cortical organoids (UBA5 compound heterozygous) ORGANOID Multi-electrode recording demonstrates abnormal neuronal activity in the organoids.
Downstream
Drug-Resistant Epilepsy Abnormal network activity is the proposed cellular substrate for the clinical seizure disorder.
Epileptic Spasms The organoid firing abnormality is a candidate cellular correlate of the clinical spasms, not a demonstrated direct cause.
Hypsarrhythmia Links the human-model electrophysiology to the interictal EEG phenotype without claiming that the organoid assay reproduces hypsarrhythmia.
Multifocal Epileptiform Discharges Links abnormal model firing to a reported clinical EEG manifestation while leaving the intervening circuit mechanism unresolved.
Show evidence (1 reference)
PMID:40333994 SUPPORT In Vitro
"We demonstrated aberrant neuronal firing and reduction in size of patient-derived organoids"
Supports abnormal network electrophysiology, and separately the organoid size reduction curated on the microcephaly node.
Reduced Organoid Growth
Patient-derived cortical organoids show reduced size. Curated as a tissue-scale growth phenotype in a human model, distinct from the clinical microcephaly phenotype it plausibly corresponds to.
Experimental models
Patient-derived cortical organoids (UBA5 compound heterozygous) ORGANOID Patient-derived organoids are smaller than the comparator cultures.
Downstream
Postnatal Microcephaly Smaller patient-derived cortical organoids model impaired neural-tissue growth, but have not been shown to cause or quantitatively predict postnatal head-growth failure.
Show evidence (1 reference)
PMID:40333994 SUPPORT In Vitro
"We demonstrated aberrant neuronal firing and reduction in size of patient-derived organoids"
Supports the organoid growth deficit as a measured model phenotype.
Drug-Resistant Epilepsy
The clinical seizure disorder. In one genotyped sibship, epileptic spasms beginning in the first year progressed to seizures that resisted antiseizure medication.
Show evidence (1 reference)
PMID:28965491 SUPPORT Human Clinical
"The sisters, born in 2004 and 2006, presented with infantile spasms at six months of age, which later progressed to recurrent, treatment-resistant seizures"
Documents the spasms-to-refractory-seizures course in a genotyped sibship.
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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 UBA5-Related Developmental and Epileptic Encephalopathy 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

19
Head and Neck 1
Postnatal 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:27545674 SUPPORT Human Clinical
"the majority of individuals display postnatal microcephaly and epilepsy and develop spasticity"
Records microcephaly as postnatal and present in the majority of the series.
Musculoskeletal 1
Spasticity HP:0001257 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spasticity (HP:0001257). HP:0001257 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27545674 SUPPORT Human Clinical
"the majority of individuals display postnatal microcephaly and epilepsy and develop spasticity"
Directly supports spasticity as a feature emerging in a majority of the founding cohort without forcing a narrower numerical frequency band.
Nervous System 9
Epileptic Spasms HP:0011097 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epileptic spasm (HP:0011097). HP:0011097 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28965491 SUPPORT Human Clinical
"The sisters, born in 2004 and 2006, presented with infantile spasms at six months of age"
Documents epileptic spasms as the presenting seizure type.
PMID:40217280 SUPPORT Human Clinical
"epileptic spasms (sometimes occuring in clusters)"
Independent case report recording the same seizure type and its clustering.
Context-specific annotations (1)
Onset: INFANTILE; mean 0.5y
Both affected sisters in this report presented with spasms at six months; this is a cohort-specific onset observation, not a population mean.
Show evidence (1 reference)
PMID:28965491 SUPPORT Human Clinical
"presented with infantile spasms at six months of age"
Supports infantile onset at six months in both sisters.
Hypsarrhythmia HP:0002521 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypsarrhythmia (HP:0002521). HP:0002521 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28965491 SUPPORT Human Clinical
"An electroencephalogram, performed at the time, showed modified hypsarrhythmia"
Direct EEG finding at the older sister's infantile-spasm presentation.
Global Developmental Delay VERY_FREQUENT 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 (2 references)
PMID:33811063 SUPPORT Human Clinical
"All five children presented with global developmental delay, epilepsy, axial hypotonia, appendicular hypertonia, and a movement disorder, including dystonia in four"
Five of five children in this series, supporting the VERY_FREQUENT band (80-99%) on a small cohort; the same sentence supports the hypotonia and hypertonia phenotypes.
PMID:27545674 SUPPORT Human Clinical
"The affected individuals (n = 9) presented in early infancy with severe irritability, followed by dystonia and stagnation of development"
Independent nine-patient series describing developmental stagnation.
Dystonia HP:0001332 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dystonia (HP:0001332). HP:0001332 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33811063 SUPPORT Human Clinical
"a movement disorder, including dystonia in four"
Four of five children in this series had dystonia.
PMID:27545674 SUPPORT Human Clinical
"presented in early infancy with severe irritability, followed by dystonia and stagnation of development"
Independent series placing dystonia in the early clinical sequence.
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:27545681 SUPPORT Human Clinical
"five children from four unrelated families affected with a similar pattern of severe intellectual deficiency, microcephaly, movement disorders, and/or early-onset intractable epilepsy"
Names severe intellectual deficiency as part of the founding phenotype description.
Delayed Myelination HP:0012448 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed myelination (HP:0012448). HP:0012448 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38079206 SUPPORT Other
"Delayed myelination, thinning of the corpus callosum, and white matter hyperintensities have also been documented with magnetic resonance imaging (MRI)"
Documents delayed myelination as an established MRI finding across the reported literature. The same sentence supports the thin corpus callosum and white matter hyperintensity phenotypes below.
White Matter Hyperintensities Hyperintensity of cerebral white matter on MRI HP:0030890 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperintensity of cerebral white matter on MRI (HP:0030890). HP:0030890 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38079206 SUPPORT Other
"Delayed myelination, thinning of the corpus callosum, and white matter hyperintensities have also been documented with magnetic resonance imaging (MRI)"
Names white matter hyperintensities among the established MRI findings.
Cerebral Atrophy HP:0002059 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral atrophy (HP:0002059). HP:0002059 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28965491 SUPPORT Human Clinical
"mild cerebral atrophy (Additional file 1: Figure S1)"
Imaging finding in a genotype-confirmed sibship.
Cerebellar Atrophy HP:0001272 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar atrophy (HP:0001272). HP:0001272 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37130202 SUPPORT Human Clinical
"Brain MR imaging showed cerebral and cerebellar volume reduction consistent with UBA5-related disorder"
Direct MRI finding in a child described as having developmental epileptic encephalopathy.
Respiratory 1
Respiratory Failure HP:0002878 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Respiratory failure (HP:0002878). HP:0002878 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40217280 SUPPORT Human Clinical
"the child died of type I respiratory failure at the age of 1 year and 4 months"
Records the outcome in one child; it does not establish prevalence or mechanism.
Growth 1
Failure to Thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38079206 SUPPORT Other
"Many individuals also have seizures, failure to thrive, and microcephaly"
Places failure to thrive alongside seizures and microcephaly as a recurring feature across affected individuals.
Other 6
Drug-Resistant Epilepsy Refractory drug response HP:0020174 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Refractory drug response (HP:0020174). HP:0020174 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28965491 SUPPORT Human Clinical
"which later progressed to recurrent, treatment-resistant seizures"
Records the treatment-resistant course directly.
Multifocal Epileptiform Discharges HP:0010841 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Multifocal epileptiform discharges (HP:0010841). HP:0010841 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40217280 SUPPORT Human Clinical
"multifocal and generalized epileptiform discharges throughout the entire brain region"
Directly records the mixed multifocal/generalized interictal discharge pattern.
Axial Hypotonia HP:0008936 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Axial hypotonia (HP:0008936). HP:0008936 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33811063 SUPPORT Human Clinical
"All five children presented with global developmental delay, epilepsy, axial hypotonia, appendicular hypertonia, and a movement disorder"
Documents axial hypotonia in all five children of the series.
Appendicular Hypertonia Limb hypertonia HP:0002509 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Limb hypertonia (HP:0002509). HP:0002509 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33811063 SUPPORT Human Clinical
"All five children presented with global developmental delay, epilepsy, axial hypotonia, appendicular hypertonia, and a movement disorder"
Documents appendicular hypertonia in all five children of the series.
Poor Visual Fixation Abnormal visual fixation HP:0025404 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal visual fixation (HP:0025404). HP:0025404 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:40217280 SUPPORT Human Clinical
"the child could not stand up, tended to stare with poor fixation, could not grasp objects"
Records poor visual fixation in a genotype-confirmed DEE44 child at one year.
PMID:28965491 SUPPORT Human Clinical
"difficulties with visual fixation and following"
Independent observation in two affected sisters, whose retinal and optic-nerve examinations were otherwise normal.
Thin Corpus Callosum HP:0033725 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin corpus callosum (HP:0033725). HP:0033725 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:40217280 SUPPORT Human Clinical
"MRI showed thinning of the corpus callosum"
Direct imaging finding in a genotype-confirmed DEE44 case.
PMID:38046095 SUPPORT Other
"Brain imaging frequently does not reveal abnormalities at the onset of disease; however, non-specific findings such as mildly delayed myelination, white matter hyperintensities, thinning of the thalamus and the corpus callosum, cerebellar hypoplasia or generalized brain atrophy are detected as..."
This article's synthesis of reported human cases supports the variable, evolving imaging course; it is not a prospective natural-history estimate.
🧬

Genetic Associations

1
UBA5 (UBA5 encodes the E1 activating enzyme of the UFM1 cascade. Pathogenic variants are missense, nonsense, frameshift and splice-affecting, and their functional consequence ranges from mild attenuation to near-complete loss. The recurrent c.1111G>A (p.Ala371Thr) partial-function allele carries an allele frequency of 0.28% in the founding European dataset and is found in trans with a more severe variant in many affected individuals. Across a 25-person retrospective allelic analysis, 21 carried a mild Group IA/IB allele with a severe Group III/IV allele, while two symptomatic partial-function plus partial-function combinations show that this is a hierarchy, not an absolute genotype rule.)
Gene: UBA5 hgnc:23230 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is UBA5 (hgnc:23230). hgnc:23230 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (4 references)
PMID:27545674 SUPPORT Human Clinical
"The affected individuals were compound heterozygous for a missense substitution, c.1111G>A (p.Ala371Thr; allele frequency of 0.28% in Europeans), and a nonsense variant or c.164G>A that encodes an amino acid substitution p.Arg55His"
Gives the recurrent hypomorphic allele, its population frequency, and the compound-heterozygous architecture.
PMID:33811063 SUPPORT Human Clinical
"All have the recurrent mild c.1111G > A (p.Ala371Thr) variant in trans with a second UBA5 variant"
Independent series confirming the same recurrent-allele-in-trans pattern.
PMID:38079206 SUPPORT Human Clinical
"Most (21/25) individuals are compound heterozygous for one allele from Group IA or IB and another allele from Group III or IV"
Quantifies the mild-plus-severe pairing across the reported cohort using the functionally defined allelic-strength groups, which is what makes the architecture a measurement rather than an impression.
+ 1 more reference
Variants (1)
NM_024818.6(UBA5):c.1111G>A (p.Ala371Thr)
Gene: UBA5 hgnc:23230 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in UBA5 (hgnc:23230). hgnc:23230 is a gene from the HUGO Gene Nomenclature Committee. missense
Recurrent very mild partial-loss-of-function allele. It impairs UFM1 transfer to UFC1 in vitro, yet adult homozygotes without an apparent neurologic phenotype show that it is not sufficient alone to cause DEE44. Its disease relevance is therefore genotype-context dependent, most often in trans with a more severe UBA5 allele.
Show evidence (2 references)
PMID:27545674 SUPPORT In Vitro
"we show that the p.Ala371Thr variant is hypomorphic with attenuated ability to transfer the activated UFM1 to UFC1"
Establishes a partial biochemical defect rather than complete loss of function.
PMID:28965491 SUPPORT Human Clinical
"we have identified three adult Icelanders homozygous for the p.Ala371Thr mutation who show no signs of neurological disease"
Shows directly that homozygosity for this very mild allele is not sufficient for the DEE44 phenotype in the three observed adults.
💊

Medical Actions

4
Antiseizure Medication
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: vigabatrin CHEBI:63638 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses vigabatrin (CHEBI:63638). CHEBI:63638 is a therapeutic agent from Chemical Entities of Biological Interest.
Multiple antiseizure agents are used symptomatically. Published individual-level data show both transient response and persistent seizures on high-dose multidrug therapy; they do not establish a preferred disease-specific regimen.
Target Phenotypes: Epileptic spasm HP:0011097 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Epileptic spasm (HP:0011097). HP:0011097 is a phenotype from the Human Phenotype Ontology. Refractory drug response HP:0020174 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Refractory drug response (HP:0020174). HP:0020174 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28965491 SUPPORT Human Clinical
"Her seizures initially responded to vigabatrin, the infantile spasms disappeared and she became less irritable. After a few weeks however, the infantile spasms returned"
Directly documents a transient rather than durable response in one sister.
PMID:28965491 SUPPORT Human Clinical
"both sisters still had frequent seizures. They have shown limited response to several antiepileptic drugs in high doses"
Documents limited multidrug response in both sisters at later follow-up.
Combined ACTH and Magnesium Sulfate Trial
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: corticotropin CHEBI:3892 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses corticotropin (CHEBI:3892). CHEBI:3892 is a therapeutic agent from Chemical Entities of Biological Interest. magnesium sulfate CHEBI:32599 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses magnesium sulfate (CHEBI:32599). CHEBI:32599 is a therapeutic agent from Chemical Entities of Biological Interest.
Combined adrenocorticotropic hormone and magnesium sulfate shock therapy was given to one child, who continued to have several seizures daily. This single unsuccessful observation does not estimate population efficacy or refute either agent or antiseizure medication as a class.
Target Phenotypes: Epileptic spasm HP:0011097 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Epileptic spasm (HP:0011097). HP:0011097 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40217280 SUPPORT Human Clinical
"We administered a combined ACTH and magnesium sulfate treatment as a shock therapy based on the symptoms, but did not observe satisfactory clinical efficacy, as the child continued to experience several seizures every day"
Records the observed outcome of this combined regimen in one child without generalizing to either component, other antiseizure treatments or population-level efficacy.
Carbidopa-Levodopa Trial
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: carbidopa-levodopa CHEBI:3396 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses carbidopa-levodopa (CHEBI:3396). CHEBI:3396 is a therapeutic agent from Chemical Entities of Biological Interest.
Carbidopa-levodopa was tried for the movement disorder in one child. Perceived initial benefit was not sustained or withdrawal-dependent, so this observation does not establish efficacy.
Target Phenotypes: Dystonia HP:0001332 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Dystonia (HP:0001332). HP:0001332 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38079206 SUPPORT Human Clinical
"A trial of carbidopa–levodopa was initially thought to be helpful, but ultimately tapered off without worsening"
Directly supports an inconclusive single-patient trial and rejects a durable-benefit interpretation.
Globus Pallidus Internus Deep Brain Stimulation
Action: Deep Brain StimulationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Deep Brain Stimulation (NCIT:C21024). NCIT:C21024 is a clinical intervention from the NCI Thesaurus. NCIT:C21024
Bilateral GPi-DBS has been used for medically refractory status dystonicus in one child with UBA5-related developmental epileptic encephalopathy, with rapid control and return toward baseline. Follow-up was only four months, so this is a single-case signal rather than an established standard or durable response rate.
Target Phenotypes: Dystonia HP:0001332 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Dystonia (HP:0001332). HP:0001332 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:37130202 SUPPORT Human Clinical
"Here we report the case of a 7-year-old male with UBA5-related epilepsy-dyskinesia syndrome (NM_024818.6: c.1111G>A, (p.Ala371Thr); c.110C>T (p.Thr37Ile)) who presented with medically-refractory status dystonicus and showed a rapid and sustained response to GPi-DBS"
Directly states the genotype, indication and observed response in the UBA5 case.
PMID:37130202 SUPPORT Human Clinical
"Our report has limitations, including the relatively short follow up (4 months after DBS implantation) and unknown natural history of this ultra-rare disease"
Preserves the authors' stated follow-up and natural-history limitations.
🔬

Diagnosis

2
Video Electroencephalography
Video EEG defines seizure types and interictal abnormalities but is not specific for DEE44. Reported patterns include multifocal and generalized epileptiform discharges on a disorganized background and modified or partial hypsarrhythmia in children with epileptic spasms; available case evidence does not establish a universal signature.
Electroencephalography NCIT:C38054 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:40217280 SUPPORT Human Clinical
"showing multifocal and generalized continuous distribution and partial hypsarrhythmia"
Directly reports partial hypsarrhythmia in the detailed EEG description, avoiding a typographic error in the article's introductory prose.
PMID:40217280 SUPPORT Human Clinical
"multifocal and generalized epileptiform discharges throughout the entire brain region"
Records the interictal discharge distribution in a genotype-confirmed case.
Exome or Genome Sequencing
Exome or genome sequencing can identify biallelic UBA5 variants among the many genetic causes of an early developmental and epileptic encephalopathy. Parental segregation testing establishes whether two candidate variants are in trans; functional characterization may be needed for very mild or previously unclassified missense alleles.
Whole Exome Sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:27545681 SUPPORT Human Clinical
"Via whole-exome sequencing, we identified rare autosomal-recessive variants in UBA5 in five children from four unrelated families"
Documents exome sequencing as the route that identified UBA5 variants in four unrelated families.
PMID:28965491 SUPPORT Human Clinical
"The recent, extensive use of next-generation sequencing has identified a large number of genes in epileptic encephalopathies, including UBA5"
Places UBA5 within the genetically heterogeneous epileptic-encephalopathy testing context.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from UBA5-Related Developmental and Epileptic Encephalopathy:

Other UFMylation-pathway neurodevelopmental disorders
Overlapping Features Disorders caused by biallelic UFM1 or UFC1 variants and by UFSP2 variants overlap with DEE44 through developmental delay, hypotonia or spasticity, seizures, microcephaly and myelination abnormalities. Molecular testing distinguishes the affected UFMylation component.
Distinguishing Features
  • UFSP2 variants support developmental and epileptic encephalopathy 106 rather than DEE44.
  • Biallelic UFM1 variants support hypomyelinating leukodystrophy 14.
  • Biallelic UFC1 variants support neurodevelopmental disorder with spasticity and poor growth.
Show evidence (1 reference)
PMID:38079206 SUPPORT Other
"All these disorders cause global developmental delay, hypotonia, spasticity, seizures, delayed myelination, and microcephaly, consistent with them sharing a similar etiology"
The article synthesizes the overlapping clinical features of UFSP2-, UFM1- and UFC1-related disorders discussed immediately before this sentence.
🧫

Experimental Models

1
Patient-derived cortical organoids (UBA5 compound heterozygous) ORGANOID
Cortical organoids from two individuals, each carrying p.A371T in trans with a nonsense allele. They provide a humanized neuronal model of early neurodevelopment, while lacking mature whole-brain circuits and clinical seizure readouts.
Publication
PMID:40333994
Pathograph links
GABAergic Interneuron Development Deficit recapitulates fidelity: moderate Single-cell transcriptomics identified the interneuron-lineage defect.
Limitations: Organoids model early corticogenesis and lack mature circuit-level and behavioural correlates, so they cannot demonstrate seizures as such.
Readouts
GABAergic interneuron development
Direction: ALTERED
Interpretation: Single-cell RNA sequencing identified defects in GABAergic interneuron development.
Show evidence (1 reference)
PMID:40333994 SUPPORT In Vitro
"Single-cell RNA sequencing of 100-day organoids identified defects in GABAergic interneuron development"
The measurement behind this readout.
Show evidence (1 reference)
PMID:40333994 SUPPORT In Vitro
"We developed and characterized patient-derived cortical organoid cultures from two patients with compound heterozygous variants in UBA5"
Establishes the model as patient-derived and genotype-matched.
Endoplasmic Reticulum Stress and Unfolded Protein Response Activation recapitulates fidelity: moderate Patient-genotype models show perturbed ER homeostasis and an exacerbated UPR.
Limitations: ER/UPR abnormalities are demonstrated in cultured engineered cells and organoids, not confirmed in living patient brain tissue.
Show evidence (1 reference)
PMID:40333994 SUPPORT In Vitro
"ER homeostasis is perturbed along with an exacerbated unfolded protein response pathway in engineered U87-MG cells and patient-derived organoids expressing UBA5 pathogenic variants"
Direct qualitative support for the ER/UPR modeled-mechanism link.
Aberrant Neuronal Firing recapitulates fidelity: moderate Multi-electrode recording demonstrates abnormal neuronal activity in the organoids.
Limitations: The cached abstract establishes abnormal firing but not the direction of each electrophysiologic parameter or equivalence to clinical seizures.
Show evidence (1 reference)
PMID:40333994 SUPPORT In Vitro
"We demonstrated aberrant neuronal firing and reduction in size of patient-derived organoids"
Supports abnormal firing without imposing an unsupported direction.
Reduced Organoid Growth recapitulates fidelity: moderate Patient-derived organoids are smaller than the comparator cultures.
Limitations: Reduced organoid size is an early tissue-model phenotype, not a calibrated proxy for head circumference or later clinical progression.
Show evidence (1 reference)
PMID:40333994 SUPPORT In Vitro
"We demonstrated aberrant neuronal firing and reduction in size of patient-derived organoids"
Supports qualitative reduction in organoid size without importing uncached percentages.
Show evidence (1 reference)
PMID:40333994 SUPPORT In Vitro
"We also assessed two potential therapeutic modalities that augmented UBA5 protein abundance to rescue aberrant molecular and cellular phenotypes"
Records preclinical UBA5-upregulation rescue at the qualitative level available in the cached abstract; it is not clinical treatment evidence.
🐁

Animal Models

2
uba5 mutant zebrafish
Two independent CRISPR-engineered uba5 mutant lines with mitochondrial findings in central nervous system, peripheral nerve and skeletal muscle.
Species
Zebrafish
Genotype
uba5ex1s (p.E5Ffs*1) and uba5ex3d (p.A73_V80del)
Publication
PMID:38046095
Pathograph links
Reduced Global UFM1 Conjugation recapitulates fidelity: high Directly measures the conjugation deficit that defines the biochemical lesion.
Readouts
Ufm1-conjugate level
Direction: DECREASED
Interpretation: Conjugates fall to 30% of wild type in the reported reducing-condition assay. The free-Ufm1 pool is not interpreted here because its direction changes with assay conditions.
Show evidence (1 reference)
PMID:38046095 SUPPORT Model Organism
"Ufm1-conjugate levels were reduced to 30%, in uba5 mutant animals"
Quantifies the conjugated pool without conflating the assay-dependent free-Ufm1 results.
Show evidence (1 reference)
PMID:38046095 SUPPORT Model Organism
"decrease in Ufm1 conjugates seen in both mutant strains"
Supports treating both independent lines as informative for reduced conjugation.
Mitochondrial Structural Damage recapitulates fidelity: moderate Ultrastructural mitochondrial pathology across CNS, PNS and skeletal muscle.
Limitations: Mitochondrial pathology is established in zebrafish tissue; the corresponding ultrastructural finding has not been demonstrated in human patient tissue, so the arm rests on model evidence.
Readouts
Mitochondrial ultrastructure in cerebellar neurons and nerve terminals
Direction: ALTERED
Interpretation: Elongated mitochondria and double-membraned degenerative profiles.
Show evidence (1 reference)
PMID:38046095 SUPPORT Model Organism
"Furthermore, we detected elongated mitochondria and 'onion-ring' double membranous structures at the peripheral nerve terminals, indicating mitochondrial degradation"
The ultrastructural measurement behind this readout.
Show evidence (1 reference)
PMID:38046095 SUPPORT Model Organism
"Additionally, degenerating mitochondria, visible as 'onion-ring' structures with a double membrane, and dark cytoplasmic condensations were identified within cerebellar neurons, indicating neuronal death"
Supports the model as informative for mitochondrial damage in CNS neurons specifically.
Humanized UBA5 allelic-series Drosophila
A humanized fly platform in which human reference UBA5 rescues severe fly Uba5 loss and patient variants are compared across viability, development, lifespan, locomotion and bang sensitivity. It grades residual allele function rather than reproducing the full human encephalopathy.
Species
Drosophila melanogaster
Genotype
Uba5T2A-Gal4 severe-loss-of-function allele expressing human reference or variant UBA5 cDNA
Publication
PMID:38079206
Pathograph links
Biallelic UBA5 Variants Reducing E1 Enzyme Function measures fidelity: moderate Variant-dependent rescue of fly Uba5 loss provides an in-vivo allelic-strength measurement complementary to biochemical assays.
Limitations: Cross-species developmental and behavioral readouts classify allele strength but do not model the human compound-heterozygous brain, EEG or clinical course directly.
Readouts
Variant-dependent viability, development, lifespan, locomotion and bang sensitivity
Direction: ALTERED
Interpretation: Increasingly severe patient alleles show progressively less rescue across these in-vivo readouts.
Show evidence (1 reference)
PMID:38079206 SUPPORT Model Organism
"we observed a broad spectrum of phenotypes in viability, developmental timing, lifespan, locomotor activity, and bang sensitivity"
Names the in-vivo outcome panel used to grade human UBA5 variants.
Show evidence (1 reference)
PMID:38079206 SUPPORT Model Organism
"Expression of reference UBA5 cDNA fully rescues the loss of Uba5, showing that the proteins are functionally similar"
Establishes the functional basis for using human UBA5 cDNA in the fly platform.
{ }

Source YAML

click to show 
name: UBA5-Related Developmental and Epileptic Encephalopathy
creation_date: "2026-08-20T00:20:00Z"
category: Mendelian
synonyms:
- Developmental and epileptic encephalopathy 44
- DEE44
- EIEE44
- Early infantile epileptic encephalopathy 44
- UBA5-associated encephalopathy
description: >-
  UBA5-related developmental and epileptic encephalopathy (DEE44) is an autosomal
  recessive disorder caused by biallelic variants in UBA5, the E1 activating enzyme of
  the ubiquitin-fold modifier 1 (UFM1) conjugation cascade. UFMylation is a ubiquitin-like
  modification system distinct from canonical ubiquitination. Affected children present in the first
  weeks to months of life with severe irritability, dystonia and stagnation of
  development, followed by drug-resistant epilepsy, often including epileptic
  spasms - together with axial hypotonia, appendicular hypertonia, postnatal
  microcephaly and failure to thrive. Most reported individuals are compound
  heterozygous for a mild partial-function allele - often recurrent c.1111G>A
  (p.Ala371Thr) - and a more severe allele, although symptomatic partial-function plus
  partial-function combinations are also reported. Functional allelic strength appears
  to contribute substantially to severity, but does not by itself establish an exact
  clinical prognosis.
disease_term:
  preferred_term: developmental and epileptic encephalopathy, 44
  term:
    id: MONDO:0014933
    label: developmental and epileptic encephalopathy, 44
parents:
- Epilepsy
- Neurological Disease
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic UBA5 variants are required. Most reported symptomatic individuals carry a
    mild or intermediate partial-function allele in trans with a severe loss-of-function
    allele. Exceptions with two partial-function alleles are known, while homozygous
    p.Ala371Thr adults without an apparent neurologic phenotype show that this recurrent
    allele is not sufficient by itself to cause DEE44.
  evidence:
  - reference: PMID:27545674
    reference_title: "Biallelic Variants in UBA5 Link Dysfunctional UFM1 Ubiquitin-like Modifier Pathway to Severe Infantile-Onset Encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "our data imply that the combination of a hypomorphic p.Ala371Thr variant in
      trans with a loss-of-function allele in UBA5 underlies a severe infantile-onset
      encephalopathy"
    explanation: >-
      States the biallelic, compound-heterozygous architecture that defines the disorder.
  - reference: PMID:28965491
    reference_title: "Compound heterozygous mutations in UBA5 causing early-onset epileptic encephalopathy in two sisters."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we have identified three adult Icelanders homozygous for the p.Ala371Thr
      mutation who show no signs of neurological disease"
    explanation: >-
      Shows that homozygosity for this very mild allele is not sufficient to cause the
      DEE44 phenotype in the three observed adults.
  - reference: PMID:38079206
    reference_title: "Allelic strengths of encephalopathy-associated UBA5 variants correlate between in vivo and in vitro assays."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, two individuals from a previous report (IA/II) and this study
      (IB/II) show that the disease is also associated with a combination of two partial
      LoF alleles"
    explanation: >-
      Documents exceptions to the usual mild-plus-severe pairing.

pathophysiology:

- name: Biallelic UBA5 Variants Reducing E1 Enzyme Function
  biological_scale: MOLECULAR
  description: >-
    The initiating lesion. Pathogenic UBA5 variants reduce the activity of the UFM1 E1
    activating enzyme, by impairing catalysis, ATP binding, or protein stability
    depending on where the residue sits. This node is the genetic lesion only; the
    separate enzymatic steps it disrupts are curated as their own nodes below, because
    the sources measure them separately.
  genes:
  - preferred_term: UBA5
    term:
      id: hgnc:23230
      label: UBA5
  molecular_functions:
  - preferred_term: UFM1 activating enzyme activity
    modifier: DECREASED
    term:
      id: GO:0071566
      label: UFM1 activating enzyme activity
  evidence:
  - reference: PMID:27545681
    reference_title: "Biallelic Variants in UBA5 Reveal that Disruption of the UFM1 Cascade Can Result in Early-Onset Encephalopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Biochemical studies of mutant UBA5 proteins and studies in fibroblasts from
      affected individuals revealed that UBA5 mutations impair the process of ufmylation"
    explanation: >-
      Establishes that patient variants impair UFMylation, measured biochemically and in
      patient fibroblasts.
  downstream:
  - target: Impaired UFM1 Adenylation and Thioester Formation
    causal_link_type: DIRECT
    description: >-
      Loss of enzyme function acts first on the two catalytic steps UBA5 performs.

- name: Impaired UFM1 Adenylation and Thioester Formation
  biological_scale: MOLECULAR
  description: >-
    UBA5 is a non-canonical E1 that carries its catalytic cysteine inside the adenylation
    domain rather than in a separate domain. It adenylates the UFM1 C-terminal glycine
    and then forms a thioester bond through Cys250. This node covers those two steps on
    the enzyme itself, and is kept separate from the handoff to UFC1 because the two are
    assayed independently and specific variants dissociate them - p.Tyr53Phe leaves E1
    activity at 3.4% but transthiolation at 6.8% of wild type.
  molecular_functions:
  - preferred_term: UFM1 adenylation and thioester bond formation at Cys250
    modifier: DECREASED
    term:
      id: GO:0071566
      label: UFM1 activating enzyme activity
  evidence:
  - reference: PMID:28360427
    reference_title: "Novel insights into the interaction of UBA5 with UFM1 via a UFM1-interacting sequence."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In the activation process UBA5 adenylates UFM1 C-terminal Gly and then forms
      a thioester bond with the UFM1 C-terminus via its active site Cys250"
    explanation: >-
      Defines the two catalytic steps this node covers and names the catalytic residue.
  - reference: PMID:28360427
    reference_title: "Novel insights into the interaction of UBA5 with UFM1 via a UFM1-interacting sequence."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "UBA5 is a non-canonical E1 activating enzyme that possesses an adenylation
      domain but lacks a distinct cysteine domain"
    explanation: >-
      Explains why the catalytic cysteine sits inside the adenylation domain, which is
      why a single missense change can affect both steps.
  downstream:
  - target: Impaired UFM1 Transfer to UFC1
    causal_link_type: DIRECT
    description: >-
      A charged E1 is the substrate for the transthiolation handoff.

- name: Impaired UFM1 Transfer to UFC1
  biological_scale: MOLECULAR
  description: >-
    Transthiolation - transfer of activated UFM1 from the UBA5 active-site cysteine to
    the E2 enzyme UFC1. The recurrent hypomorphic p.Ala371Thr allele was characterised
    specifically at this step, showing attenuated rather than absent transfer, consistent
    with its classification as a very mild partial-function allele.
  molecular_functions:
  - preferred_term: transthiolation transfer of UFM1 to the E2 enzyme UFC1
    modifier: DECREASED
    term:
      id: GO:0071566
      label: UFM1 activating enzyme activity
  evidence:
  - reference: PMID:27545674
    reference_title: "Biallelic Variants in UBA5 Link Dysfunctional UFM1 Ubiquitin-like Modifier Pathway to Severe Infantile-Onset Encephalopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we show that the p.Ala371Thr variant is hypomorphic with attenuated ability
      to transfer the activated UFM1 to UFC1"
    explanation: >-
      Localises the recurrent hypomorphic allele's defect to this specific step, and
      records it as attenuated rather than abolished.
  downstream:
  - target: Reduced Global UFM1 Conjugation
    causal_link_type: DIRECT
    description: >-
      Failure of the handoff reduces activated UFM1 available for downstream substrates.

- name: Reduced Global UFM1 Conjugation
  biological_scale: CELLULAR
  description: >-
    The cell-level readout of the enzymatic defect - the pool of UFM1-conjugated
    substrates falls. Curated as its own node rather than merged with the enzymology
    because it is measured differently (conjugate levels on blot, in an intact animal).
    Free-Ufm1 results are assay-condition dependent and are not incorporated in this node.
  biological_processes:
  - preferred_term: protein ufmylation
    modifier: DECREASED
    term:
      id: GO:0071569
      label: protein ufmylation
  evidence:
  - reference: PMID:38046095
    reference_title: "Genetic model of UBA5 deficiency highlights the involvement of both peripheral and central nervous systems and identifies widespread mitochondrial abnormalities."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We found that Ufm1-conjugated proteins of ∼25 kDa were reduced in
      uba5−/− fish, indicating that ufmylation is impaired, at 6 dpf"
    explanation: >-
      Directly records impaired UFM1 conjugation in an intact animal. The free-Ufm1
      direction is omitted because the study reports different directions under reducing
      and non-reducing assay conditions.
  downstream:
  - target: Endoplasmic Reticulum Stress and Unfolded Protein Response Activation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Loss of UFMylation is associated with ER abnormalities and an exaggerated unfolded
      protein response, but the intervening substrate-level route is not established here.
  - target: Mitochondrial Structural Damage
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Mitochondrial pathology is a separate downstream arm, reported in the same mutant
      animals but not shown to run through the ER arm.

- name: Endoplasmic Reticulum Stress and Unfolded Protein Response Activation
  biological_scale: CELLULAR
  description: >-
    Loss of UFMylation is associated with perturbed ER homeostasis and an exaggerated
    unfolded protein response. The findings have been shown in patient fibroblasts as
    abnormal ER structure and in patient-derived organoids and engineered cells as an
    exacerbated UPR.
  cellular_components:
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
  biological_processes:
  - preferred_term: response to endoplasmic reticulum stress
    modifier: INCREASED
    term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
  - preferred_term: response to unfolded protein
    modifier: INCREASED
    term:
      id: GO:0006986
      label: response to unfolded protein
  evidence:
  - reference: PMID:27545681
    reference_title: "Biallelic Variants in UBA5 Reveal that Disruption of the UFM1 Cascade Can Result in Early-Onset Encephalopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "UBA5 mutations impair the process of ufmylation, resulting in an abnormal
      endoplasmic reticulum structure"
    explanation: >-
      Links the UFMylation defect to ER abnormality in cells from affected individuals.
  - reference: PMID:40333994
    reference_title: "Patient-derived models of UBA5-associated encephalopathy identify defects in neurodevelopment and highlight potential therapeutic avenues."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we showed that ER homeostasis is perturbed along with an exacerbated
      unfolded protein response pathway in engineered U87-MG cells and patient-derived
      organoids expressing UBA5 pathogenic variants"
    explanation: >-
      Confirms the ER/UPR arm in a humanized neuronal model carrying patient genotypes.
- name: Mitochondrial Structural Damage
  biological_scale: CELLULAR
  description: >-
    Curated as a parallel arm because its relationship to the ER arm, and whether it is a
    direct or downstream effect of UBA5 deficiency, remain unresolved. Mutant animals show
    enlarged mitochondria with abnormal cristae, vacuolar degeneration, and double-membraned
    "onion-ring" profiles in cerebellar neurons, peripheral nerve terminals and skeletal muscle.
  cellular_components:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  biological_processes:
  - preferred_term: mitochondrion organization
    modifier: ABNORMAL
    term:
      id: GO:0007005
      label: mitochondrion organization
  evidence:
  - reference: PMID:38046095
    reference_title: "Genetic model of UBA5 deficiency highlights the involvement of both peripheral and central nervous systems and identifies widespread mitochondrial abnormalities."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we detected elongated mitochondria and ‘onion-ring’ double membranous
      structures at the peripheral nerve terminals, indicating mitochondrial degradation"
    explanation: >-
      Direct ultrastructural evidence of mitochondrial degeneration in mutant peripheral
      nerve terminals.
  - reference: PMID:38046095
    reference_title: "Genetic model of UBA5 deficiency highlights the involvement of both peripheral and central nervous systems and identifies widespread mitochondrial abnormalities."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We found that there was an increase in full-length Pink1 isoform levels"
    explanation: >-
      Adds the measured PINK1 damage-response readout. It does not establish increased
      mitophagic flux, so no separate mitophagy-activation node is asserted.

- name: GABAergic Interneuron Development Deficit
  biological_scale: CELLULAR
  description: >-
    Single-cell RNA sequencing of patient-derived cortical organoids identified defects in
    the development of GABAergic interneurons. The available abstract does not establish
    loss of the interneuron population, a direction of functional inhibition, or a causal
    relationship to the firing abnormality measured in the same model.
  cell_types:
  - preferred_term: GABAergic interneuron
    term:
      id: CL:0000617
      label: GABAergic neuron
  evidence:
  - reference: PMID:40333994
    reference_title: "Patient-derived models of UBA5-associated encephalopathy identify defects in neurodevelopment and highlight potential therapeutic avenues."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Single-cell RNA sequencing of 100-day organoids identified defects in
      GABAergic interneuron development"
    explanation: >-
      Establishes the interneuron-lineage deficit in organoids carrying patient genotypes.
- name: Aberrant Neuronal Firing
  biological_scale: CELLULAR
  description: >-
    Patient-derived organoids show abnormal neuronal firing on multi-electrode recording.
    Curated at the level the source states it - "aberrant" - without asserting a direction,
    because the abstract that is available establishes that firing is abnormal but does
    not, in the text accessible here, specify which parameters rose and which fell. See
    the knowledge-gap discussion on this point.
  evidence:
  - reference: PMID:40333994
    reference_title: "Patient-derived models of UBA5-associated encephalopathy identify defects in neurodevelopment and highlight potential therapeutic avenues."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We demonstrated aberrant neuronal firing and reduction in size of
      patient-derived organoids"
    explanation: >-
      Supports abnormal network electrophysiology, and separately the organoid size
      reduction curated on the microcephaly node.
  downstream:
  - target: Drug-Resistant Epilepsy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Abnormal network activity is the proposed cellular substrate for the clinical
      seizure disorder.
  - target: Epileptic Spasms
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The organoid firing abnormality is a candidate cellular correlate of the clinical
      spasms, not a demonstrated direct cause.
  - target: Hypsarrhythmia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Links the human-model electrophysiology to the interictal EEG phenotype without
      claiming that the organoid assay reproduces hypsarrhythmia.
  - target: Multifocal Epileptiform Discharges
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Links abnormal model firing to a reported clinical EEG manifestation while leaving
      the intervening circuit mechanism unresolved.

- name: Reduced Organoid Growth
  biological_scale: TISSUE
  description: >-
    Patient-derived cortical organoids show reduced size. Curated as a tissue-scale growth
    phenotype in a human model, distinct from the clinical microcephaly phenotype it
    plausibly corresponds to.
  evidence:
  - reference: PMID:40333994
    reference_title: "Patient-derived models of UBA5-associated encephalopathy identify defects in neurodevelopment and highlight potential therapeutic avenues."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We demonstrated aberrant neuronal firing and reduction in size of
      patient-derived organoids"
    explanation: >-
      Supports the organoid growth deficit as a measured model phenotype.
  downstream:
  - target: Postnatal Microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Smaller patient-derived cortical organoids model impaired neural-tissue growth, but
      have not been shown to cause or quantitatively predict postnatal head-growth failure.

- name: Drug-Resistant Epilepsy
  biological_scale: ORGANISM
  description: >-
    The clinical seizure disorder. In one genotyped sibship, epileptic spasms beginning in
    the first year progressed to seizures that resisted antiseizure medication.
  conforms_to: "epilepsy_excitation_inhibition_imbalance#Recurrent Unprovoked Seizures"
  evidence:
  - reference: PMID:28965491
    reference_title: "Compound heterozygous mutations in UBA5 causing early-onset epileptic encephalopathy in two sisters."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The sisters, born in 2004 and 2006, presented with infantile spasms at six
      months of age, which later progressed to recurrent, treatment-resistant seizures"
    explanation: >-
      Documents the spasms-to-refractory-seizures course in a genotyped sibship.

phenotypes:

- category: Neurological
  name: Epileptic Spasms
  description: >-
    A prominent reported seizure type at onset, sometimes occurring in clusters and
    documented within the first year of life.
  phenotype_term:
    preferred_term: Epileptic spasm
    term:
      id: HP:0011097
      label: Epileptic spasm
  evidence:
  - reference: PMID:28965491
    reference_title: "Compound heterozygous mutations in UBA5 causing early-onset epileptic encephalopathy in two sisters."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The sisters, born in 2004 and 2006, presented with infantile spasms at six
      months of age"
    explanation: >-
      Documents epileptic spasms as the presenting seizure type.
  - reference: PMID:40217280
    reference_title: "Developmental and epileptic encephalopathy 44 due to compound heterozygous variants in the UBA5 gene: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "epileptic spasms (sometimes occuring in clusters)"
    explanation: >-
      Independent case report recording the same seizure type and its clustering.
  phenotype_contexts:
  - onset:
      onset_category: INFANTILE
      mean_age_years: 0.5
    notes: >-
      Both affected sisters in this report presented with spasms at six months; this is a
      cohort-specific onset observation, not a population mean.
    evidence:
    - reference: PMID:28965491
      reference_title: "Compound heterozygous mutations in UBA5 causing early-onset epileptic encephalopathy in two sisters."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "presented with infantile spasms at six months of age"
      explanation: >-
        Supports infantile onset at six months in both sisters.

- category: Neurological
  name: Drug-Resistant Epilepsy
  description: >-
    Treatment-resistant seizures have been documented, including persistent frequent
    seizures despite trials of several high-dose antiseizure medications in two sisters.
  phenotype_term:
    preferred_term: Refractory drug response
    term:
      id: HP:0020174
      label: Refractory drug response
  evidence:
  - reference: PMID:28965491
    reference_title: "Compound heterozygous mutations in UBA5 causing early-onset epileptic encephalopathy in two sisters."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "which later progressed to recurrent, treatment-resistant seizures"
    explanation: >-
      Records the treatment-resistant course directly.

- category: Neurological
  name: Hypsarrhythmia
  description: >-
    Hypsarrhythmia or a modified/partial hypsarrhythmic pattern has been recorded
    interictally in children presenting with epileptic spasms. It is a reported pattern,
    not established as universal in DEE44.
  phenotype_term:
    preferred_term: Hypsarrhythmia
    term:
      id: HP:0002521
      label: Hypsarrhythmia
  electrophysiology:
    electrophysiology_modality: EEG
    ictal_state: INTERICTAL
  evidence:
  - reference: PMID:28965491
    reference_title: "Compound heterozygous mutations in UBA5 causing early-onset epileptic encephalopathy in two sisters."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An electroencephalogram, performed at the time, showed modified
      hypsarrhythmia"
    explanation: >-
      Direct EEG finding at the older sister's infantile-spasm presentation.

- category: Neurological
  name: Multifocal Epileptiform Discharges
  description: >-
    Multifocal discharges can coexist with generalized epileptiform activity and a highly
    disorganized background on video EEG. The detailed pattern is documented in a single
    genotype-confirmed case and should not be treated as a universal signature.
  phenotype_term:
    preferred_term: Multifocal epileptiform discharges
    term:
      id: HP:0010841
      label: Multifocal epileptiform discharges
  electrophysiology:
    electrophysiology_modality: EEG
    ictal_state: INTERICTAL
  evidence:
  - reference: PMID:40217280
    reference_title: "Developmental and epileptic encephalopathy 44 due to compound heterozygous variants in the UBA5 gene: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "multifocal and generalized epileptiform discharges throughout the entire
      brain region"
    explanation: >-
      Directly records the mixed multifocal/generalized interictal discharge pattern.

- category: Neurological
  name: Global Developmental Delay
  description: >-
    Severe global delay is a central reported feature. The Finnish series describes it as
    stagnation of development following an early irritable phase, rather than loss of
    skills already firmly acquired.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:33811063
    reference_title: "A description of novel variants and review of phenotypic spectrum in UBA5-related early epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All five children presented with global developmental delay, epilepsy, axial
      hypotonia, appendicular hypertonia, and a movement disorder, including dystonia in
      four"
    explanation: >-
      Five of five children in this series, supporting the VERY_FREQUENT band (80-99%) on
      a small cohort; the same sentence supports the hypotonia and hypertonia phenotypes.
  - reference: PMID:27545674
    reference_title: "Biallelic Variants in UBA5 Link Dysfunctional UFM1 Ubiquitin-like Modifier Pathway to Severe Infantile-Onset Encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The affected individuals (n = 9) presented in early infancy with severe
      irritability, followed by dystonia and stagnation of development"
    explanation: >-
      Independent nine-patient series describing developmental stagnation.

- category: Neurological
  name: Axial Hypotonia
  description: >-
    Low truncal tone was reported together with increased tone in the limbs in all five
    children in one series; the paired findings are recorded separately here.
  phenotype_term:
    preferred_term: Axial hypotonia
    term:
      id: HP:0008936
      label: Axial hypotonia
  evidence:
  - reference: PMID:33811063
    reference_title: "A description of novel variants and review of phenotypic spectrum in UBA5-related early epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All five children presented with global developmental delay, epilepsy, axial
      hypotonia, appendicular hypertonia, and a movement disorder"
    explanation: >-
      Documents axial hypotonia in all five children of the series.

- category: Neurological
  name: Appendicular Hypertonia
  description: >-
    Increased tone in the limbs, coexisting with axial hypotonia.
  phenotype_term:
    preferred_term: Limb hypertonia
    term:
      id: HP:0002509
      label: Limb hypertonia
  evidence:
  - reference: PMID:33811063
    reference_title: "A description of novel variants and review of phenotypic spectrum in UBA5-related early epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All five children presented with global developmental delay, epilepsy, axial
      hypotonia, appendicular hypertonia, and a movement disorder"
    explanation: >-
      Documents appendicular hypertonia in all five children of the series.

- category: Neurological
  name: Spasticity
  description: >-
    Pyramidal limb spasticity can emerge after the early irritable and dystonic phase and
    overlaps clinically with appendicular hypertonia; the founding cohort reported it in
    the majority rather than every affected individual.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:27545674
    reference_title: "Biallelic Variants in UBA5 Link Dysfunctional UFM1 Ubiquitin-like Modifier Pathway to Severe Infantile-Onset Encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the majority of individuals display postnatal microcephaly and epilepsy and
      develop spasticity"
    explanation: >-
      Directly supports spasticity as a feature emerging in a majority of the founding
      cohort without forcing a narrower numerical frequency band.

- category: Neurological
  name: Dystonia
  description: >-
    Dystonia was present in four of five children in one series and can escalate to status
    dystonicus.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:33811063
    reference_title: "A description of novel variants and review of phenotypic spectrum in UBA5-related early epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a movement disorder, including dystonia in four"
    explanation: >-
      Four of five children in this series had dystonia.
  - reference: PMID:27545674
    reference_title: "Biallelic Variants in UBA5 Link Dysfunctional UFM1 Ubiquitin-like Modifier Pathway to Severe Infantile-Onset Encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presented in early infancy with severe irritability, followed by dystonia
      and stagnation of development"
    explanation: >-
      Independent series placing dystonia in the early clinical sequence.

- category: Neurological
  name: Postnatal Microcephaly
  description: >-
    Microcephaly is usually acquired rather than congenital, developing after birth as
    head growth falls away.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:27545674
    reference_title: "Biallelic Variants in UBA5 Link Dysfunctional UFM1 Ubiquitin-like Modifier Pathway to Severe Infantile-Onset Encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the majority of individuals display postnatal microcephaly and epilepsy and
      develop spasticity"
    explanation: >-
      Records microcephaly as postnatal and present in the majority of the series.

- category: Neurological
  name: Intellectual Disability
  description: >-
    Severe intellectual impairment in survivors.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:27545681
    reference_title: "Biallelic Variants in UBA5 Reveal that Disruption of the UFM1 Cascade Can Result in Early-Onset Encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "five children from four unrelated families affected with a similar pattern of
      severe intellectual deficiency, microcephaly, movement disorders, and/or early-onset
      intractable epilepsy"
    explanation: >-
      Names severe intellectual deficiency as part of the founding phenotype description.

- category: Growth
  name: Failure to Thrive
  description: >-
    Failure to thrive is recurrently reported alongside seizures and microcephaly.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:38079206
    reference_title: "Allelic strengths of encephalopathy-associated UBA5 variants correlate between in vivo and in vitro assays."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Many individuals also have seizures, failure to thrive, and microcephaly"
    explanation: >-
      Places failure to thrive alongside seizures and microcephaly as a recurring feature
      across affected individuals.

- category: Respiratory
  name: Respiratory Failure
  description: >-
    Type I respiratory failure was the terminal event in one genotype-confirmed child.
    A recurrent primary respiratory phenotype has not been established, so this record
    preserves the observed severe outcome without assigning a frequency or causal route.
  phenotype_term:
    preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
  evidence:
  - reference: PMID:40217280
    reference_title: "Developmental and epileptic encephalopathy 44 due to compound heterozygous variants in the UBA5 gene: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the child died of type I respiratory failure at the age of 1 year and 4
      months"
    explanation: >-
      Records the outcome in one child; it does not establish prevalence or mechanism.

- category: Neuroimaging
  name: Delayed Myelination
  description: >-
    Delayed myelination is a repeatedly documented but non-specific imaging finding.
  phenotype_term:
    preferred_term: Delayed myelination
    term:
      id: HP:0012448
      label: Delayed myelination
  evidence:
  - reference: PMID:38079206
    reference_title: "Allelic strengths of encephalopathy-associated UBA5 variants correlate between in vivo and in vitro assays."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Delayed myelination, thinning of the corpus callosum, and white matter
      hyperintensities have also been documented with magnetic resonance imaging (MRI)"
    explanation: >-
      Documents delayed myelination as an established MRI finding across the reported
      literature. The same sentence supports the thin corpus callosum and white matter
      hyperintensity phenotypes below.

- category: Neuroimaging
  name: White Matter Hyperintensities
  description: >-
    White matter signal abnormality on MRI, reported alongside delayed myelination and
    callosal thinning.
  phenotype_term:
    preferred_term: Hyperintensity of cerebral white matter on MRI
    term:
      id: HP:0030890
      label: Hyperintensity of cerebral white matter on MRI
  evidence:
  - reference: PMID:38079206
    reference_title: "Allelic strengths of encephalopathy-associated UBA5 variants correlate between in vivo and in vitro assays."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Delayed myelination, thinning of the corpus callosum, and white matter
      hyperintensities have also been documented with magnetic resonance imaging (MRI)"
    explanation: >-
      Names white matter hyperintensities among the established MRI findings.

- category: Neuroimaging
  name: Cerebral Atrophy
  description: >-
    Cerebral atrophy on MRI, reported in genotype-confirmed patients.
  phenotype_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
  evidence:
  - reference: PMID:28965491
    reference_title: "Compound heterozygous mutations in UBA5 causing early-onset epileptic encephalopathy in two sisters."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mild cerebral atrophy (Additional file 1: Figure S1)"
    explanation: >-
      Imaging finding in a genotype-confirmed sibship.

- category: Neuroimaging
  name: Cerebellar Atrophy
  description: >-
    Cerebellar volume loss has been documented in a child with the DEE44 phenotype. It is
    also prominent in the separate SCAR24 presentation, so cerebellar atrophy alone does
    not collapse those two clinical disease concepts.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: PMID:37130202
    reference_title: "Deep brain stimulation for medically refractory status dystonicus in UBA5-related disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain MR imaging showed cerebral and cerebellar volume reduction consistent
      with UBA5-related disorder"
    explanation: >-
      Direct MRI finding in a child described as having developmental epileptic
      encephalopathy.

- category: Ophthalmological
  name: Poor Visual Fixation
  description: >-
    Poor visual fixation and following are described in severely affected children. Normal
    retinal and optic-nerve examinations in two sisters argue against assuming a primary
    ocular lesion or a quantified acuity deficit from these observations alone.
  phenotype_term:
    preferred_term: Abnormal visual fixation
    term:
      id: HP:0025404
      label: Abnormal visual fixation
  evidence:
  - reference: PMID:40217280
    reference_title: "Developmental and epileptic encephalopathy 44 due to compound heterozygous variants in the UBA5 gene: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the child could not stand up, tended to stare with poor fixation, could not
      grasp objects"
    explanation: >-
      Records poor visual fixation in a genotype-confirmed DEE44 child at one year.
  - reference: PMID:28965491
    reference_title: "Compound heterozygous mutations in UBA5 causing early-onset epileptic encephalopathy in two sisters."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "difficulties with visual fixation and following"
    explanation: >-
      Independent observation in two affected sisters, whose retinal and optic-nerve
      examinations were otherwise normal.

- category: Neuroimaging
  name: Thin Corpus Callosum
  description: >-
    Thinning of the corpus callosum on MRI. A literature synthesis notes that imaging can
    be normal at onset and later show non-specific abnormalities, so an early normal MRI
    does not exclude the molecular diagnosis.
  phenotype_term:
    preferred_term: Thin corpus callosum
    term:
      id: HP:0033725
      label: Thin corpus callosum
  evidence:
  - reference: PMID:40217280
    reference_title: "Developmental and epileptic encephalopathy 44 due to compound heterozygous variants in the UBA5 gene: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MRI showed thinning of the corpus callosum"
    explanation: >-
      Direct imaging finding in a genotype-confirmed DEE44 case.
  - reference: PMID:38046095
    reference_title: "Genetic model of UBA5 deficiency highlights the involvement of both peripheral and central nervous systems and identifies widespread mitochondrial abnormalities."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Brain imaging frequently does not reveal abnormalities at the onset of
      disease; however, non-specific findings such as mildly delayed myelination, white
      matter hyperintensities, thinning of the thalamus and the corpus callosum, cerebellar
      hypoplasia or generalized brain atrophy are detected as the disease progresses"
    explanation: >-
      This article's synthesis of reported human cases supports the variable, evolving
      imaging course; it is not a prospective natural-history estimate.

genetic:
- name: UBA5
  gene_term:
    preferred_term: UBA5
    term:
      id: hgnc:23230
      label: UBA5
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: >-
    UBA5 encodes the E1 activating enzyme of the UFM1 cascade. Pathogenic variants are
    missense, nonsense, frameshift and splice-affecting, and their functional consequence
    ranges from mild attenuation to near-complete loss. The recurrent c.1111G>A
    (p.Ala371Thr) partial-function allele carries an allele frequency of 0.28% in the
    founding European dataset and is found in trans with a more severe variant in many
    affected individuals. Across a 25-person retrospective allelic analysis, 21 carried a
    mild Group IA/IB allele with a severe Group III/IV allele, while two symptomatic
    partial-function plus partial-function combinations show that this is a hierarchy,
    not an absolute genotype rule.
  variants:
  - name: NM_024818.6(UBA5):c.1111G>A (p.Ala371Thr)
    type: missense
    gene:
      preferred_term: UBA5
      term:
        id: hgnc:23230
        label: UBA5
    description: >-
      Recurrent very mild partial-loss-of-function allele. It impairs UFM1 transfer to
      UFC1 in vitro, yet adult homozygotes without an apparent neurologic phenotype show
      that it is not sufficient alone to cause DEE44. Its disease relevance is therefore
      genotype-context dependent, most often in trans with a more severe UBA5 allele.
    evidence:
    - reference: PMID:27545674
      reference_title: "Biallelic Variants in UBA5 Link Dysfunctional UFM1 Ubiquitin-like Modifier Pathway to Severe Infantile-Onset Encephalopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "we show that the p.Ala371Thr variant is hypomorphic with attenuated ability
        to transfer the activated UFM1 to UFC1"
      explanation: >-
        Establishes a partial biochemical defect rather than complete loss of function.
    - reference: PMID:28965491
      reference_title: "Compound heterozygous mutations in UBA5 causing early-onset epileptic encephalopathy in two sisters."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "we have identified three adult Icelanders homozygous for the p.Ala371Thr
        mutation who show no signs of neurological disease"
      explanation: >-
        Shows directly that homozygosity for this very mild allele is not sufficient for
        the DEE44 phenotype in the three observed adults.
  evidence:
  - reference: PMID:27545674
    reference_title: "Biallelic Variants in UBA5 Link Dysfunctional UFM1 Ubiquitin-like Modifier Pathway to Severe Infantile-Onset Encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The affected individuals were compound heterozygous for a missense
      substitution, c.1111G>A (p.Ala371Thr; allele frequency of 0.28% in Europeans), and a
      nonsense variant or c.164G>A that encodes an amino acid substitution p.Arg55His"
    explanation: >-
      Gives the recurrent hypomorphic allele, its population frequency, and the
      compound-heterozygous architecture.
  - reference: PMID:33811063
    reference_title: "A description of novel variants and review of phenotypic spectrum in UBA5-related early epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All have the recurrent mild c.1111G > A (p.Ala371Thr) variant in trans with a
      second UBA5 variant"
    explanation: >-
      Independent series confirming the same recurrent-allele-in-trans pattern.
  - reference: PMID:38079206
    reference_title: "Allelic strengths of encephalopathy-associated UBA5 variants correlate between in vivo and in vitro assays."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most (21/25) individuals are compound heterozygous for one allele from Group
      IA or IB and another allele from Group III or IV"
    explanation: >-
      Quantifies the mild-plus-severe pairing across the reported cohort using the
      functionally defined allelic-strength groups, which is what makes the architecture a
      measurement rather than an impression.
  - reference: PMID:38079206
    reference_title: "Allelic strengths of encephalopathy-associated UBA5 variants correlate between in vivo and in vitro assays."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, two individuals from a previous report (IA/II) and this study
      (IB/II) show that the disease is also associated with a combination of two partial
      LoF alleles"
    explanation: >-
      Documents the partial-function plus partial-function exceptions to the dominant
      mild-plus-severe pattern.
  notes: >-
    The UBA5 allelic spectrum also includes autosomal recessive spinocerebellar ataxia 24
    (SCAR24, OMIM 617133) and a severe congenital neuropathy presentation. They overlap
    mechanistically but remain distinct clinical disease concepts; this entry is limited
    to MONDO:0014933 DEE44.

diagnosis:
- name: Video Electroencephalography
  description: >-
    Video EEG defines seizure types and interictal abnormalities but is not specific for
    DEE44. Reported patterns include multifocal and generalized epileptiform discharges on
    a disorganized background and modified or partial hypsarrhythmia in children with
    epileptic spasms; available case evidence does not establish a universal signature.
  diagnosis_term:
    preferred_term: Electroencephalography
    term:
      id: NCIT:C38054
      label: Electroencephalography
  evidence:
  - reference: PMID:40217280
    reference_title: "Developmental and epileptic encephalopathy 44 due to compound heterozygous variants in the UBA5 gene: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "showing multifocal and generalized continuous distribution and partial
      hypsarrhythmia"
    explanation: >-
      Directly reports partial hypsarrhythmia in the detailed EEG description, avoiding a
      typographic error in the article's introductory prose.
  - reference: PMID:40217280
    reference_title: "Developmental and epileptic encephalopathy 44 due to compound heterozygous variants in the UBA5 gene: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "multifocal and generalized epileptiform discharges throughout the entire
      brain region"
    explanation: >-
      Records the interictal discharge distribution in a genotype-confirmed case.

- name: Exome or Genome Sequencing
  description: >-
    Exome or genome sequencing can identify biallelic UBA5 variants among the many genetic
    causes of an early developmental and epileptic encephalopathy. Parental segregation
    testing establishes whether two candidate variants are in trans; functional
    characterization may be needed for very mild or previously unclassified missense
    alleles.
  diagnosis_term:
    preferred_term: Whole Exome Sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:27545681
    reference_title: "Biallelic Variants in UBA5 Reveal that Disruption of the UFM1 Cascade Can Result in Early-Onset Encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Via whole-exome sequencing, we identified rare autosomal-recessive variants
      in UBA5 in five children from four unrelated families"
    explanation: >-
      Documents exome sequencing as the route that identified UBA5 variants in four
      unrelated families.
  - reference: PMID:28965491
    reference_title: "Compound heterozygous mutations in UBA5 causing early-onset epileptic encephalopathy in two sisters."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The recent, extensive use of next-generation sequencing has identified a
      large number of genes in epileptic encephalopathies, including UBA5"
    explanation: >-
      Places UBA5 within the genetically heterogeneous epileptic-encephalopathy testing
      context.

differential_diagnoses:
- name: Other UFMylation-pathway neurodevelopmental disorders
  description: >-
    Disorders caused by biallelic UFM1 or UFC1 variants and by UFSP2 variants overlap with
    DEE44 through developmental delay, hypotonia or spasticity, seizures, microcephaly and
    myelination abnormalities. Molecular testing distinguishes the affected UFMylation
    component.
  distinguishing_features:
  - UFSP2 variants support developmental and epileptic encephalopathy 106 rather than DEE44.
  - Biallelic UFM1 variants support hypomyelinating leukodystrophy 14.
  - Biallelic UFC1 variants support neurodevelopmental disorder with spasticity and poor growth.
  evidence:
  - reference: PMID:38079206
    reference_title: "Allelic strengths of encephalopathy-associated UBA5 variants correlate between in vivo and in vitro assays."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "All these disorders cause global developmental delay, hypotonia, spasticity,
      seizures, delayed myelination, and microcephaly, consistent with them sharing a
      similar etiology"
    explanation: >-
      The article synthesizes the overlapping clinical features of UFSP2-, UFM1- and
      UFC1-related disorders discussed immediately before this sentence.

- name: UBA5-related SCAR24 and severe congenital neuropathy presentations
  description: >-
    Biallelic UBA5 variants also occur in childhood-onset spinocerebellar ataxia 24 and a
    severe congenital neuropathy presentation. These are mechanistically allelic to DEE44
    but remain distinct clinical concepts rather than subtypes curated inside this entry.
  distinguishing_features:
  - Infantile encephalopathy with developmental stagnation and epilepsy favors DEE44.
  - Childhood-onset gait and limb ataxia with cerebellar atrophy favors SCAR24.
  - Reduced fetal movements and severe sensorimotor neuropathy without central nervous system involvement favor the congenital neuropathy presentation.
  evidence:
  - reference: PMID:38079206
    reference_title: "Allelic strengths of encephalopathy-associated UBA5 variants correlate between in vivo and in vitro assays."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Biallelic UBA5 has also been associated with spinocerebellar ataxia 24
      (OMIM: #617133), which is characterized by a childhood-onset gait and limb ataxia"
    explanation: >-
      Defines the principal clinical boundary between SCAR24 and infantile DEE44.
  - reference: PMID:38046095
    reference_title: "Genetic model of UBA5 deficiency highlights the involvement of both peripheral and central nervous systems and identifies widespread mitochondrial abnormalities."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "five individuals with severe congenital neuropathy associated with reduced
      fetal movements and severe sensory-motor peripheral neuropathy, with no central
      nervous system involvement"
    explanation: >-
      Defines the peripheral, antenatal-presentation boundary of the congenital neuropathy
      pole.

treatments:
- name: Antiseizure Medication
  description: >-
    Multiple antiseizure agents are used symptomatically. Published individual-level data
    show both transient response and persistent seizures on high-dose multidrug therapy;
    they do not establish a preferred disease-specific regimen.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: vigabatrin
      term:
        id: CHEBI:63638
        label: vigabatrin
  target_phenotypes:
  - preferred_term: Epileptic spasm
    term:
      id: HP:0011097
      label: Epileptic spasm
  - preferred_term: Refractory drug response
    term:
      id: HP:0020174
      label: Refractory drug response
  evidence:
  - reference: PMID:28965491
    reference_title: "Compound heterozygous mutations in UBA5 causing early-onset epileptic encephalopathy in two sisters."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Her seizures initially responded to vigabatrin, the infantile spasms
      disappeared and she became less irritable. After a few weeks however, the infantile
      spasms returned"
    explanation: >-
      Directly documents a transient rather than durable response in one sister.
  - reference: PMID:28965491
    reference_title: "Compound heterozygous mutations in UBA5 causing early-onset epileptic encephalopathy in two sisters."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "both sisters still had frequent seizures. They have shown limited response
      to several antiepileptic drugs in high doses"
    explanation: >-
      Documents limited multidrug response in both sisters at later follow-up.
  notes: >-
    This record describes reported use and outcomes; it is not a treatment recommendation
    or comparative efficacy claim.

- name: Combined ACTH and Magnesium Sulfate Trial
  description: >-
    Combined adrenocorticotropic hormone and magnesium sulfate shock therapy was given to
    one child, who continued to have several seizures daily. This single unsuccessful
    observation does not estimate population efficacy or refute either agent or
    antiseizure medication as a class.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: corticotropin
      term:
        id: CHEBI:3892
        label: corticotropin
    - preferred_term: magnesium sulfate
      term:
        id: CHEBI:32599
        label: magnesium sulfate
  target_phenotypes:
  - preferred_term: Epileptic spasm
    term:
      id: HP:0011097
      label: Epileptic spasm
  evidence:
  - reference: PMID:40217280
    reference_title: "Developmental and epileptic encephalopathy 44 due to compound heterozygous variants in the UBA5 gene: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We administered a combined ACTH and magnesium sulfate treatment as a shock
      therapy based on the symptoms, but did not observe satisfactory clinical efficacy,
      as the child continued to experience several seizures every day"
    explanation: >-
      Records the observed outcome of this combined regimen in one child without
      generalizing to either component, other antiseizure treatments or population-level
      efficacy.

- name: Carbidopa-Levodopa Trial
  description: >-
    Carbidopa-levodopa was tried for the movement disorder in one child. Perceived initial
    benefit was not sustained or withdrawal-dependent, so this observation does not
    establish efficacy.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: carbidopa-levodopa
      term:
        id: CHEBI:3396
        label: Carbidopa-levodopa
  target_phenotypes:
  - preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:38079206
    reference_title: "Allelic strengths of encephalopathy-associated UBA5 variants correlate between in vivo and in vitro assays."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A trial of carbidopa–levodopa was initially thought to be helpful, but
      ultimately tapered off without worsening"
    explanation: >-
      Directly supports an inconclusive single-patient trial and rejects a durable-benefit
      interpretation.

- name: Globus Pallidus Internus Deep Brain Stimulation
  description: >-
    Bilateral GPi-DBS has been used for medically refractory status dystonicus in
    one child with UBA5-related developmental epileptic encephalopathy, with rapid control
    and return toward baseline. Follow-up was only four months, so this is a single-case
    signal rather than an established standard or durable response rate.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Deep Brain Stimulation
    term:
      id: NCIT:C21024
      label: Deep Brain Stimulation
  target_phenotypes:
  - preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:37130202
    reference_title: "Deep brain stimulation for medically refractory status dystonicus in UBA5-related disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report the case of a 7-year-old male with UBA5-related
      epilepsy-dyskinesia syndrome (NM_024818.6: c.1111G>A, (p.Ala371Thr); c.110C>T
      (p.Thr37Ile)) who presented with medically-refractory status dystonicus and showed a
      rapid and sustained response to GPi-DBS"
    explanation: >-
      Directly states the genotype, indication and observed response in the UBA5 case.
  - reference: PMID:37130202
    reference_title: "Deep brain stimulation for medically refractory status dystonicus in UBA5-related disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our report has limitations, including the relatively short follow up (4
      months after DBS implantation) and unknown natural history of this ultra-rare
      disease"
    explanation: >-
      Preserves the authors' stated follow-up and natural-history limitations.

animal_models:
- name: uba5 mutant zebrafish
  species: Zebrafish
  genotype: uba5ex1s (p.E5Ffs*1) and uba5ex3d (p.A73_V80del)
  publication: PMID:38046095
  description: >-
    Two independent CRISPR-engineered uba5 mutant lines with mitochondrial findings in
    central nervous system, peripheral nerve and skeletal muscle.
  modeled_mechanisms:
  - target: Reduced Global UFM1 Conjugation
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Directly measures the conjugation deficit that defines the biochemical lesion.
    readouts:
    - name: Ufm1-conjugate level
      target: Reduced Global UFM1 Conjugation
      direction: DECREASED
      interpretation: >-
        Conjugates fall to 30% of wild type in the reported reducing-condition assay. The
        free-Ufm1 pool is not interpreted here because its direction changes with assay
        conditions.
      evidence:
      - reference: PMID:38046095
        reference_title: "Genetic model of UBA5 deficiency highlights the involvement of both peripheral and central nervous systems and identifies widespread mitochondrial abnormalities."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Ufm1-conjugate levels were reduced to 30%, in uba5 mutant animals"
        explanation: >-
          Quantifies the conjugated pool without conflating the assay-dependent free-Ufm1
          results.
    evidence:
    - reference: PMID:38046095
      reference_title: "Genetic model of UBA5 deficiency highlights the involvement of both peripheral and central nervous systems and identifies widespread mitochondrial abnormalities."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "decrease in Ufm1 conjugates seen in both mutant strains"
      explanation: >-
        Supports treating both independent lines as informative for reduced conjugation.
  - target: Mitochondrial Structural Damage
    relationship: RECAPITULATES
    fidelity: MODERATE
    limitations: >-
      Mitochondrial pathology is established in zebrafish tissue; the corresponding
      ultrastructural finding has not been demonstrated in human patient tissue, so the
      arm rests on model evidence.
    description: >-
      Ultrastructural mitochondrial pathology across CNS, PNS and skeletal muscle.
    readouts:
    - name: Mitochondrial ultrastructure in cerebellar neurons and nerve terminals
      target: Mitochondrial Structural Damage
      direction: ALTERED
      interpretation: >-
        Elongated mitochondria and double-membraned degenerative profiles.
      evidence:
      - reference: PMID:38046095
        reference_title: "Genetic model of UBA5 deficiency highlights the involvement of both peripheral and central nervous systems and identifies widespread mitochondrial abnormalities."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Furthermore, we detected elongated mitochondria and 'onion-ring' double
          membranous structures at the peripheral nerve terminals, indicating
          mitochondrial degradation"
        explanation: >-
          The ultrastructural measurement behind this readout.
    evidence:
    - reference: PMID:38046095
      reference_title: "Genetic model of UBA5 deficiency highlights the involvement of both peripheral and central nervous systems and identifies widespread mitochondrial abnormalities."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Additionally, degenerating mitochondria, visible as 'onion-ring'
        structures with a double membrane, and dark cytoplasmic condensations were
        identified within cerebellar neurons, indicating neuronal death"
      explanation: >-
        Supports the model as informative for mitochondrial damage in CNS neurons
        specifically.

- name: Humanized UBA5 allelic-series Drosophila
  species: Drosophila melanogaster
  genotype: Uba5T2A-Gal4 severe-loss-of-function allele expressing human reference or variant UBA5 cDNA
  publication: PMID:38079206
  description: >-
    A humanized fly platform in which human reference UBA5 rescues severe fly Uba5 loss
    and patient variants are compared across viability, development, lifespan, locomotion
    and bang sensitivity. It grades residual allele function rather than reproducing the
    full human encephalopathy.
  modeled_mechanisms:
  - target: Biallelic UBA5 Variants Reducing E1 Enzyme Function
    relationship: MEASURES
    fidelity: MODERATE
    limitations: >-
      Cross-species developmental and behavioral readouts classify allele strength but do
      not model the human compound-heterozygous brain, EEG or clinical course directly.
    description: >-
      Variant-dependent rescue of fly Uba5 loss provides an in-vivo allelic-strength
      measurement complementary to biochemical assays.
    readouts:
    - name: Variant-dependent viability, development, lifespan, locomotion and bang sensitivity
      target: Biallelic UBA5 Variants Reducing E1 Enzyme Function
      direction: ALTERED
      interpretation: >-
        Increasingly severe patient alleles show progressively less rescue across these
        in-vivo readouts.
      evidence:
      - reference: PMID:38079206
        reference_title: "Allelic strengths of encephalopathy-associated UBA5 variants correlate between in vivo and in vitro assays."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "we observed a broad spectrum of phenotypes in viability, developmental
          timing, lifespan, locomotor activity, and bang sensitivity"
        explanation: >-
          Names the in-vivo outcome panel used to grade human UBA5 variants.
    evidence:
    - reference: PMID:38079206
      reference_title: "Allelic strengths of encephalopathy-associated UBA5 variants correlate between in vivo and in vitro assays."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Expression of reference UBA5 cDNA fully rescues the loss of Uba5, showing
        that the proteins are functionally similar"
      explanation: >-
        Establishes the functional basis for using human UBA5 cDNA in the fly platform.

experimental_models:
- name: Patient-derived cortical organoids (UBA5 compound heterozygous)
  experimental_model_type: ORGANOID
  description: >-
    Cortical organoids from two individuals, each carrying p.A371T in trans with a
    nonsense allele. They provide a humanized neuronal model of early neurodevelopment,
    while lacking mature whole-brain circuits and clinical seizure readouts.
  publication: PMID:40333994
  modeled_mechanisms:
  - target: GABAergic Interneuron Development Deficit
    relationship: RECAPITULATES
    fidelity: MODERATE
    limitations: >-
      Organoids model early corticogenesis and lack mature circuit-level and behavioural
      correlates, so they cannot demonstrate seizures as such.
    description: >-
      Single-cell transcriptomics identified the interneuron-lineage defect.
    readouts:
    - name: GABAergic interneuron development
      target: GABAergic Interneuron Development Deficit
      direction: ALTERED
      interpretation: >-
        Single-cell RNA sequencing identified defects in GABAergic interneuron development.
      evidence:
      - reference: PMID:40333994
        reference_title: "Patient-derived models of UBA5-associated encephalopathy identify defects in neurodevelopment and highlight potential therapeutic avenues."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Single-cell RNA sequencing of 100-day organoids identified defects in
          GABAergic interneuron development"
        explanation: >-
          The measurement behind this readout.
    evidence:
    - reference: PMID:40333994
      reference_title: "Patient-derived models of UBA5-associated encephalopathy identify defects in neurodevelopment and highlight potential therapeutic avenues."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We developed and characterized patient-derived cortical organoid cultures
        from two patients with compound heterozygous variants in UBA5"
      explanation: >-
        Establishes the model as patient-derived and genotype-matched.
  - target: Endoplasmic Reticulum Stress and Unfolded Protein Response Activation
    relationship: RECAPITULATES
    fidelity: MODERATE
    limitations: >-
      ER/UPR abnormalities are demonstrated in cultured engineered cells and organoids,
      not confirmed in living patient brain tissue.
    description: >-
      Patient-genotype models show perturbed ER homeostasis and an exacerbated UPR.
    evidence:
    - reference: PMID:40333994
      reference_title: "Patient-derived models of UBA5-associated encephalopathy identify defects in neurodevelopment and highlight potential therapeutic avenues."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "ER homeostasis is perturbed along with an exacerbated unfolded protein
        response pathway in engineered U87-MG cells and patient-derived organoids
        expressing UBA5 pathogenic variants"
      explanation: >-
        Direct qualitative support for the ER/UPR modeled-mechanism link.
  - target: Aberrant Neuronal Firing
    relationship: RECAPITULATES
    fidelity: MODERATE
    limitations: >-
      The cached abstract establishes abnormal firing but not the direction of each
      electrophysiologic parameter or equivalence to clinical seizures.
    description: >-
      Multi-electrode recording demonstrates abnormal neuronal activity in the organoids.
    evidence:
    - reference: PMID:40333994
      reference_title: "Patient-derived models of UBA5-associated encephalopathy identify defects in neurodevelopment and highlight potential therapeutic avenues."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We demonstrated aberrant neuronal firing and reduction in size of
        patient-derived organoids"
      explanation: >-
        Supports abnormal firing without imposing an unsupported direction.
  - target: Reduced Organoid Growth
    relationship: RECAPITULATES
    fidelity: MODERATE
    limitations: >-
      Reduced organoid size is an early tissue-model phenotype, not a calibrated proxy for
      head circumference or later clinical progression.
    description: >-
      Patient-derived organoids are smaller than the comparator cultures.
    evidence:
    - reference: PMID:40333994
      reference_title: "Patient-derived models of UBA5-associated encephalopathy identify defects in neurodevelopment and highlight potential therapeutic avenues."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We demonstrated aberrant neuronal firing and reduction in size of
        patient-derived organoids"
      explanation: >-
        Supports qualitative reduction in organoid size without importing uncached
        percentages.
  evidence:
  - reference: PMID:40333994
    reference_title: "Patient-derived models of UBA5-associated encephalopathy identify defects in neurodevelopment and highlight potential therapeutic avenues."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We also assessed two potential therapeutic modalities that augmented UBA5
      protein abundance to rescue aberrant molecular and cellular phenotypes"
    explanation: >-
      Records preclinical UBA5-upregulation rescue at the qualitative level available in
      the cached abstract; it is not clinical treatment evidence.

discussions:

- discussion_id: gap_which_downstream_arm_drives_the_seizures
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Aberrant Neuronal Firing
  prompt: >-
    Which downstream consequence of reduced UFMylation - ER stress, mitochondrial damage,
    or the GABAergic interneuron deficit - actually produces the seizures?
  rationale: >-
    Three downstream arms are established, each in a different model system: ER stress and
    UPR activation in patient fibroblasts and organoids, mitochondrial damage in zebrafish,
    and a GABAergic interneuron deficit in organoids. No source demonstrates that any one
    of them causes the abnormal network activity, and none is shown to be upstream of
    another. This entry therefore hangs the ER and mitochondrial arms off the conjugation
    node in parallel rather than in series. No causal edge is added from the GABAergic
    interneuron development deficit to aberrant firing; that relationship remains
    unresolved, consistent with the following firing-direction knowledge gap. Placing the
    findings in a chain would assert a precedence that has not been established.
  proposed_experiments:
  - experiment_id: exp_arm_specific_rescue_in_organoids
    name: Arm-specific rescue in patient-derived organoids
    description: >-
      Rescue each arm independently in the patient-derived organoid model - a chemical
      chaperone or UPR modulator for the ER arm, a mitophagy or mitochondrial-protective
      agent for the mitochondrial arm - and ask which, if either, normalizes the
      multi-electrode firing phenotype without correcting UBA5 abundance itself.

- discussion_id: gap_direction_of_the_organoid_firing_abnormality
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Aberrant Neuronal Firing
  prompt: >-
    In which direction is network activity abnormal in UBA5 patient organoids, and does it
    match the hyperexcitability the clinical phenotype implies?
  rationale: >-
    The pathophysiology node deliberately says "aberrant" rather than "increased". The
    accessible source text establishes that firing is abnormal but does not specify which
    parameters move which way. The same abstract reports a GABAergic-interneuron
    development defect, but does not describe loss of that population or show that the
    development finding causes the firing abnormality. Curating a direction or causal link
    that the quotable evidence does not state would manufacture that finding.
  proposed_experiments:
  - experiment_id: exp_report_directional_mea_parameters
    name: Directional reporting of organoid multi-electrode parameters
    description: >-
      Report, from the multi-electrode organoid data, the separate directions of mean
      firing rate, single-electrode burst frequency and network burst frequency, so that a
      concordance or divergence between cellular and network excitability can be curated
      explicitly.

- discussion_id: mismatch_null_mouse_models_a_different_lethal_mechanism
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Biallelic UBA5 Variants Reducing E1 Enzyme Function
  prompt: >-
    Can a complete-null animal model inform a disease represented clinically by genotypes
    that retain partial UBA5 function?
  rationale: >-
    No biallelic-null affected individual is represented in the cited clinical series,
    while most functionally analysed affected individuals carry at least one mild or
    partial-function allele. A germline null therefore is not genotype matched to those
    documented cohorts. The CNS-specific Ufm1 knockout is informative in a different way -
    it causes neonatal death with microcephaly and neuronal apoptosis, establishing that
    the pathway is essential for CNS development - but essentiality of the pathway is a
    weaker claim than fidelity to the human hypomorphic disease. The zebrafish lines and
    humanized flies, which grade residual activity, are better-matched models.
  proposed_experiments:
  - experiment_id: exp_patient_matched_hypomorphic_mouse
    name: Patient-genotype-matched hypomorphic mouse
    description: >-
      Generate a mouse carrying the human-equivalent p.Ala371Thr allele in trans with a
      null, matching the actual patient genotype, and ask whether it reproduces the
      seizure and movement phenotype that the null cannot be used to test.

- discussion_id: controversy_can_modest_upregulation_be_therapeutic
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Reduced Global UFM1 Conjugation
  prompt: >-
    Is increasing UBA5 abundance a viable therapeutic strategy, and what dose and
    durability would be required?
  rationale: >-
    Asymptomatic adults homozygous for the mild p.Ala371Thr allele show that this genotype
    can be compatible with health, but they do not establish that modest upregulation is
    sufficient in affected compound genotypes. Two approaches that augment UBA5 protein
    abundance rescued phenotypes in cultured models. Durability, minimum effective dose,
    upper safe bound and in-vivo translation remain unknown; the absence of an overt
    phenotype after fly overexpression does not establish human safety.
  proposed_experiments:
  - experiment_id: exp_uba5_dose_response_window
    name: UBA5 abundance dose-response and durability
    description: >-
      Establish a dose-response relationship between UBA5 protein abundance and correction
      of the organoid electrophysiological and ER-stress phenotypes, identifying both the
      minimum effective and maximum tolerated increase, and measure the durability of
      correction beyond the intervals so far reported.

notes: >-
  Scope: this entry curates DEE44 only. UBA5 also causes autosomal recessive
  spinocerebellar ataxia 24 (SCAR24, OMIM 617133) at the mild end of the same allelic
  spectrum, and a severe congenital neuropathy phenotype at the other; both are referenced
  for contrast but are not modeled here as part of DEE44.
📚

References & Deep Research

Deep Research

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UBA5-Related Developmental and Epileptic Encephalopathy: Comprehensive Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 17 citations 2026-08-20T03:55:11.691845

UBA5-Related Developmental and Epileptic Encephalopathy: Comprehensive Research Report

1. Disease Information

Overview

UBA5-related developmental and epileptic encephalopathy — formally Developmental and Epileptic Encephalopathy 44 (DEE44), and historically termed "Early Infantile Epileptic Encephalopathy-44 (EIEE44)" — is an ultra-rare, autosomal recessive neurodevelopmental disorder caused by biallelic (homozygous or compound heterozygous) loss-of-function variants in UBA5, which encodes the E1-like activating enzyme of the UFMylation post-translational modification pathway. The disorder was first described in 2016 in three back-to-back reports (Colin et al., Duan et al., Muona et al., all Am J Hum Genet 99(3)), making UBA5 "the first gene from the ufmylation pathway... linked to disease" (PMC8208045). It is characterized by early-onset (typically first weeks to months of life) refractory epilepsy/infantile spasms, severe global developmental delay/intellectual disability, hypotonia with limb hypertonia, dystonia, microcephaly, failure to thrive, and progressive white-matter/cerebellar abnormalities on MRI (OMIM #617132; eLife 89891).

Biallelic UBA5 variants produce a phenotypic spectrum along a severity continuum rather than a single discrete disease, spanning three overlapping presentations: 1. DEE44 — severe infantile-onset encephalopathy with/without seizures (the majority phenotype) 2. Autosomal recessive spinocerebellar ataxia 24 (SCAR24, OMIM #617133) — milder, childhood-onset progressive gait/limb ataxia with normal-to-preserved cognition 3. Severe congenital neuropathy — profound sensorimotor peripheral neuropathy, sometimes fatal in infancy, with or without CNS involvement

(Genomics England PanelApp; PMC10691876)

Key Identifiers

  • OMIM disease: #617132 (DEE44); related #617133 (SCAR24)
  • OMIM gene: *610552 (UBA5)
  • Gene: UBA5 — HGNC:23230, chromosome 3q22.1
  • UniProt: Q9GZZ9
  • Inheritance: Autosomal recessive
  • Synonyms: Early infantile epileptic encephalopathy 44 (EIEE44, older nomenclature); UBA5-related encephalopathy; UBA5-associated encephalopathy; UBA5 deficiency

Data Source Type

Nearly all clinical knowledge derives from aggregated case reports and small case series (individual patients and sibships) rather than large EHR-based cohorts, reflecting the extreme rarity of the condition — as of the most comprehensive published review, 24 individuals from ~17–19 families had been reported (PMC8208045; eLife 89891, reporting "21/25" analyzed individuals).

2. Etiology

Disease Causal Factor

Purely monogenic/genetic: biallelic pathogenic variants in UBA5 causing partial-to-severe loss of UFM1-activating (E1) enzymatic function. There is no known environmental, infectious, or purely acquired cause.

Genetic Risk Factors

  • Compound heterozygosity is the dominant genotype: most reported patients carry one severe/null allele in trans with a hypomorphic (partial-function) allele — a pattern essential to viability, since complete biallelic null UBA5 is likely embryonic/perinatally lethal (consistent with murine data below).
  • Recurrent hypomorphic allele p.Ala371Thr (c.1111G>A): found in ~65–70% of DEE44 alleles reported (12/17 families in one series), functioning as a weak/mild hypomorphic variant that preserves partial E1 activity. Population database carrier frequencies are estimated at 1 in 84 in Finnish populations and 1 in 200 in non-Finnish Europeans, and homozygosity for p.A371T alone is reported in asymptomatic adults in population databases — establishing it as a "very weak allele" below a pathogenic threshold on its own (PMC8208045; eLife 89891).
  • Founder homozygous variant p.Arg11Trp (c.31C>T) identified in a consanguineous multigenerational family, associated with a fatal congenital neuropathy phenotype (ResearchGate/J Med Genet).
  • No modifier genes have yet been formally established, though allelic strength (see §4) is itself the principal determinant of phenotype severity.

Risk Factors

  • Consanguinity increases risk of biallelic pathogenic combinations, particularly for the severe congenital-neuropathy phenotype.
  • No age, sex, lifestyle, or occupational risk factors are known (Mendelian recessive disease).

Protective Factors

  • Genetically, inheriting two mild/hypomorphic alleles (e.g., homozygous p.A371T) appears protective/asymptomatic — a genotype–phenotype threshold effect rather than a distinct "protective variant."
  • No environmental or lifestyle protective factors identified.

Gene-Environment Interactions

None established; this is considered a purely monogenic disorder with no reported environmental modifiers of penetrance or expressivity.

3. Phenotypes

Core Clinical Features (with suggested HPO terms)

Phenotype Frequency (from reviewed cohorts) Suggested HPO term
Global developmental delay / intellectual disability (severe–profound) ~95% HP:0001263 / HP:0001249
Axial hypotonia with appendicular hypertonia Majority HP:0008936 / HP:0002540
Dystonia / movement disorder 20/24 (83%) HP:0001332
Failure to thrive (despite adequate caloric intake) 75% HP:0001508
Seizures/epilepsy (infantile spasms most common) Majority; infantile spasms ~54% HP:0001250; infantile spasms HP:0011097
Microcephaly (often acquired/progressive) Common HP:0000252
Drug-resistant/refractory epilepsy Common HP:0011451
Visual impairment Reported HP:0000505
Delayed myelination on MRI ~100% of imaged cases HP:0012448
Thin/abnormal corpus callosum Common HP:0033725
Cerebellar/cerebral atrophy Common HP:0001272 / HP:0002059
White matter hyperintensities Common HP:0030890
Peripheral sensorimotor neuropathy (in neuropathy-predominant subtype) Subtype-specific HP:0007141
Gait/limb ataxia, dysarthria, nystagmus, cataracts (SCAR24 phenotype) SCAR24 subtype HP:0001288/HP:0001260/HP:0000639/HP:0000518

Phenotype Characteristics

  • Onset: Most cases present in early infancy — "refractory infantile spasms or myoclonus usually in the first weeks or months of life, up to about 12 months of age" (OMIM). The most severe reported genotype caused burst-suppression encephalopathy within hours of birth, with death at 16 days. Conversely, seizure onset was delayed to childhood in some patients, and the milder SCAR24 phenotype presents with ataxia onset at 5–8 years of age.
  • Severity: Highly variable, ranging from neonatal-lethal encephalopathy to milder ataxia-predominant disease with preserved cognition in adulthood — directly correlating with residual UFM1-activating enzymatic activity (allelic strength; see §4/§6).
  • Progression: Generally progressive for both the encephalopathy (worsening motor/cognitive trajectory, evolving MRI abnormalities — "imaging was normal in the first months of life but later showed abnormalities" in many patients) and the SCAR24 ataxia phenotype (one adult sibling lost ambulation by age 39).
  • Frequency among affected individuals: See table above; based on small aggregated cohorts (n≈24–25), so percentages should be interpreted cautiously.

Quality of Life Impact

Severely affected individuals experience profound lifelong disability: non-ambulation, minimal-to-absent verbal communication, inability to hold the head upright, and dependence on caregivers for all activities of daily living. Refractory dystonia/status dystonicus can be life-threatening and has required emergency deep brain stimulation (PMID:37130202). Failure to thrive despite adequate nutrition adds additional medical burden; the pituitary gland is notably the highest UBA5-expressing tissue in GTEx, raising a hypothesized but unconfirmed growth-hormone-axis contribution.

4. Genetic/Molecular Information

Causal Gene

  • UBA5 (OMIM *610552), chromosome 3q22.1, encodes an E1-like ubiquitin-activating enzyme (EC 6.2.1.45) that is the sole known activator of UFM1 (ubiquitin-fold modifier 1).

Pathogenic Variants

  • Gene: UBA5, HGNC:23230
  • Variant classification: Missense (majority — affecting the adenylation/catalytic domain), nonsense (e.g., p.Arg188*), frameshift, and rare intronic/splice variants, all loss-of-function to varying degrees.
  • Variant type/class and functional impact: Systematic biochemical and in vivo (humanized Drosophila) characterization of 13+ missense variants stratified them into four allelic-strength classes — Group IA/IB (mild hypomorphs; full or near-full lethality rescue in flies but progressive phenotypes), Group II (partial rescue; developmental delay, seizure-like behavior), and Group III (severe loss-of-function; failed rescue, insoluble/misfolded protein), plus Group IV null/frameshift alleles (eLife 89891). "There is a strong correlation between in vivo and in vitro phenotypes, establishing a classification of LoF variants into mild, intermediate, and severe allelic strengths."
  • Key recurrent variants:
  • p.Ala371Thr (c.1111G>A) — recurrent hypomorphic allele in ~65–70% of DEE44 alleles, always found in trans with a more severe variant in symptomatic individuals; homozygous in some asymptomatic adults; shows temperature-dependent loss of UFM1 transthiolation activity at 22°C but not 37°C in vitro.
  • p.Tyr53Phe (c.158A>T) (homozygous) — associated with the most severe reported phenotype (death from status epilepticus); E1 activity reduced to 3.4% and E2 (transthiolation) activity to 6.8% of wild type.
  • p.Arg11Trp (c.31C>T) (homozygous, founder in a consanguineous family) — fatal congenital neuropathy.
  • p.Cys303Arg, p.Leu254Pro — novel variants causing significant functional impairment, each identified in two unrelated families/sibships.
  • Catalytic residue: Cys250 forms the active-site thioester bond with UFM1's C-terminal glycine after ATP-dependent adenylation; the engineered enzyme-dead control p.Cys250Ala is used as a null reference in functional assays.
  • Allele frequency: p.A371T carrier frequency ~1/84 (Finnish) and ~1/200 (non-Finnish European) in population databases (gnomAD-derived), consistent with a founder/recurrent hypomorphic allele rather than a fully deleterious one.
  • Somatic vs. germline: Exclusively germline; no somatic mosaicism reported.
  • Functional consequence: Loss of function (partial to near-complete) of UBA5's E1-activating enzymatic activity — reduced ATP binding, reduced UFM1 adenylation, reduced thioester (transthiolation) formation, and/or reduced protein stability/solubility, depending on variant location (buried structural residues → misfolding/insolubility; ATP-pocket residues → reduced catalysis without stability loss).

Modifier Genes

None formally established; allelic strength of the two UBA5 alleles themselves is the principal known modifier of phenotype.

Epigenetic Information

Not established for this disease specifically (UFMylation itself is increasingly recognized as intersecting broadly with chromatin/DNA-damage-response biology, but disease-specific epigenetic data are not reported).

Chromosomal Abnormalities

None reported; this is a single-gene point-mutation/small-indel disorder, not a copy-number or structural chromosomal condition.

5. Environmental Information

No environmental toxins, occupational exposures, lifestyle factors, or infectious triggers have been implicated in UBA5-DEE44 — it is a purely monogenic disease. No infectious agents are associated.

6. Mechanism / Pathophysiology

Molecular Pathway: UFMylation Cascade

UBA5 is the E1-activating enzyme of UFMylation, a ubiquitin-like post-translational modification (PTM) system parallel to but distinct from canonical ubiquitination. The cascade proceeds:

UBA5 (E1) → UFC1 (E2, UFM1-conjugating enzyme) → UFL1/UFBP1/CDK5RAP3 (E3 ligase complex) → substrate conjugation with UFM1

Mechanistically, UBA5 forms a homodimer that enables a trans-binding mechanism: UFM1 binds one subunit while the active site resides in the partner subunit. UBA5 first adenylates the C-terminal glycine of UFM1 (ATP-dependent), then forms a thioester bond via active-site Cys250, and finally transfers activated UFM1 to UFC1 (transthiolation) (BRENDA EC 6.2.1.45; PMC5428781).

Causal Chain (Trigger → Manifestation)

  1. Biallelic UBA5 hypomorphic/null variants → reduced UBA5 protein stability, ATP binding, or catalytic (adenylation/thioester) activity
  2. → Reduced global UFMylation flux (reduced UBA5–UFM1 and downstream substrate–UFM1 conjugates; zebrafish models show Ufm1-conjugates reduced to ~30% of wild type)
  3. → Perturbed endoplasmic reticulum (ER) homeostasis and exacerbated unfolded protein response (UPR) — elevated phospho-PERK and phospho-eIF2α, increased nuclear ATF6 translocation and CHOP expression, decreased IRE1α stability and reduced spliced XBP1, ER expansion (calnexin staining), and increased PARP cleavage (apoptosis) in patient-derived organoid/cell models (Science Translational Medicine 2024/2025, PMID:38328212 preprint / PMID:40333994 published)
  4. → Mitochondrial dysfunction: widespread mitochondrial pathology (abnormal cristae, vacuolated/"onion-ring" degenerating mitochondria, elevated full-length PINK1 indicating mitophagy activation) in zebrafish CNS, PNS, and skeletal muscle (Brain Communications 2023, PMC10691876)
  5. → Neurodevelopmental disruption, most strikingly a severe GABAergic interneuron deficit in patient-derived cortical organoids (~15% GABAergic interneuron population vs. ~40% in controls, with reduced GAD1/GAD2/CALB2/SCGN expression) and microcephaly (patient organoids ~25% smaller than controls)
  6. → Aberrant network electrophysiology: increased weighted mean firing rate and burst frequency, but paradoxically decreased network burst frequency, indicating impaired coordinated neuronal activity → clinical epileptogenesis and encephalopathy
  7. → Downstream peripheral neurodegeneration (axonal/mitochondrial pathology in peripheral nerves) explains the neuropathy-predominant phenotypic pole, while cerebellar Purkinje/neuronal degeneration explains the ataxia-predominant pole (SCAR24)

Cell Types and Biological Processes Involved

  • GABAergic interneurons (loss/reduced differentiation) — candidate CL term: CL:0000617 (GABAergic neuron)
  • Cortical excitatory neurons (aberrant firing)
  • Cerebellar neurons/Purkinje cells (degeneration in SCAR24-type phenotype and in zebrafish cerebellar pathology at 14 dpf)
  • Peripheral sensorimotor neurons (axonal degeneration in neuropathy-predominant phenotype)
  • Skeletal muscle (mitochondrial pathology in zebrafish)
  • Suggested GO terms: GO:0071569 (protein UFmylation), GO:0006986 (response to unfolded protein / UPR), GO:0034976 (response to ER stress), GO:0007005 (mitochondrion organization), GO:0000422 (mitophagy)

Protein Dysfunction

Depending on variant location: loss of catalytic (adenylation/thioester) function at the active site, loss of ATP-binding capacity, or structural misfolding/insolubility for variants affecting buried hydrophobic residues (e.g., Gly168, Cys303) — demonstrated via thermal shift assays and purification studies in the eLife allelic-series paper.

Advanced/Omics Technologies Applied

  • Patient-derived iPSC-cortical organoids with single-cell/marker-based transcriptomic characterization (GABAergic marker panel) and multi-electrode-array electrophysiology
  • CRISPR-engineered isogenic cell lines (U-87 MG) modeling specific compound-heterozygous genotypes (UBA5^A371T/R55H, UBA5^A371T/F292*)
  • CRISPRa (dCas9-VP64-p65-Rta) gene-activation and SINEUP synthetic lncRNA approaches to therapeutically upregulate UBA5 translation

7. Anatomical Structures Affected

  • Organ level (primary): Central nervous system (brain — cortex, cerebellum, white matter, corpus callosum, thalami, hippocampus); in a subset of patients, the peripheral nervous system (peripheral nerves)
  • Secondary/systemic: Growth failure/failure to thrive (possible pituitary/growth-hormone axis involvement, speculative); in SCAR24, eyes (cataracts) are also affected
  • Body systems: Nervous system (primary); endocrine/growth axis (secondary, unconfirmed mechanism); musculoskeletal (secondary to hypertonia/dystonia)
  • Tissue/cell level: Cerebral cortical neurons and GABAergic interneurons; cerebellar neurons; peripheral sensorimotor axons; skeletal muscle (mitochondrial pathology in models)
  • Subcellular level: Endoplasmic reticulum (UPR activation, ER expansion), mitochondria (structural/functional pathology, mitophagy activation) — candidate GO Cellular Component terms: GO:0005783 (endoplasmic reticulum), GO:0005739 (mitochondrion)
  • Localization (UBERON): UBERON:0000955 (brain), UBERON:0002037 (cerebellum), UBERON:0002336 (corpus callosum white matter), UBERON:0001017 (central nervous system), UBERON:0000010 (peripheral nervous system)
  • Laterality: Bilateral/diffuse — not a lateralized process

8. Temporal Development

  • Onset: Typically neonatal-to-early-infantile (first weeks to ~12 months) for DEE44; childhood (5–8 years) for the SCAR24 ataxia phenotype; congenital (in utero, reduced fetal movements) for the severe neuropathy phenotype.
  • Onset pattern: Acute-to-subacute for the most severe neonatal encephalopathy (burst suppression within hours of birth in the most severe case); insidious/progressive for ataxia and developmental phenotypes.
  • Progression: Generally progressive — worsening motor/developmental trajectory, evolving neuroimaging abnormalities (many patients have normal early imaging that becomes abnormal over time), and in SCAR24, progressive loss of ambulation over decades (one sibling lost independent ambulation at age 39).
  • Disease course pattern: Chronic-progressive rather than relapsing-remitting; punctuated by episodes of status epilepticus or status dystonicus that can themselves be acutely life-threatening.
  • Disease duration: Chronic, lifelong in survivors; the most severe genotypes are neonatally or infantile lethal (e.g., death at 16 days in one report; the congenital neuropathy phenotype causes "early death in infancy" in a consanguineous family).
  • Critical periods: Early infancy appears to be a critical window for both diagnosis (before irreversible neurodevelopmental injury) and, per model-system data, for potential UBA5-upregulation therapeutics (organoid electrophysiology correction was only transient, suggesting narrow/ongoing dosing windows may matter).

9. Inheritance and Population

  • Epidemiology: Ultra-rare — approximately 24–25 individuals from ~17–19 families reported in the literature as of the most recent comprehensive reviews (2021 review; 2023 eLife series). True population prevalence/incidence is not established (likely underdiagnosed given phenotypic overlap with other genetic epilepsies/encephalopathies).
  • Inheritance pattern: Autosomal recessive.
  • Penetrance: Complete for the disease-causing genotype combinations reported, but with a documented threshold effect — biallelic combinations of very mild hypomorphic alleles (e.g., homozygous p.A371T) are reported as asymptomatic in population databases, indicating incomplete penetrance is possible for the mildest allelic combinations depending on residual enzymatic activity.
  • Expressivity: Highly variable — spanning fatal neonatal encephalopathy/congenital neuropathy to adult-onset ataxia with normal cognition, driven largely by the combined "allelic strength" of the two inherited variants.
  • Genetic anticipation: Not reported/not applicable (not a repeat-expansion disorder).
  • Germline mosaicism: Not specifically documented in the literature reviewed.
  • Founder effects: p.Ala371Thr shows an elevated carrier frequency consistent with a founder/recurrent allele in Finnish (1/84) and other European (1/200) populations; p.Arg11Trp is a founder variant in a specific consanguineous family lineage.
  • Consanguinity: A recognized contributor, particularly for the homozygous severe congenital-neuropathy phenotype (large consanguineous multigenerational family reported).
  • Carrier frequency: See p.A371T figures above; overall UBA5 pathogenic-variant carrier frequency in the general population is not separately quantified.
  • Population demographics: Reported cases span diverse ancestries; SCAR24 was first reported in Chinese siblings; DEE44 cases span European, Finnish, and other backgrounds. No clear geographic endemicity beyond the Finnish/European founder-allele signal.
  • Sex ratio: No sex predilection reported (autosomal recessive).
  • Age distribution: Reported individuals span neonates to adults in their late 30s (the oldest reported SCAR24 patient).

10. Diagnostics

Clinical/Laboratory Tests

  • No specific disease biomarker exists; diagnosis relies on genetic confirmation in the context of a compatible clinical/EEG/MRI phenotype.
  • EEG: Near-universal abnormality — spikes/polyspikes with background slowing and disorganization; hypsarrhythmia in infantile-spasms presentations; burst suppression in the most severe neonatal cases.
  • Brain MRI: Delayed myelination, thin/dysmorphic corpus callosum, cerebral/cerebellar atrophy, white matter hyperintensities, diminutive thalami, abnormal hippocampal orientation, and altered U-fiber pattern; often normal in early infancy with abnormalities emerging over time — serial imaging is informative.
  • Nerve conduction studies/EMG: Relevant in the neuropathy-predominant phenotype to document severe sensorimotor peripheral neuropathy.

Genetic Testing

  • Whole exome sequencing (WES) or whole genome sequencing (WGS) is the primary diagnostic approach given the phenotypic overlap of DEE44 with dozens of other genetic developmental and epileptic encephalopathies; UBA5 is included on epilepsy/DEE gene panels.
  • Targeted gene panels for early infantile epileptic encephalopathy / developmental and epileptic encephalopathy routinely include UBA5.
  • Single-gene/Sanger confirmation of variants identified by panel/exome sequencing, and segregation testing in parents to confirm compound heterozygosity (trans configuration).
  • Functional/biochemical variant classification (as developed in the eLife allelic-series study) is emerging as a research-grade tool to help interpret novel missense VUS by comparison to characterized allelic-strength groups.

Clinical Diagnostic Criteria

No formal consensus diagnostic criteria exist (ultra-rare disease); diagnosis is genotype-driven (biallelic UBA5 pathogenic/likely pathogenic variants) combined with compatible phenotype per OMIM clinical synopsis and case-series-derived phenotype descriptions.

Differential Diagnosis

Other genetic developmental and epileptic encephalopathies (e.g., CDKL5 deficiency disorder, STXBP1-DEE, other early infantile epileptic encephalopathies), other UFMylation-pathway disorders (UFM1, UFC1, UFSP2, UFBP1/DDRGK1, CDK5RAP3 — all now linked to overlapping hypomyelinating leukodystrophy/encephalopathy phenotypes), and other causes of hypotonia/failure-to-thrive with epilepsy.

Screening

No population-based newborn or carrier screening program specifically targets UBA5 given its rarity; carrier screening could theoretically be offered in populations with elevated p.A371T-type founder frequencies, but this is not standard practice.

11. Outcome/Prognosis

  • Survival/mortality: Ranges from neonatal/infantile death (most severe genotypes — e.g., death at 16 days from a homozygous severely hypomorphic variant; early infant death in the fatal congenital neuropathy family) to survival into adulthood with milder genotypes (SCAR24 patients surviving into their 30s–40s with progressive but non-lethal disease course).
  • Morbidity/function: Severely affected individuals have profound, lifelong intellectual disability, non-ambulation, and dependence on caregivers; refractory epilepsy and dystonia (including life-threatening status dystonicus) are major sources of morbidity.
  • Complications: Status epilepticus (a reported cause of death), status dystonicus requiring emergency intervention, failure to thrive/malnutrition, aspiration risk from severe motor impairment.
  • Recovery potential: No cure exists; supportive/symptomatic management is the current standard. Investigational UBA5-upregulation approaches (see below) show preclinical proof-of-concept for partial phenotype correction.
  • Prognostic factors: Genotype (allelic strength of both variants) is the dominant known prognostic determinant — severe/severe or severe/null combinations are neonatally lethal or profoundly disabling, while mild/mild combinations may be asymptomatic-to-mildly affected (SCAR24-type or subclinical).

12. Treatment

There is no disease-modifying or curative therapy; management is entirely supportive/symptomatic.

Pharmacotherapy

  • Antiepileptic drugs (AEDs): Multiple AEDs are typically required given drug-resistant seizures; specific agent selection is individualized and not standardized for this ultra-rare disease. NCIT term: NCIT:C15632/NCIT:C15986 categories apply generically (Pharmacotherapy/anticonvulsant therapy).
  • Levodopa: Reported to provide "moderate improvement" in the movement disorder for at least one patient.
  • Prophylactic antiepileptic treatment: Used in some patients based on EEG abnormalities even before clinical seizures manifest.

Advanced/Interventional

  • Deep brain stimulation (globus pallidus internus, GPi-DBS): Used for medically refractory dystonia/status dystonicus in UBA5-related disorder, with one report describing "dramatic improvement in dystonia" and a dedicated case report of DBS for medically refractory status dystonicus (PMID:37130202, Movement Disorders 2023). NCIT candidate term: device/procedural intervention (DBS has no precise NCIT clinical-action term identified; would require DEVICE modality classification).

Dietary/Supportive

  • Ketogenic diet: A generic option for drug-resistant epilepsy broadly (not UBA5-specific evidence identified, but plausible extrapolated management given refractory-epilepsy phenotype); NCIT:C15447 (Dietary Intervention).
  • Nutritional support for failure to thrive (feeding tube support commonly needed in severe developmental and epileptic encephalopathies generally).
  • Physical, occupational, and speech therapy: Standard supportive rehabilitative care (NCIT:C15302 Physical Therapy; NCIT:C15315 Rehabilitation).

Experimental/Investigational

No registered UBA5-specific clinical trials were identified (ClinicalTrials.gov search did not surface an active interventional trial). Preclinical therapeutic strategies under active research development, targeting the core mechanism (increasing residual UBA5 protein/activity), include: - SINEUP synthetic long non-coding RNA — increased UBA5 translation ~1.5-fold in patient organoids, transiently normalizing aberrant electrophysiology (effect lasted 2–4 days) (Science Translational Medicine, PMID:40333994) - CRISPRa (dCas9-VP64-p65-Rta) gene activation — achieved ~2-fold UBA5 protein increase, restoring ER-homeostasis/UPR markers - Rationale: because the common p.A371T hypomorphic allele is compatible with an asymptomatic state when both alleles are equally mild, modest (not excessive — overexpression is itself detrimental) upregulation of UBA5 expression is hypothesized as a therapeutic strategy for patients carrying at least one A371T-class allele.

Treatment Outcomes

Given the small numbers, no systematic response-rate or adverse-event data exist beyond individual case reports; drug-resistant epilepsy is the norm, and DBS/levodopa responses are anecdotal.

Treatment Strategy

No formal treatment algorithm exists; management follows general refractory-DEE/movement-disorder principles (stepwise AED trials → ketogenic diet consideration → DBS for refractory dystonia) individualized by clinical team, informed by emerging genotype-function data as a potential future guide to prognosis counseling.

13. Prevention

  • Primary prevention: Not applicable in the traditional sense (monogenic recessive disease); genetic/carrier counseling for at-risk families (especially those with known founder alleles or consanguinity) is the main preventive lever, alongside prenatal diagnosis or preimplantation genetic testing (PGT) for families with a previously affected child and known biallelic variants.
  • Secondary prevention: Early genetic diagnosis via WES/WGS in infants presenting with unexplained early-onset encephalopathy/refractory seizures allows earlier supportive intervention (though no disease-modifying treatment currently changes the trajectory).
  • Tertiary prevention: Aggressive seizure and dystonia management (including DBS) to reduce morbidity/mortality from status epilepticus or status dystonicus; nutritional support to prevent complications of failure to thrive.
  • Genetic counseling: Recommended for parents of an affected child (25% recurrence risk per pregnancy) and for extended family members in consanguineous or founder-allele-enriched populations (NCIT:C15240 Genetic Counseling).
  • Carrier screening: Not part of standard population carrier screening panels currently, but could be considered in populations with elevated p.A371T carrier frequency (e.g., Finnish population) as awareness grows.

14. Other Species / Natural Disease

  • No spontaneously occurring UBA5-related disease has been reported in domestic animals, companion animals, or wildlife (OMIA search did not surface a natural veterinary UBA5 disease). This section is not applicable beyond engineered laboratory models (see §15).
  • Orthologous gene: UBA5 orthologs are highly conserved; the Drosophila melanogaster ortholog (Uba5) shares 64% amino acid identity / 75% similarity with human UBA5, sufficient for successful "humanization" (replacement with human UBA5 cDNA) in fly disease models.

15. Model Organisms

Mouse

  • Germline Uba5 knockout mice are embryonic lethal at E12.5, caused by hematopoietic defects — this precludes direct study of the neurological phenotype and demonstrates that complete loss of UBA5 function is incompatible with development, consistent with the human observation that all reported patients carry at least one partial-function (hypomorphic) allele (MGI:1913913).
  • Conditional/hypomorphic mouse alleles that better model human disease were not identified as established in the sources reviewed here — this is a noted gap (relevant to a HUMAN_MODEL_MISMATCH framing: the null mouse model fails to recapitulate the human neurological phenotype and instead demonstrates a distinct hematopoietic-lethal mechanism).

Zebrafish (the leading in vivo model)

  • Two independent CRISPR-Cas9-engineered uba5 mutant zebrafish lines: uba5ex1s (exon 1 nonsense/frameshift, p.E5Ffs1, truncated non-functional protein) and uba5ex3d* (exon 3 in-frame deletion of the ATP-binding domain, p.A73_V80del) (Brain Communications 2023, PMC10691876).
  • Phenotype recapitulation (RECAPITULATES): 41–45% reduced swimming distance at 6 dpf; 40–50% reduced body length from 14 dpf; severely reduced survival (only 4% surviving past 39 dpf, max lifespan 70 dpf) — closely mirroring human motor impairment, growth failure, and reduced life expectancy.
  • CNS findings: cerebellar neuronal degeneration at 14 dpf (abnormal membranous swirls, degenerating mitochondria); no gross brain/cerebellar volume change at 6 dpf.
  • PNS findings: peripheral nerve abnormalities at 6 dpf (autophagic structures, large vesicles, elongated/degenerating mitochondria in nerve terminals) — directly modeling the human neuropathy-predominant phenotypic pole.
  • Mitochondrial pathology: widespread abnormal cristae, vacuolated/"onion-ring" mitochondria, elevated full-length PINK1 (mitophagy activation), and reduced Ufm1-conjugates to ~30% of wild type — providing the strongest evidence to date for mitochondrial dysfunction as a downstream consequence of UFMylation loss.
  • Applications: motor function assays (high-throughput swimming/locomotor tracking), survival/lifespan assays, ultrastructural (EM) study of CNS/PNS/muscle mitochondrial pathology, and validation of variant pathogenicity.

Drosophila melanogaster

  • "Humanized" fly models expressing human UBA5 variants under the control of the endogenous Uba5 promoter (replacing/complementing the fly ortholog, 64% identity/75% similarity to human) were used to systematically test 13+ patient missense variants plus synthetic controls (e.g., enzyme-dead p.Cys250Ala) across viability, developmental timing, lifespan, locomotor activity, and bang-sensitivity (seizure-like) assays (eLife 89891).
  • Variants stratified into Groups IA/IB/II/III/IV by degree of phenotype rescue, which strongly correlated with in vitro biochemical severity (thermal stability, ATP binding, UbiReal fluorescence-polarization transthiolation assays) — establishing the fly platform as a validated variant-classification tool bridging genotype to phenotype severity, directly informative for VUS interpretation in newly identified patients.
  • Clinical correlation: 21/25 analyzed affected individuals carried one Group IA/IB (mild) allele in trans with one Group III/IV (severe) allele, mechanistically explaining why "mild + severe" combinations are viable and symptomatic while "severe + severe" combinations are presumed embryonic/perinatally lethal (paralleling the mouse null-lethality finding).

Patient-Derived Cellular/Organoid Models

  • iPSC-derived cortical organoids from two probands (compound heterozygous UBA5 variants) plus isogenic parental controls, and CRISPR-engineered U-87 MG glioma cell lines carrying specific patient genotypes (UBA5^A371T/R55H; UBA5^A371T/F292*) and a benign control (UBA5^A371T/A371T homozygous) (Science Translational Medicine, PMID:40333994; preprint PMID:38328212).
  • Fidelity: High construct validity for modeling human-specific neurodevelopmental features (GABAergic interneuron specification, cortical organoid electrophysiology) not accessible in mouse/fish; RECAPITULATES microcephaly (~25% organoid size reduction), GABAergic interneuron deficit (~15% vs ~40% in controls), ER stress/UPR activation, and network-level electrophysiological abnormality.
  • Limitations: Organoids model early corticogenesis and lack mature circuit-level, in vivo behavioral correlates (seizures, motor phenotype); therapeutic rescue (SINEUP) was only transient (2–4 days), an unresolved translational gap.
  • Research applications: Mechanistic dissection of ER/UPR and GABAergic-lineage pathology; platform for testing UBA5-upregulation therapeutic strategies (SINEUP RNA, CRISPRa) prior to any in vivo/clinical translation.

Summary Table: Key Evidence Citations

Claim PMID / Source
First disease description (2016) Colin et al. AJHG 99(3):695-703; Muona et al. AJHG 99(3):683-694 (PMID:27545675 region); Duan et al. 2016 (SCAR24)
Compound heterozygous mutations, two sisters PMID:28965491
Novel variants / phenotypic spectrum review (24 individuals, 19 families) PMC8208045
OMIM DEE44 clinical synopsis OMIM #617132
OMIM SCAR24 OMIM #617133
Allelic strength classification, Drosophila + biochemistry eLife 89891 / PMC10371176
Zebrafish model, mitochondrial abnormalities Brain Communications, PMC10691876
Patient-derived organoid model & therapeutic strategies Science Translational Medicine, PMID:40333994; preprint PMID:38328212
Fatal congenital neuropathy, p.Arg11Trp J Med Genet, ResearchGate summary
DBS for status dystonicus PMID:37130202
Case report, compound heterozygous DEE44 PMC11960287 / PMID:40217280

Note on gaps: No formal GeneReviews chapter, no MONDO ID, and no large systematic natural-history study (>25 patients) were identified in this search — these represent genuine literature gaps rather than omissions, consistent with UBA5-DEE44's status as an ultra-rare, recently-described (2016) condition. No active registered clinical trial was found. Mouse knockout data reflect a HUMAN_MODEL_MISMATCH-type limitation (embryonic lethality via a hematopoietic, not neurological, mechanism) rather than a validated CNS/PNS disease model, in contrast to the zebrafish and Drosophila platforms.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 12
Resolved 12
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 1
Quoted claims found in source 0
Quoted claims not found in source 1
References weighed for topical relevance 12
On topic 9
Off topic 0

Quotes not found in the cited source

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

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

  • PMC:PMC8208045 (abstract only): "the first gene from the ufmylation pathway... linked to disease"
  • closest text in source: "Early infantile epileptic encephalopathy-44 (EIEE44, MIM: 617132) is a previously described condition resulting from biallelic variants in UBA5, a gene involved in a ubiquitin-like post-translational modification system called UFMylation"