UGDH-related developmental and epileptic encephalopathy 84

Mendelian MONDO:0032918 Pathograph 17 Show in embeddings browser genetic developmental and epileptic encephalopathy congenital disorder of glycosylation

UGDH-related developmental and epileptic encephalopathy 84 is an autosomal recessive glycan-precursor disorder caused by biallelic loss-of-function variants in UGDH, which encodes UDP-glucose 6-dehydrogenase. Reduced UGDH activity limits conversion of UDP-glucose to UDP-glucuronic acid, decreasing the glucuronic-acid precursor pool needed for glycosaminoglycan, proteoglycan, and glycolipid production. The downstream disease is dominated by developmental and epileptic encephalopathy, hypotonia, motor disorder, developmental delay, intellectual disability, and variable brain growth or myelination abnormalities.

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1
Inheritance
5
Pathophys.
15
Phenotypes
2
Gaps
17
Pathograph
1
Genes
2
Medical Actions
3
Models
1
References
🏷

Classifications

ICIMD (Inherited Metabolic Disorders)
o linked protein glycosylation
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Affected individuals have biallelic germline UGDH variants consistent with autosomal recessive inheritance.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:32001716 SUPPORT Human Clinical
"Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia."
The cohort directly establishes recessive UGDH mutations as the disease cause.
?

Discussions and Knowledge Gaps

2
How do reduced glycosaminoglycan synthesis and impaired neural-progenitor proliferation produce the human epilepsy and developmental phenotype?
KNOWLEDGE GAP OPEN gap_ugdh_cellular_mechanism_to_human_dee
Attached to
pathophysiology#Reduced hyaluronic acid synthesis pathophysiology#Reduced neural progenitor proliferation pathophysiology#UGDH-Related Neurodevelopmental and Epileptic Dysfunction
Patient cells and organoids establish biochemical and developmental effects, but the study does not demonstrate a causal chain from either cellular result to seizures or the individual human phenotypes.
Show evidence (1 reference)
PMID:32001716 SUPPORT In Vitro
"while UGDH is not required for proper function of isolated neurons in culture, its absence significantly affects neuronal differentiation in cerebral organoids"
The contrasting model results define the remaining mechanistic gap.
Why does zygotic ugdh depletion fail to reproduce the human neurologic phenotype while patient-derived human organoids show impaired progenitor proliferation?
HUMAN MODEL MISMATCH OPEN mismatch_ugdh_zebrafish_and_human_organoid
Attached to
pathophysiology#Reduced neural progenitor proliferation
Species, developmental timing, and allele context may alter the dependence of neural development on UGDH.
Show evidence (1 reference)
PMID:32001716 SUPPORT Model Organism
"While mutant ugdh zebrafish did not phenocopy the disease, we bring evidence that patient-derived cerebral organoids"
The paper explicitly contrasts the negative animal model with the human organoid model.
⚙

Pathophysiology

5
UGDH loss of function
Pathogenic biallelic UGDH variants reduce the stability, oligomerization, or catalytic activity of UDP-glucose 6-dehydrogenase.
UGDH hgnc:12525 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves UGDH (hgnc:12525). hgnc:12525 is a gene from the HUGO Gene Nomenclature Committee.
UDP-glucose 6-dehydrogenase activity GO:0003979 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased UDP-glucose 6-dehydrogenase activity (GO:0003979). GO:0003979 is a molecular function from the Gene Ontology. ↓ DECREASED
Experimental models
Patient-derived primary dermal fibroblasts PRIMARY CELL CULTURE Patient cells measure endogenous protein abundance and enzymatic activity.
Animal models
jekyll ugdh hypomorphic zebrafish Danio rerio perturbs The hypomorphic allele perturbs zygotic Ugdh activity but does not satisfactorily reproduce the human neurologic syndrome.
Downstream
UDP-glucuronic acid precursor depletion Reduced UGDH activity decreases production of UDP-glucuronic acid from UDP-glucose.
Reduced neural progenitor proliferation Patient-derived cerebral organoids show impaired proliferation of neural progenitors downstream of reduced UGDH activity.
Show evidence (1 reference)
PMID:32001716 SUPPORT In Vitro
"Consistent with being loss-of-function alleles, we show using patients' primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity."
Patient-cell and biochemical assays support reduced UGDH function as the proximal molecular defect.
UDP-glucuronic acid precursor depletion
UDP-glucuronic acid shortage impairs production of glycosaminoglycan-rich extracellular matrix components, including proteoglycans and glycolipids that are important in human brain development.
glycosaminoglycan biosynthetic process GO:0006024 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased glycosaminoglycan biosynthetic process (GO:0006024). GO:0006024 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Reduced hyaluronic acid synthesis UDP-glucuronic acid depletion reduces synthesis of hyaluronic acid in patient fibroblasts.
Show evidence (1 reference)
PMID:32001716 SUPPORT In Vitro
"Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development."
This supports the precursor-to-ECM branch of the pathograph.
Reduced hyaluronic acid synthesis
Patient fibroblasts carrying homozygous UGDH A82T produce less hyaluronic acid, a direct glycosaminoglycan readout of UDP-glucuronate shortage.
hyaluronan biosynthetic process GO:0030213 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased hyaluronan biosynthetic process (GO:0030213). GO:0030213 is a biological process from the Gene Ontology. ↓ DECREASED
Experimental models
Patient-derived primary dermal fibroblasts PRIMARY CELL CULTURE HA in conditioned media provides a direct UGDH-dependent glycosaminoglycan readout.
Show evidence (1 reference)
PMID:32001716 SUPPORT In Vitro
"Patient’s cells with the homozygous A82T mutation also exhibited a reduction in the synthesis of hyaluronic acid (HA)"
Patient fibroblasts provide a direct glycosaminoglycan readout.
Reduced neural progenitor proliferation
Patient-derived cerebral organoids are smaller and contain less proliferative SOX2-positive neural progenitor zones, while differentiated neuron and astrocyte markers are not comparably reduced.
neural stem cell CL:0000047 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neural stem cell (CL:0000047). CL:0000047 is a cell type from the Cell Ontology.
neural precursor cell proliferation GO:0061351 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased neural precursor cell proliferation (GO:0061351). GO:0061351 is a biological process from the Gene Ontology. ↓ DECREASED
Experimental models
Patient-derived cerebral organoids ORGANOID Mutant organoids are smaller and contain less proliferative SOX2-positive progenitor zones.
Downstream
UGDH-Related Neurodevelopmental and Epileptic Dysfunction Impaired progenitor proliferation is associated with the human neurodevelopmental and epileptic syndrome through unresolved tissue- and circuit-level intermediates.
Show evidence (1 reference)
PMID:32001716 SUPPORT In Vitro
"These results argue that reduced UGDH activity is associated with impaired neuronal development in vitro, causing atrophy of patient-derived cerebral organoids."
Patient-derived organoids support a neural-progenitor developmental mechanism.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for UGDH-related developmental and epileptic encephalopathy 84 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

15
Digestive 1
Dysphagia VERY_FREQUENT HP:0002015 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysphagia (HP:0002015). HP:0002015 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32001716 SUPPORT Human Clinical
"Twenty-four out of the 30 (80%) were noted to have swallowing difficulties and gastrostomy tubes were required for feeding in 12 infants."
Swallowing difficulties in 24/30 patients equals 80%, which falls in the VERY_FREQUENT frequency band.
Head and Neck 1
Mild facial dysmorphism Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32001716 SUPPORT Human Clinical
"Dysmorphic facial features such as short and flattened philtrum, outward protruding earlobes, ptosis, or blepharophimosis were mild but frequently present"
The cohort describes the recurrent mild facial gestalt.
Musculoskeletal 2
Hypotonia OBLIGATE HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32001716 SUPPORT Human Clinical
"All patients had a severe motor disorder with axial hypotonia."
The cohort directly reports axial hypotonia in all patients.
Spasticity FREQUENT HP:0001257 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spasticity (HP:0001257). HP:0001257 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32001716 SUPPORT Human Clinical
"some patients presented with limb spasticity (43%), dystonia (17%), ataxia, chorea, and tremor"
The reported 43% maps to FREQUENT.
Nervous System 9
Global developmental delay OBLIGATE HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32001716 SUPPORT Human Clinical
"All 30 patients carrying biallelic mutations in UGDH presented with a common core phenotype consisting of marked developmental delay, epilepsy, mild dysmorphism, and motor disorder with axial hypotonia"
The cohort directly reports marked developmental delay in all 30 patients.
Intellectual disability OBLIGATE 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:32001716 SUPPORT Human Clinical
"A moderate to severe intellectual disability was observed in all patients."
The cohort reports intellectual disability in all patients, supporting the OBLIGATE frequency band for that cohort.
Epilepsy VERY_FREQUENT Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epilepsy, annotated with Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32001716 SUPPORT Human Clinical
"Most patients have severe epilepsy ranging from neonatal onset developmental epileptic encephalopathy to infantile developmental epileptic encephalopathy (27 patients, 90%)"
Epilepsy in 27/30 equals 90%, within the VERY_FREQUENT band.
Dystonia OCCASIONAL HP:0001332 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dystonia (HP:0001332). HP:0001332 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32001716 SUPPORT Human Clinical
"some patients presented with limb spasticity (43%), dystonia (17%), ataxia, chorea, and tremor"
The reported 17% maps to OCCASIONAL.
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:32001716 SUPPORT Human Clinical
"MRI revealed a spectrum of abnormalities with delayed myelination and enlarged ventricles probably due to cerebral and cerebellar atrophy"
MRI directly documents variable delayed myelination.
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:32001716 SUPPORT Human Clinical
"MRI revealed a spectrum of abnormalities with delayed myelination and enlarged ventricles probably due to cerebral and cerebellar atrophy"
Imaging supports cerebral and cerebellar atrophy in the severe subgroup.
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:32001716 SUPPORT Human Clinical
"MRI revealed a spectrum of abnormalities with delayed myelination and enlarged ventricles probably due to cerebral and cerebellar atrophy"
Imaging explicitly documents cerebellar as well as cerebral atrophy.
Profound motor delay VERY_FREQUENT HP:0001270 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Motor delay (HP:0001270). HP:0001270 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32001716 SUPPORT Human Clinical
"None but two patients (F5-II:1 and II:2) achieved sitting ability."
Failure to achieve sitting in 28/30 (93%) supports VERY_FREQUENT profound motor delay.
Ventriculomegaly HP:0002119 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventriculomegaly (HP:0002119). HP:0002119 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32001716 SUPPORT Human Clinical
"MRI revealed a spectrum of abnormalities with delayed myelination and enlarged ventricles probably due to cerebral and cerebellar atrophy"
The imaging series directly reports enlarged ventricles.
Other 2
Developmental and epileptic encephalopathy HP:0200134 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epileptic encephalopathy (HP:0200134). HP:0200134 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32001716 SUPPORT Human Clinical
"presenting with epileptic encephalopathy with developmental delay and hypotonia."
The cohort directly reports epileptic encephalopathy.
Infantile spasms FREQUENT HP:0012469 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Infantile spasms (HP:0012469). HP:0012469 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32001716 SUPPORT Human Clinical
"Most patients have severe epilepsy ranging from neonatal onset developmental epileptic encephalopathy to infantile developmental epileptic encephalopathy (27 patients, 90%), of which 16 (53%) had infantile spasms"
Infantile spasms were reported in 16 patients, 53% of the cohort, which falls in the FREQUENT frequency band.
🧬

Genetic Associations

1
UGDH (Biallelic loss-of-function variants)
Gene: UGDH hgnc:12525 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is UGDH (hgnc:12525). hgnc:12525 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:32001716 SUPPORT Human Clinical
"Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia."
The cohort establishes UGDH as the causal gene for DEE84.
💊

Medical Actions

2
Symptomatic antiseizure therapy
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
Most severe cases were refractory to antiseizure treatment. Two milder fever-associated seizure cases were seizure-free on sodium valproate, and one other patient appeared to benefit from ketogenic diet; these observations do not establish a generally effective disease-specific treatment.
Target Phenotypes: Epilepsy HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Epilepsy, annotated with Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32001716 SUPPORT Human Clinical
"Only these two patients were seizure-free on sodium valproate. All other patients, except for one patient who seemed to benefit from ketogenic diet, did not respond to antiepileptic treatment."
The cohort documents limited individual responses and predominant refractoriness.
Gastrostomy feeding support
Action: Gastrostomy tube procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Gastrostomy tube procedure (NCIT:C157864). NCIT:C157864 is a clinical intervention from the NCI Thesaurus. Ontology label: Gastrostomy Tube Procedure NCIT:C157864
Gastrostomy was used for feeding in 12 infants with swallowing difficulties; treatment efficacy was not evaluated.
Target Phenotypes: Dysphagia HP:0002015 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Dysphagia (HP:0002015). HP:0002015 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32001716 SUPPORT Human Clinical
"Twenty-four out of the 30 (80%) were noted to have swallowing difficulties and gastrostomy tubes were required for feeding in 12 infants."
The cohort directly documents use of gastrostomy feeding support.
🔬

Diagnosis

3
Molecular genetic testing
Exome sequencing with segregation analysis identifies biallelic UGDH variants after exclusion of known neurologic-disease genes.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Results: Biallelic rare UGDH variants segregating with disease support DEE84.
Show evidence (2 references)
PMID:32001716 SUPPORT Human Clinical
"we performed exome sequencing on two affected siblings. No mutations in genes known to be associated with neurological disorders"
Exome sequencing initiated the causal-gene discovery workflow.
PMID:32001716 SUPPORT Human Clinical
"only one missense variant c.244G > A in the UGDH gene was found to segregate with the disease"
Familial segregation supports molecular confirmation.
Electroencephalography
EEG characterizes neonatal burst suppression, hypsarrhythmia, or later focal/generalized spike-wave complexes.
electroencephalography NCIT:C38054 NCI Thesaurus (NCIT)
Results: Age-dependent severe epileptiform abnormalities support the clinical DEE diagnosis.
Show evidence (1 reference)
PMID:32001716 SUPPORT Human Clinical
"Electroencephalography (EEG) was markedly abnormal with a burst suppression pattern in the neonatal period, hypsarrhythmia in affected children with infantile spasms, and focal and/or generalized spike-wave complexes in childhood"
The cohort directly reports the EEG spectrum.
Brain MRI
MRI evaluates myelination and atrophy; normal early imaging does not exclude DEE84.
magnetic resonance imaging procedure NCIT:C16809 NCI Thesaurus (NCIT)
Results: Findings range from normal imaging to delayed myelination, ventriculomegaly, and cerebral or cerebellar atrophy.
Show evidence (1 reference)
PMID:32001716 SUPPORT Human Clinical
"displaying variable abnormalities ranging from abnormal myelination and/or cerebral or cerebellar atrophy, to normal findings"
The imaging series establishes both the variable abnormalities and normal-MRI possibility.
📈

Progression

2
Neonatal period to infancy
Severe epilepsy can begin neonatally or in infancy; motor abnormalities may precede seizures.
Show evidence (1 reference)
PMID:32001716 SUPPORT Human Clinical
"ataxia, chorea, and tremor, which were often present prior to onset of seizures"
The cohort establishes that movement abnormalities can precede epilepsy.
Infancy through childhood
Severe motor and intellectual disability persist; a minority died between four months and six years.
Show evidence (1 reference)
PMID:32001716 SUPPORT Human Clinical
"Three patients were deceased between 4 months and 6 years of age"
The clinical series documents early mortality in three patients.
⚖️

Clinical Burden

High
The syndrome commonly produces refractory epilepsy, profound motor and intellectual disability, dysphagia requiring feeding support, and early mortality.
Show evidence (1 reference)
PMID:32001716 SUPPORT Human Clinical
"None but two patients (F5-II:1 and II:2) achieved sitting ability. A moderate to severe intellectual disability was observed in all patients."
The cohort shows profound motor and cognitive burden.
🧫

Experimental Models

2
Patient-derived primary dermal fibroblasts PRIMARY_CELL_CULTURE
Patient fibroblasts model allele-dependent UGDH protein loss, reduced enzymatic activity, and reduced HA synthesis.
fibroblast CL:0000057 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
Primary dermal fibroblasts from four patients and one unaffected carrier parent
Publication
PMID:32001716
Pathograph links
UGDH loss of function measures fidelity: high Patient cells measure endogenous protein abundance and enzymatic activity.
Show evidence (1 reference)
PMID:32001716 SUPPORT In Vitro
"we then derived and biobanked primary dermal fibroblasts from patients F3-II:1 (R393W/A410S), F4-II:1 (Y14C/S72P), F5-II:1 (A82T/A82T) and F6-II:1 (R65*/Y367C)"
The study identifies the patient-derived primary-cell panel.
Reduced hyaluronic acid synthesis measures fidelity: moderate HA in conditioned media provides a direct UGDH-dependent glycosaminoglycan readout.
Show evidence (1 reference)
PMID:32001716 SUPPORT In Vitro
"Patient’s cells with the homozygous A82T mutation also exhibited a reduction in the synthesis of hyaluronic acid (HA)"
The fibroblast assay directly measures reduced HA synthesis.
Show evidence (1 reference)
PMID:32001716 SUPPORT In Vitro
"Using patients’ primary fibroblasts and biochemical assays, we demonstrate that these are loss-of-function alleles."
The authors directly establish the patient fibroblasts as a functional disease model.
Patient-derived cerebral organoids ORGANOID
Cerebral organoids generated from patient iPSCs model reduced neural-progenitor proliferation and organoid growth.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Tissue
brain UBERON:0000955 Uberon multi-species anatomy ontology (UBERON) Relation: this experimental model uses this anatomical location This experimental model uses brain (UBERON:0000955). UBERON:0000955 is an anatomical location from the Uberon multi-species anatomy ontology.
Cell source
Patient-derived induced pluripotent stem cells and an unaffected carrier-parent control
Culture
Ten-week cerebral organoid differentiation
Publication
PMID:32001716
Pathograph links
Reduced neural progenitor proliferation recapitulates fidelity: moderate Mutant organoids are smaller and contain less proliferative SOX2-positive progenitor zones.
Limitations: Replication with additional wild-type and complete UGDH-knockout lines is needed because iPSC differentiation is variable.
Show evidence (1 reference)
PMID:32001716 SUPPORT In Vitro
"ventricular zones marked by SOX2-positive neuronal progenitors were appreciably less proliferative"
The organoid directly reports reduced progenitor proliferation.
Show evidence (1 reference)
PMID:32001716 SUPPORT In Vitro
"patient-derived cerebral organoids, which were smaller due to a reduced number of proliferating neuronal progenitors, can serve as an alternative disease-in-a-dish model"
The paper explicitly presents patient organoids as an alternative disease model.
🐁

Animal Models

1
jekyll ugdh hypomorphic zebrafish
Zygotic ugdh depletion did not reproduce spontaneous seizures or altered PTZ responsiveness and therefore fails to model the human epileptic disease.
Species
Danio rerio
Genotype
Homozygous ugdh c.992T>A (p.I331D) jekyll m151 hypomorphic allele
Pathograph links
UGDH loss of function perturbs fidelity: low The hypomorphic allele perturbs zygotic Ugdh activity but does not satisfactorily reproduce the human neurologic syndrome.
Limitations: Zygotic zebrafish depletion differs from the human biallelic hypomorphic alleles; neural-progenitor proliferation was not measured, and fish die before 14 days post fertilization.
Show evidence (1 reference)
PMID:32001716 SUPPORT Model Organism
"fish depleted of Ugdh activity do not exhibit spontaneous seizure and are equally responsive to PTZ treatment"
The experiment confirms Ugdh perturbation while documenting the absent seizure phenotype.
UGDH-Related Neurodevelopmental and Epileptic Dysfunction fails to recapitulate fidelity: low The zebrafish does not reproduce the defining spontaneous epileptic phenotype.
Limitations: Zygotic hypomorphic depletion, early lethality, and species-specific developmental context limit translation to the human biallelic syndrome.
Show evidence (1 reference)
PMID:32001716 SUPPORT Model Organism
"fish depleted of Ugdh activity do not exhibit spontaneous seizure and are equally responsive to PTZ treatment"
The negative seizure result substantiates failure to recapitulate the human clinical consequence.
Show evidence (1 reference)
PMID:32001716 SUPPORT Model Organism
"Homozygous mutant larvae did not show signs of increased c-fos expression at basal state"
The negative neural-activity readout supports failure to phenocopy spontaneous seizures.
{ }

Source YAML

click to show 
name: UGDH-related developmental and epileptic encephalopathy 84
creation_date: "2026-07-06T06:04:18Z"
description: >-
  UGDH-related developmental and epileptic encephalopathy 84 is an autosomal
  recessive glycan-precursor disorder caused by biallelic loss-of-function
  variants in UGDH, which encodes UDP-glucose 6-dehydrogenase. Reduced UGDH
  activity limits conversion of UDP-glucose to UDP-glucuronic acid, decreasing
  the glucuronic-acid precursor pool needed for glycosaminoglycan,
  proteoglycan, and glycolipid production. The downstream disease is dominated
  by developmental and epileptic encephalopathy, hypotonia, motor disorder,
  developmental delay, intellectual disability, and variable brain growth or
  myelination abnormalities.
category: Mendelian
disease_term:
  preferred_term: developmental and epileptic encephalopathy, 84
  term:
    id: MONDO:0032918
    label: developmental and epileptic encephalopathy, 84
synonyms:
- DEE84
- EIEE84
- UGDH-related disorder
parents:
- genetic developmental and epileptic encephalopathy
- congenital disorder of glycosylation
classifications:
  icimd_category:
  - classification_value: o_linked_protein_glycosylation
    notes: >-
      ICIMD's O-linked protein-glycosylation group explicitly includes
      glycosaminoglycan synthesis. UGDH supplies the obligate UDP-glucuronic-acid
      precursor for glycosaminoglycans; this is more specific than the
      multiple-pathway group, whose definition concerns dolichol, Golgi, and
      sialic-acid disorders.
    evidence:
    - reference: PMID:32001716
      reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        UDP-GlcA is not only needed for detoxification via glucuronidation, but
        is also an obligate precursor for the synthesis of glycosaminoglycans
      explanation: UGDH supplies the obligate precursor for the glycosaminoglycan-synthesis branch of O-linked glycosylation.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Affected individuals have biallelic germline UGDH variants consistent with
    autosomal recessive inheritance.
  evidence:
  - reference: PMID:32001716
    reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report an allelic series of germline recessive mutations in UGDH
      in 36 cases from 25 families presenting with epileptic encephalopathy with
      developmental delay and hypotonia.
    explanation: >-
      The cohort directly establishes recessive UGDH mutations as the disease
      cause.
pathophysiology:
- name: UGDH loss of function
  description: >-
    Pathogenic biallelic UGDH variants reduce the stability, oligomerization, or
    catalytic activity of UDP-glucose 6-dehydrogenase.
  role: trigger
  biological_scale: MOLECULAR
  genes:
  - preferred_term: UGDH
    term:
      id: hgnc:12525
      label: UGDH
  molecular_functions:
  - preferred_term: UDP-glucose 6-dehydrogenase activity
    modifier: DECREASED
    term:
      id: GO:0003979
      label: UDP-glucose 6-dehydrogenase activity
  chemical_entities:
  - preferred_term: UDP-D-glucose
    term:
      id: CHEBI:18066
      label: UDP-D-glucose
  - preferred_term: UDP-D-glucuronic acid
    modifier: DECREASED
    term:
      id: CHEBI:197331
      label: UDP-D-glucuronic acid
  evidence:
  - reference: PMID:32001716
    reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Consistent with being loss-of-function alleles, we show using patients'
      primary fibroblasts and biochemical assays, that these mutations either
      impair UGDH stability, oligomerization, or enzymatic activity.
    explanation: >-
      Patient-cell and biochemical assays support reduced UGDH function as the
      proximal molecular defect.
  downstream:
  - target: UDP-glucuronic acid precursor depletion
    description: >-
      Reduced UGDH activity decreases production of UDP-glucuronic acid from
      UDP-glucose.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32001716
      reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        UGDH encodes an oxidoreductase that converts UDP-glucose to
        UDP-glucuronic acid, a key component of specific proteoglycans and
        glycolipids.
      explanation: >-
        The abstract directly links UGDH enzymatic function to the
        UDP-glucuronic acid product.
  - target: Reduced neural progenitor proliferation
    description: Patient-derived cerebral organoids show impaired proliferation of neural progenitors downstream of reduced UGDH activity.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32001716
      reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        ventricular zones marked by SOX2-positive neuronal progenitors were
        appreciably less proliferative
      explanation: Patient-derived organoids directly show reduced neural-progenitor proliferation.
- name: UDP-glucuronic acid precursor depletion
  description: >-
    UDP-glucuronic acid shortage impairs production of glycosaminoglycan-rich
    extracellular matrix components, including proteoglycans and glycolipids
    that are important in human brain development.
  role: central_effector
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: glycosaminoglycan biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0006024
      label: glycosaminoglycan biosynthetic process
  chemical_entities:
  - preferred_term: glycosaminoglycan
    modifier: DECREASED
    term:
      id: CHEBI:18085
      label: glycosaminoglycan
  evidence:
  - reference: PMID:32001716
    reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Our study defines UGDH as a key player for the production of extracellular
      matrix components that are essential for human brain development.
    explanation: >-
      This supports the precursor-to-ECM branch of the pathograph.
  downstream:
  - target: Reduced hyaluronic acid synthesis
    description: >-
      UDP-glucuronic acid depletion reduces synthesis of hyaluronic acid in
      patient fibroblasts.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32001716
      reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Patient’s cells with the homozygous A82T mutation also exhibited a
        reduction in the synthesis of hyaluronic acid (HA), which requires
        UDP-glucuronate, a product of UGDH enzymatic activity
      explanation: Patient cells directly connect reduced precursor production to reduced HA synthesis.
- name: Reduced hyaluronic acid synthesis
  description: >-
    Patient fibroblasts carrying homozygous UGDH A82T produce less hyaluronic
    acid, a direct glycosaminoglycan readout of UDP-glucuronate shortage.
  role: downstream
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: hyaluronan biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0030213
      label: hyaluronan biosynthetic process
  evidence:
  - reference: PMID:32001716
    reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Patient’s cells with the homozygous A82T mutation also exhibited a
      reduction in the synthesis of hyaluronic acid (HA)
    explanation: Patient fibroblasts provide a direct glycosaminoglycan readout.
- name: Reduced neural progenitor proliferation
  description: >-
    Patient-derived cerebral organoids are smaller and contain less proliferative
    SOX2-positive neural progenitor zones, while differentiated neuron and
    astrocyte markers are not comparably reduced.
  role: downstream
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: neural stem cell
    term:
      id: CL:0000047
      label: neural stem cell
  biological_processes:
  - preferred_term: neural precursor cell proliferation
    modifier: DECREASED
    term:
      id: GO:0061351
      label: neural precursor cell proliferation
  evidence:
  - reference: PMID:32001716
    reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These results argue that reduced UGDH activity is associated with impaired
      neuronal development in vitro, causing atrophy of patient-derived cerebral
      organoids.
    explanation: >-
      Patient-derived organoids support a neural-progenitor developmental mechanism.
  downstream:
  - target: UGDH-Related Neurodevelopmental and Epileptic Dysfunction
    description: >-
      Impaired progenitor proliferation is associated with the human
      neurodevelopmental and epileptic syndrome through unresolved tissue- and
      circuit-level intermediates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32001716
      reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        patient-derived cerebral organoids, which were smaller due to a reduced
        number of proliferating neuronal progenitors, can serve as an alternative
        disease-in-a-dish model
      explanation: Links the organoid developmental defect to the disease model while leaving the human causal intermediates unresolved.
- name: UGDH-Related Neurodevelopmental and Epileptic Dysfunction
  description: >-
    The clinical consequence of biallelic UGDH loss is a developmental and
    epileptic encephalopathy with global delay, hypotonia, intellectual
    disability, and seizures; the cellular-to-circuit bridge remains unresolved.
  role: consequence
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:32001716
    reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All 30 patients carrying biallelic mutations in UGDH presented with a
      common core phenotype consisting of marked developmental delay, epilepsy,
      mild dysmorphism, and motor disorder with axial hypotonia
    explanation: The 30-patient cohort defines the shared clinical consequence.
  downstream:
  - target: Developmental and epileptic encephalopathy
    description: Biallelic UGDH disease manifests as developmental and epileptic encephalopathy.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32001716
      reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: presenting with epileptic encephalopathy with developmental delay and hypotonia.
      explanation: Directly names the defining clinical syndrome.
  - target: Global developmental delay
    description: Marked developmental delay is part of the universal cohort core phenotype.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32001716
      reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All 30 patients carrying biallelic mutations in UGDH presented with a
        common core phenotype consisting of marked developmental delay, epilepsy,
        mild dysmorphism, and motor disorder with axial hypotonia
      explanation: Directly supports developmental delay in all 30 patients.
  - target: Hypotonia
    description: Axial hypotonia is part of the universal cohort core phenotype.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32001716
      reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: All patients had a severe motor disorder with axial hypotonia.
      explanation: Directly supports axial hypotonia in all patients.
  - target: Intellectual disability
    description: Moderate-to-severe intellectual disability is part of the clinical syndrome.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32001716
      reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: A moderate to severe intellectual disability was observed in all patients.
      explanation: Directly supports intellectual disability in all patients.
  - target: Epilepsy
    description: Severe epilepsy is a very frequent component of the clinical syndrome.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32001716
      reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Most patients have severe epilepsy ranging from neonatal onset
        developmental epileptic encephalopathy to infantile developmental
        epileptic encephalopathy (27 patients, 90%)
      explanation: Directly supports severe epilepsy in 27 of 30 patients.
phenotypes:
- name: Developmental and epileptic encephalopathy
  description: >-
    Epileptic encephalopathy with developmental delay is the defining clinical
    presentation.
  phenotype_term:
    preferred_term: Epileptic encephalopathy
    term:
      id: HP:0200134
      label: Epileptic encephalopathy
  evidence:
  - reference: PMID:32001716
    reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      presenting with epileptic encephalopathy with developmental delay and
      hypotonia.
    explanation: The cohort directly reports epileptic encephalopathy.
- name: Global developmental delay
  frequency: OBLIGATE
  description: Developmental delay is part of the recurrent core phenotype.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:32001716
    reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All 30 patients carrying biallelic mutations in UGDH presented with a
      common core phenotype consisting of marked developmental delay, epilepsy,
      mild dysmorphism, and motor disorder with axial hypotonia
    explanation: The cohort directly reports marked developmental delay in all 30 patients.
- name: Hypotonia
  frequency: OBLIGATE
  description: Axial hypotonia is a core motor feature.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:32001716
    reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had a severe motor disorder with axial hypotonia.
    explanation: The cohort directly reports axial hypotonia in all patients.
- name: Intellectual disability
  frequency: OBLIGATE
  description: Moderate to severe intellectual disability is reported in all affected individuals.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:32001716
    reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A moderate to severe intellectual disability was observed in all patients.
    explanation: >-
      The cohort reports intellectual disability in all patients, supporting the
      OBLIGATE frequency band for that cohort.
- name: Dysphagia
  frequency: VERY_FREQUENT
  description: Swallowing difficulties are common and may require gastrostomy feeding.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:32001716
    reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Twenty-four out of the 30 (80%) were noted to have swallowing difficulties
      and gastrostomy tubes were required for feeding in 12 infants.
    explanation: >-
      Swallowing difficulties in 24/30 patients equals 80%, which falls in the
      VERY_FREQUENT frequency band.
- name: Infantile spasms
  frequency: FREQUENT
  description: Infantile spasms are a frequent seizure type in UGDH-related DEE84.
  phenotype_term:
    preferred_term: Infantile spasms
    term:
      id: HP:0012469
      label: Infantile spasms
  evidence:
  - reference: PMID:32001716
    reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most patients have severe epilepsy ranging from neonatal onset
      developmental epileptic encephalopathy to infantile developmental
      epileptic encephalopathy (27 patients, 90%), of which 16 (53%) had
      infantile spasms
    explanation: >-
      Infantile spasms were reported in 16 patients, 53% of the cohort, which
      falls in the FREQUENT frequency band.
- name: Epilepsy
  frequency: VERY_FREQUENT
  description: Severe neonatal- or infantile-onset epilepsy occurred in 27 of 30 patients.
  phenotype_term:
    preferred_term: Epilepsy
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:32001716
    reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most patients have severe epilepsy ranging from neonatal onset
      developmental epileptic encephalopathy to infantile developmental
      epileptic encephalopathy (27 patients, 90%)
    explanation: Epilepsy in 27/30 equals 90%, within the VERY_FREQUENT band.
- name: Spasticity
  frequency: FREQUENT
  description: Limb spasticity occurred in 43% of the cohort.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:32001716
    reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      some patients presented with limb spasticity (43%), dystonia (17%),
      ataxia, chorea, and tremor
    explanation: The reported 43% maps to FREQUENT.
- name: Dystonia
  frequency: OCCASIONAL
  description: Dystonia occurred in 17% of the cohort.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:32001716
    reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      some patients presented with limb spasticity (43%), dystonia (17%),
      ataxia, chorea, and tremor
    explanation: The reported 17% maps to OCCASIONAL.
- name: Mild facial dysmorphism
  description: Mild dysmorphic features were part of the common core phenotype and were frequently present.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:32001716
    reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dysmorphic facial features such as short and flattened philtrum, outward
      protruding earlobes, ptosis, or blepharophimosis were mild but frequently present
    explanation: The cohort describes the recurrent mild facial gestalt.
- name: Delayed myelination
  description: MRI abnormalities can include delayed myelination, although some patients have normal imaging.
  phenotype_term:
    preferred_term: Delayed myelination
    term:
      id: HP:0012448
      label: Delayed myelination
  evidence:
  - reference: PMID:32001716
    reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MRI revealed a spectrum of abnormalities with delayed myelination and
      enlarged ventricles probably due to cerebral and cerebellar atrophy
    explanation: MRI directly documents variable delayed myelination.
- name: Cerebral atrophy
  description: Cerebral atrophy occurs in more severely affected patients and can progress on serial MRI.
  phenotype_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
  evidence:
  - reference: PMID:32001716
    reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MRI revealed a spectrum of abnormalities with delayed myelination and
      enlarged ventricles probably due to cerebral and cerebellar atrophy
    explanation: Imaging supports cerebral and cerebellar atrophy in the severe subgroup.
- name: Cerebellar atrophy
  description: Cerebellar atrophy occurs in a subset of more severely affected patients.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: PMID:32001716
    reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MRI revealed a spectrum of abnormalities with delayed myelination and
      enlarged ventricles probably due to cerebral and cerebellar atrophy
    explanation: Imaging explicitly documents cerebellar as well as cerebral atrophy.
- name: Profound motor delay
  frequency: VERY_FREQUENT
  description: Only two of 30 patients achieved independent sitting, indicating profound motor-development impairment in 28 of 30.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:32001716
    reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      None but two patients (F5-II:1 and II:2) achieved sitting ability.
    explanation: Failure to achieve sitting in 28/30 (93%) supports VERY_FREQUENT profound motor delay.
- name: Ventriculomegaly
  description: Enlarged ventricles occur within the variable MRI spectrum in more severely affected patients.
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
  evidence:
  - reference: PMID:32001716
    reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MRI revealed a spectrum of abnormalities with delayed myelination and
      enlarged ventricles probably due to cerebral and cerebellar atrophy
    explanation: The imaging series directly reports enlarged ventricles.
genetic:
- name: UGDH
  association: Biallelic loss-of-function variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: UGDH
    term:
      id: hgnc:12525
      label: UGDH
  evidence:
  - reference: PMID:32001716
    reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report an allelic series of germline recessive mutations in UGDH
      in 36 cases from 25 families presenting with epileptic encephalopathy with
      developmental delay and hypotonia.
    explanation: >-
      The cohort establishes UGDH as the causal gene for DEE84.
diagnosis:
- name: Molecular genetic testing
  description: Exome sequencing with segregation analysis identifies biallelic UGDH variants after exclusion of known neurologic-disease genes.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  results: Biallelic rare UGDH variants segregating with disease support DEE84.
  evidence:
  - reference: PMID:32001716
    reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we performed exome sequencing on two affected siblings. No mutations in
      genes known to be associated with neurological disorders
    explanation: Exome sequencing initiated the causal-gene discovery workflow.
  - reference: PMID:32001716
    reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      only one missense variant c.244G > A in the UGDH gene was found to
      segregate with the disease
    explanation: Familial segregation supports molecular confirmation.
- name: Electroencephalography
  description: EEG characterizes neonatal burst suppression, hypsarrhythmia, or later focal/generalized spike-wave complexes.
  diagnosis_term:
    preferred_term: electroencephalography
    term:
      id: NCIT:C38054
      label: Electroencephalography
  results: Age-dependent severe epileptiform abnormalities support the clinical DEE diagnosis.
  evidence:
  - reference: PMID:32001716
    reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Electroencephalography (EEG) was markedly abnormal with a burst suppression
      pattern in the neonatal period, hypsarrhythmia in affected children with
      infantile spasms, and focal and/or generalized spike-wave complexes in childhood
    explanation: The cohort directly reports the EEG spectrum.
- name: Brain MRI
  description: MRI evaluates myelination and atrophy; normal early imaging does not exclude DEE84.
  diagnosis_term:
    preferred_term: magnetic resonance imaging procedure
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  results: Findings range from normal imaging to delayed myelination, ventriculomegaly, and cerebral or cerebellar atrophy.
  evidence:
  - reference: PMID:32001716
    reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      displaying variable abnormalities ranging from abnormal myelination and/or
      cerebral or cerebellar atrophy, to normal findings
    explanation: The imaging series establishes both the variable abnormalities and normal-MRI possibility.
treatments:
- name: Symptomatic antiseizure therapy
  description: >-
    Most severe cases were refractory to antiseizure treatment. Two milder
    fever-associated seizure cases were seizure-free on sodium valproate, and
    one other patient appeared to benefit from ketogenic diet; these observations
    do not establish a generally effective disease-specific treatment.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Epilepsy
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:32001716
    reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Only these two patients were seizure-free on sodium valproate. All other
      patients, except for one patient who seemed to benefit from ketogenic diet,
      did not respond to antiepileptic treatment.
    explanation: The cohort documents limited individual responses and predominant refractoriness.
- name: Gastrostomy feeding support
  description: Gastrostomy was used for feeding in 12 infants with swallowing difficulties; treatment efficacy was not evaluated.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Gastrostomy tube procedure
    term:
      id: NCIT:C157864
      label: Gastrostomy Tube Procedure
  target_phenotypes:
  - preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:32001716
    reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Twenty-four out of the 30 (80%) were noted to have swallowing difficulties
      and gastrostomy tubes were required for feeding in 12 infants.
    explanation: The cohort directly documents use of gastrostomy feeding support.
progression:
- phase: Neonatal period to infancy
  notes: Severe epilepsy can begin neonatally or in infancy; motor abnormalities may precede seizures.
  evidence:
  - reference: PMID:32001716
    reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ataxia, chorea, and tremor, which were often present prior to onset of seizures
    explanation: The cohort establishes that movement abnormalities can precede epilepsy.
- phase: Infancy through childhood
  notes: Severe motor and intellectual disability persist; a minority died between four months and six years.
  evidence:
  - reference: PMID:32001716
    reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three patients were deceased between 4 months and 6 years of age
    explanation: The clinical series documents early mortality in three patients.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    The syndrome commonly produces refractory epilepsy, profound motor and
    intellectual disability, dysphagia requiring feeding support, and early mortality.
  evidence:
  - reference: PMID:32001716
    reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      None but two patients (F5-II:1 and II:2) achieved sitting ability. A
      moderate to severe intellectual disability was observed in all patients.
    explanation: The cohort shows profound motor and cognitive burden.
experimental_models:
- name: Patient-derived primary dermal fibroblasts
  description: Patient fibroblasts model allele-dependent UGDH protein loss, reduced enzymatic activity, and reduced HA synthesis.
  experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  cell_source: Primary dermal fibroblasts from four patients and one unaffected carrier parent
  publication: PMID:32001716
  modeled_mechanisms:
  - target: UGDH loss of function
    relationship: MEASURES
    fidelity: HIGH
    description: Patient cells measure endogenous protein abundance and enzymatic activity.
    evidence:
    - reference: PMID:32001716
      reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        we then derived and biobanked primary dermal fibroblasts from patients
        F3-II:1 (R393W/A410S), F4-II:1 (Y14C/S72P), F5-II:1 (A82T/A82T) and
        F6-II:1 (R65*/Y367C)
      explanation: The study identifies the patient-derived primary-cell panel.
  - target: Reduced hyaluronic acid synthesis
    relationship: MEASURES
    fidelity: MODERATE
    description: HA in conditioned media provides a direct UGDH-dependent glycosaminoglycan readout.
    evidence:
    - reference: PMID:32001716
      reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Patient’s cells with the homozygous A82T mutation also exhibited a
        reduction in the synthesis of hyaluronic acid (HA)
      explanation: The fibroblast assay directly measures reduced HA synthesis.
  evidence:
  - reference: PMID:32001716
    reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Using patients’ primary fibroblasts and biochemical assays, we demonstrate
      that these are loss-of-function alleles.
    explanation: The authors directly establish the patient fibroblasts as a functional disease model.
- name: Patient-derived cerebral organoids
  description: Cerebral organoids generated from patient iPSCs model reduced neural-progenitor proliferation and organoid growth.
  experimental_model_type: ORGANOID
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  cell_source: Patient-derived induced pluripotent stem cells and an unaffected carrier-parent control
  culture_system: Ten-week cerebral organoid differentiation
  publication: PMID:32001716
  modeled_mechanisms:
  - target: Reduced neural progenitor proliferation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Mutant organoids are smaller and contain less proliferative SOX2-positive progenitor zones.
    limitations: Replication with additional wild-type and complete UGDH-knockout lines is needed because iPSC differentiation is variable.
    evidence:
    - reference: PMID:32001716
      reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        ventricular zones marked by SOX2-positive neuronal progenitors were
        appreciably less proliferative
      explanation: The organoid directly reports reduced progenitor proliferation.
  evidence:
  - reference: PMID:32001716
    reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      patient-derived cerebral organoids, which were smaller due to a reduced
      number of proliferating neuronal progenitors, can serve as an alternative
      disease-in-a-dish model
    explanation: The paper explicitly presents patient organoids as an alternative disease model.
animal_models:
- name: jekyll ugdh hypomorphic zebrafish
  species: Danio rerio
  genotype: Homozygous ugdh c.992T>A (p.I331D) jekyll m151 hypomorphic allele
  description: Zygotic ugdh depletion did not reproduce spontaneous seizures or altered PTZ responsiveness and therefore fails to model the human epileptic disease.
  modeled_mechanisms:
  - target: UGDH loss of function
    relationship: PERTURBS
    fidelity: LOW
    description: The hypomorphic allele perturbs zygotic Ugdh activity but does not satisfactorily reproduce the human neurologic syndrome.
    limitations: Zygotic zebrafish depletion differs from the human biallelic hypomorphic alleles; neural-progenitor proliferation was not measured, and fish die before 14 days post fertilization.
    evidence:
    - reference: PMID:32001716
      reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        fish depleted of Ugdh activity do not exhibit spontaneous seizure and
        are equally responsive to PTZ treatment
      explanation: The experiment confirms Ugdh perturbation while documenting the absent seizure phenotype.
  - target: UGDH-Related Neurodevelopmental and Epileptic Dysfunction
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: The zebrafish does not reproduce the defining spontaneous epileptic phenotype.
    limitations: >-
      Zygotic hypomorphic depletion, early lethality, and species-specific
      developmental context limit translation to the human biallelic syndrome.
    evidence:
    - reference: PMID:32001716
      reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        fish depleted of Ugdh activity do not exhibit spontaneous seizure and
        are equally responsive to PTZ treatment
      explanation: The negative seizure result substantiates failure to recapitulate the human clinical consequence.
  evidence:
  - reference: PMID:32001716
    reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Homozygous mutant larvae did not show signs of increased c-fos expression
      at basal state
    explanation: The negative neural-activity readout supports failure to phenocopy spontaneous seizures.
datasets: []
discussions:
- discussion_id: gap_ugdh_cellular_mechanism_to_human_dee
  prompt: How do reduced glycosaminoglycan synthesis and impaired neural-progenitor proliferation produce the human epilepsy and developmental phenotype?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Reduced hyaluronic acid synthesis
  - pathophysiology#Reduced neural progenitor proliferation
  - pathophysiology#UGDH-Related Neurodevelopmental and Epileptic Dysfunction
  rationale: >-
    Patient cells and organoids establish biochemical and developmental effects,
    but the study does not demonstrate a causal chain from either cellular result
    to seizures or the individual human phenotypes.
  evidence:
  - reference: PMID:32001716
    reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      while UGDH is not required for proper function of isolated neurons in
      culture, its absence significantly affects neuronal differentiation in
      cerebral organoids
    explanation: The contrasting model results define the remaining mechanistic gap.
- discussion_id: mismatch_ugdh_zebrafish_and_human_organoid
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Reduced neural progenitor proliferation
  prompt: Why does zygotic ugdh depletion fail to reproduce the human neurologic phenotype while patient-derived human organoids show impaired progenitor proliferation?
  rationale: Species, developmental timing, and allele context may alter the dependence of neural development on UGDH.
  evidence:
  - reference: PMID:32001716
    reference_title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      While mutant ugdh zebrafish did not phenocopy the disease, we bring
      evidence that patient-derived cerebral organoids
    explanation: The paper explicitly contrasts the negative animal model with the human organoid model.
references:
- reference: PMID:32001716
  title: "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy."
review_notes: >-
  This review uses the disease-defining 30-person clinical cohort and its
  patient-derived fibroblast and cerebral-organoid experiments. The abstract's
  phrase “36 cases” is not used as a clinical denominator because the full text
  explicitly catalogs 30 patients from 25 families. Frequency assignments are
  limited to explicit cohort counts or percentages. Causal edges are restricted
  to measured enzymatic, HA-synthesis, and organoid-proliferation relationships;
  human phenotypes remain unwired because the paper does not experimentally
  establish those downstream causal bridges. The zebrafish failure is retained
  as a model mismatch rather than presented as confirmatory evidence. No public
  disease-specific omics accession was identified in the article; source-data
  files are study supplements rather than a repository dataset. No matching
  GeneReviews chapter or repository deep-research artifact was found, and no
  disease-modifying treatment or disorder-specific clinical trial is established.
📚

References & Deep Research

References

1
PMID:32001716
Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy.
No top-level findings curated for this source.