UGP2-related developmental and epileptic encephalopathy 83

Mendelian MONDO:0032895 Pathograph 13 Show in embeddings browser genetic developmental and epileptic encephalopathy congenital disorder of glycosylation

Developmental and epileptic encephalopathy 83 (DEE83) is a severe autosomal recessive disorder caused in the reported cohort by a recurrent homozygous UGP2 variant that abolishes the short, brain-predominant isoform while leaving the long isoform functional. Reduced UGP2 and UDP-glucose in neural-lineage cells impair glycogen synthesis, activate the unfolded-protein response, and alter neuronal differentiation. Complete-knockout neural stem cells also show protein hypoglycosylation, but that readout was unchanged in the patient-genotype knock-in model. The clinical syndrome begins in early infancy with intractable seizures, profound developmental impairment, progressive microcephaly, cerebral atrophy, and visual dysfunction.

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1
Inheritance
6
Pathophys.
16
Phenotypes
1
Gaps
13
Pathograph
1
Genes
1
Medical Actions
1
Datasets
2
Models
1
References
🏷

Classifications

ICIMD (Inherited Metabolic Disorders)
multiple glycosylation pathways
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Affected individuals in the discovery cohort were homozygous for the recurrent UGP2 start-codon variant.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:31820119 SUPPORT Human Clinical
"Our study identifies a recurrent start codon mutation in UGP2 as a cause of a novel autosomal recessive DEE syndrome."
The cohort establishes recessive inheritance.
?

Discussions and Knowledge Gaps

1
Does the recurrent patient-genotype start-loss allele cause protein hypoglycosylation in a model with a complete brain-like isoform switch?
HUMAN MODEL MISMATCH OPEN mismatch_ugp2_knockin_lamp2_glycosylation
Attached to
pathophysiology#Protein hypoglycosylation
Complete-knockout NSCs show rescued LAMP2 hypoglycosylation, but the patient-genotype knock-in model retains residual UGP2 and shows no LAMP2 glycosylation change. A model completing the fetal-brain isoform switch is needed to determine whether this branch applies to the human genotype.
Show evidence (1 reference)
PMID:31820119 SUPPORT In Vitro
"The absence of changes in LAMP2 glycosylation in KI cells is likely explained by a non-complete isoform switch upon in vitro NSC differentiation, resulting in residual UGP2 levels"
The figure legend explicitly records the patient-genotype model's negative LAMP2 result and its proposed technical explanation.
⚙

Pathophysiology

6
Loss of the brain-predominant short UGP2 isoform
The recurrent c.1A>G start-loss change in the short transcript corresponds to p.Met12Val in the long transcript. It prevents translation of the brain-predominant short isoform while the altered long isoform remains functional.
UGP2 hgnc:12527 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves UGP2 (hgnc:12527). hgnc:12527 is a gene from the HUGO Gene Nomenclature Committee.
UTP:glucose-1-phosphate uridylyltransferase activity GO:0003983 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased UTP:glucose-1-phosphate uridylyltransferase activity (GO:0003983). GO:0003983 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Reduced UDP-glucose synthesis in neural-lineage cells Short-isoform loss reduces functional UGP2 after neural differentiation.
Premature neuronal differentiation Short-isoform loss produces premature differentiation in neural stem-cell models.
Neural stem-cell ER stress and unfolded-protein response Both knockout and patient-genotype knock-in neural stem cells show increased UPR-marker expression.
Developmental and epileptic encephalopathy The recurrent short-isoform start-loss genotype causes DEE83, but the intervening cellular-to-clinical chain is unresolved.
Visual impairment Reduced Ugp2 expression reproduces visual disturbance in zebrafish, but the intervening mechanism is unresolved.
Show evidence (1 reference)
PMID:31820119 SUPPORT In Vitro
"The fact that the Met12Val long isoform was able to rescue the full KO phenotype"
Rescue separates loss of short-isoform translation from long-isoform function.
Reduced UDP-glucose synthesis in neural-lineage cells
UGP2-deficient and start-loss knock-in neural stem cells have reduced capacity to synthesize UDP-glucose; long-isoform expression rescues the biochemical defect.
UGP2 hgnc:12527 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves UGP2 (hgnc:12527). hgnc:12527 is a gene from the HUGO Gene Nomenclature Committee.
Experimental models
UGP2-engineered and patient-derived neural stem-cell models IPSC DERIVED MODEL
Animal models
ugp2a/ugp2b-deficient zebrafish Danio rerio partially recapitulates
Downstream
Impaired glycogen synthesis UDP-glucose shortage limits glycogen production in neural-lineage cells.
Protein hypoglycosylation Reduced UDP-glucose impairs glycosylation in UGP2-deficient neural stem cells.
Show evidence (1 reference)
PMID:31820119 SUPPORT In Vitro
"KO NSCs showed a severely reduced ability to pro- duce UDP-glucose"
The biochemical assay directly measures impaired UDP-glucose production.
Impaired glycogen synthesis
Knockout, knock-in, and patient-derived neural stem cells show reduced or absent glycogen granules, with rescue by functional long UGP2.
glycogen biosynthetic process GO:0005978 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased glycogen biosynthetic process (GO:0005978). GO:0005978 is a biological process from the Gene Ontology. ↓ DECREASED
Experimental models
UGP2-engineered and patient-derived neural stem-cell models IPSC DERIVED MODEL
Show evidence (1 reference)
PMID:31820119 SUPPORT In Vitro
"KI NSCs showed a more severe reduction in PAS staining compared to the ESC state"
PAS staining measures reduced glycogen in the neural stem-cell state.
Protein hypoglycosylation
UGP2-knockout neural stem cells show hypoglycosylated LAMP2, rescued by either wild-type or p.Met12Val long UGP2. Patient-genotype knock-in NSCs did not show this LAMP2 change, likely because the in-vitro isoform switch was incomplete and residual UGP2 remained.
glycoprotein metabolic process GO:0009100 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased glycoprotein metabolic process (GO:0009100). GO:0009100 is a biological process from the Gene Ontology. ↓ DECREASED
Experimental models
UGP2-engineered and patient-derived neural stem-cell models IPSC DERIVED MODEL
UGP2-engineered and patient-derived neural stem-cell models IPSC DERIVED MODEL
Show evidence (2 references)
PMID:31820119 SUPPORT In Vitro
"We found that KO NSCs show hypoglycosylation of LAMP2 that is rescued by the overexpression of both WT and mutant long isoform"
LAMP2 provides a direct glycosylation readout and rescue control.
PMID:31820119 REFUTE In Vitro
"The absence of changes in LAMP2 glycosylation in KI cells is likely explained by a non-complete isoform switch upon in vitro NSC differentiation, resulting in residual UGP2 levels"
The patient-genotype knock-in model did not reproduce the complete-knockout LAMP2 defect.
Neural stem-cell ER stress and unfolded-protein response
UPR marker genes increase in UGP2-deficient and knock-in neural stem cells, but not in embryonic stem cells or patient fibroblasts with sufficient UGP2.
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
Experimental models
UGP2-engineered and patient-derived neural stem-cell models IPSC DERIVED MODEL
Show evidence (1 reference)
PMID:31820119 SUPPORT In Vitro
"This indicates that NSCs having UGP2 levels under a certain threshold are more prone to ER stress and UPR."
Increased UPR-marker expression supports neural-lineage ER stress.
Premature neuronal differentiation
UGP2-deficient neural stem cells show transcriptomic and marker changes consistent with premature neuronal differentiation; this remains a cellular mechanism rather than a demonstrated direct cause of each human phenotype.
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.
neuron differentiation GO:0030182 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased neuron differentiation (GO:0030182). GO:0030182 is a biological process from the Gene Ontology. ↑ INCREASED
Experimental models
UGP2-engineered and patient-derived neural stem-cell models IPSC DERIVED MODEL
Show evidence (1 reference)
PMID:31820119 SUPPORT In Vitro
"altered glycogen metabolism, upregulated unfolded protein response and premature neuronal differentiation"
The study reports premature differentiation in its engineered neural models.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for UGP2-related developmental and epileptic encephalopathy 83 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

16
Digestive 1
Feeding difficulties in infancy HP:0008872 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties in infancy (HP:0008872). HP:0008872 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31820119 SUPPORT Human Clinical
"milestones, causing the need for gastrointestinal tube feed- ing."
The hyphenated full-text passage directly documents tube-feeding need in infancy.
Eye 4
Visual impairment HP:0000505 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Visual impairment (HP:0000505). HP:0000505 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31820119 SUPPORT Human Clinical
"a disturbance of vision, with retinal pigment changes observed in all patients who had undergone ophthalmological examination"
The cohort consistently reports visual and retinal abnormalities.
Abnormal retinal pigmentation HP:0007703 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal retinal pigmentation (HP:0007703). HP:0007703 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31820119 SUPPORT Human Clinical
"retinal pigment changes observed in all patients who had undergone ophthalmological examination."
The cohort directly supports a specific retinal-pigmentation phenotype without licensing a whole-cohort frequency band.
Nystagmus HP:0000639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nystagmus (HP:0000639). HP:0000639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31820119 SUPPORT Human Clinical
"hypermetropia and mild nystagmus were noticed upon ophthalmological investigation."
The index-case examination directly supports nystagmus.
Hypermetropia HP:0000540 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypermetropia (HP:0000540). HP:0000540 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31820119 SUPPORT Human Clinical
"hypermetropia and mild nystagmus were noticed upon ophthalmological investigation."
The index-case examination directly supports hypermetropia.
Head and Neck 3
Progressive microcephaly HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252), qualified as course progressive. HP:0000252 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:31820119 SUPPORT Human Clinical
"she had become progressively microcephalic, with a head circumference of − 2.96 SD"
Serial assessment documents progressive microcephaly.
Highly arched eyebrow HP:0002553 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Highly arched eyebrow (HP:0002553). HP:0002553 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31820119 SUPPORT Human Clinical
"bitemporal narrowing, high hairline, arched eyebrows, pronounced philtrum, a relatively small mouth and large ears."
Arched eyebrows is an exact synonym of the selected HPO term.
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:31820119 SUPPORT Human Clinical
"all patients seem to share similar, although mild, dysmorphisms"
The authors describe a shared mild dysmorphic gestalt.
Nervous System 3
Global developmental delay Severe global developmental delay HP:0011344 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe global developmental delay (HP:0011344). HP:0011344 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31820119 SUPPORT Human Clinical
"without acquisition of any noticeable developmental milestones"
The clinical narrative documents profound developmental impairment.
Hyperreflexia HP:0001347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperreflexia (HP:0001347). HP:0001347 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31820119 SUPPORT Human Clinical
"symmetric deep tendon reflexes, more pronounced at the upper limbs."
The neurologic examination supports hyperreflexia without spanning the intervening figure legend.
Cerebral atrophy HP:0002059 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral atrophy (HP:0002059), qualified as course progressive. HP:0002059 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:31820119 SUPPORT Human Clinical
"displayed reduced white matter, that further developed into global atrophy with wide sulci"
Serial MRI documents progressive atrophy.
Other 5
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:31820119 SUPPORT Human Clinical
"presenting with a severe form of intractable epilepsy"
The cohort directly establishes refractory epilepsy.
Infantile spasms HP:0012469 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Infantile spasms (HP:0012469). HP:0012469 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31820119 SUPPORT Human Clinical
"developed into infantile spasms and severe epileptic activity on multiple electroencephalograms"
The index case had infantile spasms with repeated EEG abnormalities.
Sloping forehead HP:0000340 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sloping forehead (HP:0000340). HP:0000340 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31820119 SUPPORT Human Clinical
"including a sloping forehead, elongated head with suture ridging, bitemporal narrowing, a relatively small mouth and large ears"
The clinical description explicitly identifies the sloping forehead.
Narrow forehead HP:0000341 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Narrow forehead (HP:0000341). HP:0000341 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31820119 SUPPORT Human Clinical
"bitemporal narrowing, high hairline, arched eyebrows, pronounced philtrum, a relatively small mouth and large ears."
Bitemporal narrowing is an exact synonym of the selected HPO term.
High anterior hairline HP:0009890 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High anterior hairline (HP:0009890). HP:0009890 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31820119 SUPPORT Human Clinical
"bitemporal narrowing, high hairline, arched eyebrows, pronounced philtrum, a relatively small mouth and large ears."
The figure legend directly documents the high hairline.
🧬

Genetic Associations

1
UGP2 (Recurrent homozygous isoform-specific start-loss variant c.1A>G in the short transcript)
Gene: UGP2 hgnc:12527 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is UGP2 (hgnc:12527). hgnc:12527 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:31820119 SUPPORT Human Clinical
"Whole exome sequencing identified a recurrent, homozygous variant (chr2:64083454A > G) in the essential UDP-glucose pyrophosphorylase ( UGP2) gene in all probands."
All probands carried the same homozygous variant.
💊

Medical Actions

1
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
Multiple antiseizure drugs, ACTH, and ketogenic diet were attempted in the index case, but seizures remained daily and intractable. This documents symptomatic management and poor response, not an effective disease-specific therapy.
Target Phenotypes: Epileptic encephalopathy HP:0200134 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Epileptic encephalopathy (HP:0200134). HP:0200134 is a phenotype from the Human Phenotype Ontology. Infantile spasms HP:0012469 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Infantile spasms (HP:0012469). HP:0012469 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31820119 SUPPORT Human Clinical
"Despite the use of multiple anti-epileptic drugs, including ACTH and a ketogenic diet, seizures remained intractable and occurred daily."
The detailed case documents treatment attempts and persistent seizures.
🔬

Diagnosis

4
Isoform-aware molecular diagnosis
Exome analysis identifies the homozygous recurrent UGP2 variant; interpretation must account for its distinct consequences in the long and short transcripts, and segregation testing can confirm parental carrier status.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Results: Homozygous UGP2 short-transcript c.1A>G start loss supports DEE83.
Show evidence (1 reference)
PMID:31820119 SUPPORT Human Clinical
"Whole exome sequencing identified a recurrent, homozygous variant (chr2:64083454A > G)"
Exome sequencing found the causal recurrent variant.
Electroencephalography
EEG characterizes the severe epileptic encephalopathy and can establish a West-syndrome presentation.
electroencephalography NCIT:C38054 NCI Thesaurus (NCIT)
Results: Severe epileptic activity with a disorganized multifocal pattern may be present.
Show evidence (1 reference)
PMID:31820119 SUPPORT Human Clinical
"infantile spasms and severe epileptic activity on multiple electroencephalograms"
Repeated EEGs documented the epileptic syndrome.
Brain MRI
Serial MRI assesses reduced white matter and progressive global atrophy while excluding major malformations.
magnetic resonance imaging procedure NCIT:C16809 NCI Thesaurus (NCIT)
Results: Reduced white matter may progress to global atrophy without major structural anomalies.
Show evidence (2 references)
PMID:31820119 SUPPORT Human Clinical
"microcephaly but no major structural anomalies"
The figure description summarizes the characteristic MRI pattern.
PMID:31820119 SUPPORT Human Clinical
"displayed reduced white matter, that further developed into global atrophy with wide sulci"
Serial imaging directly supports progression from white-matter reduction to atrophy.
Ophthalmologic examination
Ophthalmologic assessment evaluates retinal pigment changes, refractive error, and nystagmus.
Results: Visual dysfunction with retinal pigment abnormalities supports the syndrome.
Show evidence (2 references)
PMID:31820119 SUPPORT Human Clinical
"hypermetropia and mild nystagmus were noticed upon ophthalmological investigation."
The clinical examination directly defines the ocular findings.
PMID:31820119 SUPPORT Human Clinical
"retinal pigment changes observed in all patients who had undergone ophthalmological examination."
The cohort supports retinal pigment assessment as a diagnostic evaluation.
📈

Progression

2
Early infancy
Irritability and jitteriness can appear in the first weeks, followed by infantile spasms and severe epilepsy.
Show evidence (1 reference)
PMID:31820119 SUPPORT Human Clinical
"which developed into infantile spasms and severe epileptic activity on multiple electroencephalograms"
The index case establishes early-infantile onset and evolution.
Infancy and early childhood
Severe developmental impairment persists while microcephaly and cerebral atrophy progress; early mortality is common in the reported cohort.
Show evidence (1 reference)
PMID:31820119 SUPPORT Human Clinical
"Ten of these individuals passed away early, with the majority before the age of 3.5 years."
The cohort documents substantial early mortality.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
The disorder-defining publication reported 22 affected individuals from 15 families; no population prevalence has been established.
Show evidence (1 reference)
PMID:31820119 SUPPORT Human Clinical
"Here we report on 22 individuals from 15 families presenting with"
The primary cohort provides the cases-in-literature count.
📊

Related Datasets

1
RNA-seq of UGP2 mutant human embryonic stem cells and in vitro differentiated neural stem cells geo:GSE137129
Transcriptomic profiles from engineered UGP2 knockout, recurrent-variant knock-in, wild-type, and rescue human stem-cell models used to identify neural-lineage transcriptional consequences of UGP2 deficiency.
human BULK RNA SEQ
Conditions: UGP2 knockout recurrent variant knock-in wild-type control long-isoform rescue
PMID:31820119
Show evidence (1 reference)
PMID:31820119 SUPPORT Other
"RNA-Seq of in vitro studies is publicly available through the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) under accession number GSE137129."
The paper's data-availability statement identifies the accession.
🧫

Experimental Models

1
UGP2-engineered and patient-derived neural stem-cell models IPSC_DERIVED_MODEL
CRISPR knockout and recurrent-variant knock-in human embryonic stem cells, together with patient iPSC-derived neural stem cells and long-isoform rescue, model the neural-lineage-specific biochemical and differentiation defects.
UGP2 knockout recurrent UGP2 variant knock-in patient-derived iPSC neural differentiation long-isoform rescue
neural stem cell CL:0000047 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses neural stem cell (CL:0000047). CL:0000047 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
Engineered human embryonic stem cells and patient-derived induced pluripotent stem cells
Culture
In-vitro neural stem-cell differentiation
Publication
PMID:31820119
Pathograph links
Reduced UDP-glucose synthesis in neural-lineage cells recapitulates
Show evidence (1 reference)
PMID:31820119 SUPPORT In Vitro
"KO NSCs showed a severely reduced ability to pro- duce UDP-glucose"
The model directly measures reduced UGP2-dependent substrate production.
Impaired glycogen synthesis recapitulates
Show evidence (1 reference)
PMID:31820119 SUPPORT In Vitro
"KI NSCs showed a more severe reduction in PAS staining compared to the ESC state"
PAS staining directly demonstrates the modeled glycogen defect.
Protein hypoglycosylation recapitulates
Show evidence (1 reference)
PMID:31820119 SUPPORT In Vitro
"We found that KO NSCs show hypoglycosylation of LAMP2 that is rescued by the overexpression of both WT and mutant long isoform"
LAMP2 directly reports the modeled glycosylation defect.
Protein hypoglycosylation fails to recapitulate
Limitations: The patient-genotype knock-in neural stem cells retained residual UGP2 because the in-vitro isoform switch was incomplete and therefore did not reproduce the complete-knockout LAMP2 glycosylation defect.
Show evidence (1 reference)
PMID:31820119 SUPPORT In Vitro
"The absence of changes in LAMP2 glycosylation in KI cells is likely explained by a non-complete isoform switch upon in vitro NSC differentiation, resulting in residual UGP2 levels"
The patient-genotype knock-in arm fails to reproduce the knockout glycosylation phenotype.
Neural stem-cell ER stress and unfolded-protein response recapitulates
Show evidence (1 reference)
PMID:31820119 SUPPORT In Vitro
"This indicates that NSCs having UGP2 levels under a certain threshold are more prone to ER stress and UPR."
UPR-marker measurements directly support this modeled mechanism.
Premature neuronal differentiation recapitulates
Show evidence (1 reference)
PMID:31820119 SUPPORT In Vitro
"altered glycogen metabolism, upregulated unfolded protein response and premature neuronal differentiation"
The model directly demonstrates the differentiation phenotype.
Show evidence (1 reference)
PMID:31820119 SUPPORT In Vitro
"Similar expression changes were observed in NSCs differentiated from induced pluripotent stem cells (iPSCs) that we had generated from family 1"
Patient-derived neural stem cells reproduce the engineered-model changes.
🐁

Animal Models

1
ugp2a/ugp2b-deficient zebrafish
Double-mutant larvae have reduced Ugp2 activity, reduced eye movements, and increased movement responses after convulsant exposure. The model supports susceptibility rather than full recapitulation of the human syndrome.
Visual disturbance Increased seizure susceptibility after 4-aminopyridine
Species
Danio rerio
Genotype
CRISPR-generated ugp2a and ugp2b double-mutant larvae
Genes
UGP2 hgnc:12527 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns UGP2 (hgnc:12527). hgnc:12527 is a gene from the HUGO Gene Nomenclature Committee.
Pathograph links
Reduced UDP-glucose synthesis in neural-lineage cells partially recapitulates
Limitations: Reduced enzyme activity and behavioral susceptibility are reproduced, but the zebrafish does not establish the full human neural-lineage or clinical syndrome.
Show evidence (1 reference)
PMID:31820119 SUPPORT Model Organism
"showing reduced Ugp2 enzyme activity in double mutant zebrafish"
The zebrafish biochemical assay reproduces reduced Ugp2 activity.
Show evidence (2 references)
PMID:31820119 SUPPORT Model Organism
"velocity compared to controls, which might indicate an increased seizure susceptibility"
Convulsant challenge demonstrates increased seizure susceptibility.
PMID:31820119 SUPPORT Model Organism
"severely reduced Ugp2a/Ugp2b levels result in a behavior defect with reduced eye movements"
The zebrafish model directly supports the eye-movement phenotype.
{ }

Source YAML

click to show 
name: UGP2-related developmental and epileptic encephalopathy 83
creation_date: "2026-07-06T06:04:18Z"
description: >-
  Developmental and epileptic encephalopathy 83 (DEE83) is a severe autosomal
  recessive disorder caused in the reported cohort by a recurrent homozygous
  UGP2 variant that abolishes the short, brain-predominant isoform while leaving
  the long isoform functional. Reduced UGP2 and UDP-glucose in neural-lineage
  cells impair glycogen synthesis, activate the unfolded-protein response, and
  alter neuronal differentiation. Complete-knockout neural stem cells also show
  protein hypoglycosylation, but that readout was unchanged in the
  patient-genotype knock-in model. The clinical
  syndrome begins in early infancy with intractable seizures, profound
  developmental impairment, progressive microcephaly, cerebral atrophy, and
  visual dysfunction.
category: Mendelian
disease_term:
  preferred_term: developmental and epileptic encephalopathy, 83
  term:
    id: MONDO:0032895
    label: developmental and epileptic encephalopathy, 83
synonyms:
- DEE83
- EIEE83
parents:
- genetic developmental and epileptic encephalopathy
- congenital disorder of glycosylation
classifications:
  icimd_category:
  - classification_value: multiple_glycosylation_pathways
    notes: >-
      UGP2 produces UDP-glucose, a substrate for glycogen synthesis and protein
      glycosylation; the classification describes the biochemical pathway and
      does not broaden this entry beyond isoform-specific DEE83. The
      classification is provisional because LAMP2 hypoglycosylation was observed
      in complete-knockout, not patient-genotype knock-in, neural stem cells.
    evidence:
    - reference: PMID:31820119
      reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        reduced synthesis of UDP-glucose, leading to defects in glycogen synthesis
        and protein glycosylation
      explanation: The biochemical evidence supports placement in a multi-pathway glycosylation category.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Affected individuals in the discovery cohort were homozygous for the
    recurrent UGP2 start-codon variant.
  evidence:
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our study identifies a recurrent start codon mutation in UGP2 as a cause
      of a novel autosomal recessive DEE syndrome.
    explanation: The cohort establishes recessive inheritance.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    The disorder-defining publication reported 22 affected individuals from 15
    families; no population prevalence has been established.
  evidence:
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report on 22 individuals from 15 families presenting with
    explanation: The primary cohort provides the cases-in-literature count.
pathophysiology:
- name: Loss of the brain-predominant short UGP2 isoform
  description: >-
    The recurrent c.1A>G start-loss change in the short transcript corresponds
    to p.Met12Val in the long transcript. It prevents translation of the
    brain-predominant short isoform while the altered long isoform remains
    functional.
  role: trigger
  biological_scale: CELLULAR
  genes:
  - preferred_term: UGP2
    term:
      id: hgnc:12527
      label: UGP2
  molecular_functions:
  - preferred_term: UTP:glucose-1-phosphate uridylyltransferase activity
    modifier: DECREASED
    term:
      id: GO:0003983
      label: UTP:glucose-1-phosphate uridylyltransferase activity
  evidence:
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The fact that the Met12Val long isoform was able to rescue the full KO
      phenotype
    explanation: Rescue separates loss of short-isoform translation from long-isoform function.
  downstream:
  - target: Reduced UDP-glucose synthesis in neural-lineage cells
    causal_link_type: DIRECT
    description: Short-isoform loss reduces functional UGP2 after neural differentiation.
    evidence:
    - reference: PMID:31820119
      reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We show that the absence of the shorter isoform leads to a reduction of
        functional UGP2 enzyme in neural stem cells
      explanation: Neural stem cells directly show the isoform-dependent enzyme deficit.
  - target: Premature neuronal differentiation
    causal_link_type: DIRECT
    description: Short-isoform loss produces premature differentiation in neural stem-cell models.
    evidence:
    - reference: PMID:31820119
      reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        altered glycogen metabolism, upregulated unfolded protein response and
        premature neuronal differentiation
      explanation: The engineered neural models directly show premature differentiation downstream of isoform loss.
  - target: Neural stem-cell ER stress and unfolded-protein response
    causal_link_type: DIRECT
    description: Both knockout and patient-genotype knock-in neural stem cells show increased UPR-marker expression.
    evidence:
    - reference: PMID:31820119
      reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        This indicates that NSCs having UGP2 levels under a certain threshold are
        more prone to ER stress and UPR.
      explanation: The result sentence supports UPR induction downstream of low UGP2 in neural stem cells.
  - target: Developmental and epileptic encephalopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The recurrent short-isoform start-loss genotype causes DEE83, but the intervening cellular-to-clinical chain is unresolved.
    evidence:
    - reference: PMID:31820119
      reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our study identifies a recurrent start codon mutation in UGP2 as a cause
        of a novel autosomal recessive DEE syndrome.
      explanation: Human genetic evidence establishes the genotype-to-DEE relationship while leaving intermediates unknown.
  - target: Visual impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced Ugp2 expression reproduces visual disturbance in zebrafish, but the intervening mechanism is unresolved.
    evidence:
    - reference: PMID:31820119
      reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Reduced expression of Ugp2a/Ugp2b in vivo in zebrafish mimics visual
        disturbance and mutant animals show a behavioral phenotype.
      explanation: The animal model supports an Ugp2-to-visual-disturbance link but not its human intermediates.
- name: Reduced UDP-glucose synthesis in neural-lineage cells
  description: >-
    UGP2-deficient and start-loss knock-in neural stem cells have reduced
    capacity to synthesize UDP-glucose; long-isoform expression rescues the
    biochemical defect.
  role: central_effector
  biological_scale: CELLULAR
  genes:
  - preferred_term: UGP2
    term:
      id: hgnc:12527
      label: UGP2
  chemical_entities:
  - preferred_term: UDP-D-glucose
    modifier: DECREASED
    term:
      id: CHEBI:18066
      label: UDP-D-glucose
  evidence:
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: |-
      KO NSCs showed a severely reduced ability to pro-
      duce UDP-glucose
    explanation: The biochemical assay directly measures impaired UDP-glucose production.
  downstream:
  - target: Impaired glycogen synthesis
    causal_link_type: DIRECT
    description: UDP-glucose shortage limits glycogen production in neural-lineage cells.
    evidence:
    - reference: PMID:31820119
      reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        reduced synthesis of UDP-glucose, leading to defects in glycogen synthesis
        and protein glycosylation
      explanation: The study directly connects substrate depletion to both defects.
  - target: Protein hypoglycosylation
    causal_link_type: DIRECT
    description: Reduced UDP-glucose impairs glycosylation in UGP2-deficient neural stem cells.
    evidence:
    - reference: PMID:31820119
      reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        reduced synthesis of UDP-glucose, leading to defects in glycogen synthesis
        and protein glycosylation
      explanation: The source directly supports the glycosylation branch.
- name: Impaired glycogen synthesis
  description: >-
    Knockout, knock-in, and patient-derived neural stem cells show reduced or
    absent glycogen granules, with rescue by functional long UGP2.
  role: downstream
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: glycogen biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0005978
      label: glycogen biosynthetic process
  evidence:
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      KI NSCs showed a more severe reduction in PAS staining compared to the
      ESC state
    explanation: PAS staining measures reduced glycogen in the neural stem-cell state.
- name: Protein hypoglycosylation
  description: >-
    UGP2-knockout neural stem cells show hypoglycosylated LAMP2, rescued by
    either wild-type or p.Met12Val long UGP2. Patient-genotype knock-in NSCs did
    not show this LAMP2 change, likely because the in-vitro isoform switch was
    incomplete and residual UGP2 remained.
  role: downstream
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: glycoprotein metabolic process
    modifier: DECREASED
    term:
      id: GO:0009100
      label: glycoprotein metabolic process
  evidence:
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We found that KO NSCs show hypoglycosylation of LAMP2 that is rescued by
      the overexpression of both WT and mutant long isoform
    explanation: LAMP2 provides a direct glycosylation readout and rescue control.
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: >-
      The absence of changes in LAMP2 glycosylation in KI cells is likely
      explained by a non-complete isoform switch upon in vitro NSC
      differentiation, resulting in residual UGP2 levels
    explanation: The patient-genotype knock-in model did not reproduce the complete-knockout LAMP2 defect.
- name: Neural stem-cell ER stress and unfolded-protein response
  description: >-
    UPR marker genes increase in UGP2-deficient and knock-in neural stem cells,
    but not in embryonic stem cells or patient fibroblasts with sufficient UGP2.
  role: downstream
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: response to endoplasmic reticulum stress
    modifier: INCREASED
    term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
  evidence:
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This indicates that NSCs having UGP2 levels under a certain threshold are
      more prone to ER stress and UPR.
    explanation: Increased UPR-marker expression supports neural-lineage ER stress.
- name: Premature neuronal differentiation
  description: >-
    UGP2-deficient neural stem cells show transcriptomic and marker changes
    consistent with premature neuronal differentiation; this remains a cellular
    mechanism rather than a demonstrated direct cause of each human phenotype.
  role: downstream
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: neural stem cell
    term:
      id: CL:0000047
      label: neural stem cell
  biological_processes:
  - preferred_term: neuron differentiation
    modifier: INCREASED
    term:
      id: GO:0030182
      label: neuron differentiation
  evidence:
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      altered glycogen metabolism, upregulated unfolded protein response and
      premature neuronal differentiation
    explanation: The study reports premature differentiation in its engineered neural models.
phenotypes:
- name: Developmental and epileptic encephalopathy
  category: Clinical
  description: Severe intractable epilepsy with profound developmental encephalopathy is the defining presentation.
  diagnostic: true
  phenotype_term:
    preferred_term: Epileptic encephalopathy
    term:
      id: HP:0200134
      label: Epileptic encephalopathy
  evidence:
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: presenting with a severe form of intractable epilepsy
    explanation: The cohort directly establishes refractory epilepsy.
- name: Infantile spasms
  category: Clinical
  description: Seizures can begin in the first weeks of life and evolve into infantile spasms and West syndrome.
  phenotype_term:
    preferred_term: Infantile spasms
    term:
      id: HP:0012469
      label: Infantile spasms
  evidence:
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      developed into infantile spasms and severe epileptic activity on multiple
      electroencephalograms
    explanation: The index case had infantile spasms with repeated EEG abnormalities.
- name: Global developmental delay
  category: Clinical
  description: Development is severely impaired, with absent milestone acquisition in the detailed index case.
  phenotype_term:
    preferred_term: Severe global developmental delay
    term:
      id: HP:0011344
      label: Severe global developmental delay
  evidence:
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      without acquisition of any noticeable developmental milestones
    explanation: The clinical narrative documents profound developmental impairment.
- name: Progressive microcephaly
  category: Clinical
  description: Microcephaly develops progressively during infancy.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      she had become progressively microcephalic, with a head circumference of
      − 2.96 SD
    explanation: Serial assessment documents progressive microcephaly.
- name: Visual impairment
  category: Clinical
  description: Visual tracking is impaired or absent; retinal pigment changes were reported in all examined individuals.
  phenotype_term:
    preferred_term: Visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
  evidence:
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a disturbance of vision, with retinal pigment changes observed in all
      patients who had undergone ophthalmological examination
    explanation: The cohort consistently reports visual and retinal abnormalities.
- name: Abnormal retinal pigmentation
  category: Clinical
  description: Retinal pigment changes were observed in every patient who underwent ophthalmologic examination; the examined denominator is not reported.
  phenotype_term:
    preferred_term: Abnormal retinal pigmentation
    term:
      id: HP:0007703
      label: Abnormal retinal pigmentation
  evidence:
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      retinal pigment changes observed in all patients who had undergone
      ophthalmological examination.
    explanation: The cohort directly supports a specific retinal-pigmentation phenotype without licensing a whole-cohort frequency band.
- name: Nystagmus
  category: Clinical
  description: Mild nystagmus was documented on ophthalmologic examination in the detailed index case.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hypermetropia and mild nystagmus were noticed upon
      ophthalmological investigation.
    explanation: The index-case examination directly supports nystagmus.
- name: Hypermetropia
  category: Clinical
  description: Hypermetropia was documented on ophthalmologic examination in the detailed index case.
  phenotype_term:
    preferred_term: Hypermetropia
    term:
      id: HP:0000540
      label: Hypermetropia
  evidence:
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hypermetropia and mild nystagmus were noticed upon
      ophthalmological investigation.
    explanation: The index-case examination directly supports hypermetropia.
- name: Hyperreflexia
  category: Clinical
  description: Symmetric deep-tendon reflexes were accentuated, especially in the upper limbs, in the detailed index case.
  phenotype_term:
    preferred_term: Hyperreflexia
    term:
      id: HP:0001347
      label: Hyperreflexia
  evidence:
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      symmetric deep tendon reflexes, more pronounced at the
      upper limbs.
    explanation: The neurologic examination supports hyperreflexia without spanning the intervening figure legend.
- name: Feeding difficulties in infancy
  category: Clinical
  description: Severe developmental impairment necessitated gastrointestinal tube feeding in infancy in the detailed index case.
  phenotype_term:
    preferred_term: Feeding difficulties in infancy
    term:
      id: HP:0008872
      label: Feeding difficulties in infancy
  evidence:
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      milestones, causing the need for gastrointestinal tube feed-
      ing.
    explanation: The hyphenated full-text passage directly documents tube-feeding need in infancy.
- name: Sloping forehead
  category: Clinical
  description: A sloping forehead was one of the recurring mild dysmorphic features described in the index case and cohort figure.
  phenotype_term:
    preferred_term: Sloping forehead
    term:
      id: HP:0000340
      label: Sloping forehead
  evidence:
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      including a sloping forehead, elongated head with suture
      ridging, bitemporal narrowing, a relatively small mouth and
      large ears
    explanation: The clinical description explicitly identifies the sloping forehead.
- name: Narrow forehead
  category: Clinical
  description: Bitemporal narrowing was documented in the recurring mild dysmorphic gestalt.
  phenotype_term:
    preferred_term: Narrow forehead
    term:
      id: HP:0000341
      label: Narrow forehead
  evidence:
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      bitemporal narrowing, high hairline,
      arched eyebrows, pronounced philtrum, a relatively small mouth
      and large ears.
    explanation: Bitemporal narrowing is an exact synonym of the selected HPO term.
- name: High anterior hairline
  category: Clinical
  description: A high anterior hairline was documented in the recurring mild dysmorphic gestalt.
  phenotype_term:
    preferred_term: High anterior hairline
    term:
      id: HP:0009890
      label: High anterior hairline
  evidence:
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      bitemporal narrowing, high hairline,
      arched eyebrows, pronounced philtrum, a relatively small mouth
      and large ears.
    explanation: The figure legend directly documents the high hairline.
- name: Highly arched eyebrow
  category: Clinical
  description: Arched eyebrows were documented in the recurring mild dysmorphic gestalt.
  phenotype_term:
    preferred_term: Highly arched eyebrow
    term:
      id: HP:0002553
      label: Highly arched eyebrow
  evidence:
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      bitemporal narrowing, high hairline,
      arched eyebrows, pronounced philtrum, a relatively small mouth
      and large ears.
    explanation: Arched eyebrows is an exact synonym of the selected HPO term.
- name: Cerebral atrophy
  category: Clinical
  description: MRI can evolve from reduced white matter in infancy to global cerebral atrophy without a major malformation.
  phenotype_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      displayed reduced white matter, that further developed into global atrophy
      with wide sulci
    explanation: Serial MRI documents progressive atrophy.
- name: Abnormal facial shape
  category: Clinical
  description: Similar mild dysmorphic facial features may make the syndrome recognizable.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      all patients seem to share similar, although mild, dysmorphisms
    explanation: The authors describe a shared mild dysmorphic gestalt.
genetic:
- name: UGP2
  association: Recurrent homozygous isoform-specific start-loss variant c.1A>G in the short transcript
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: UGP2
    term:
      id: hgnc:12527
      label: UGP2
  evidence:
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome sequencing identified a recurrent, homozygous variant
      (chr2:64083454A > G) in the essential UDP-glucose pyrophosphorylase (
      UGP2) gene in all probands.
    explanation: All probands carried the same homozygous variant.
diagnosis:
- name: Isoform-aware molecular diagnosis
  description: >-
    Exome analysis identifies the homozygous recurrent UGP2 variant;
    interpretation must account for its distinct consequences in the long and
    short transcripts, and segregation testing can confirm parental carrier status.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  results: Homozygous UGP2 short-transcript c.1A>G start loss supports DEE83.
  evidence:
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome sequencing identified a recurrent, homozygous variant
      (chr2:64083454A > G)
    explanation: Exome sequencing found the causal recurrent variant.
- name: Electroencephalography
  description: EEG characterizes the severe epileptic encephalopathy and can establish a West-syndrome presentation.
  diagnosis_term:
    preferred_term: electroencephalography
    term:
      id: NCIT:C38054
      label: Electroencephalography
  results: Severe epileptic activity with a disorganized multifocal pattern may be present.
  evidence:
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      infantile spasms and severe epileptic activity on multiple
      electroencephalograms
    explanation: Repeated EEGs documented the epileptic syndrome.
- name: Brain MRI
  description: Serial MRI assesses reduced white matter and progressive global atrophy while excluding major malformations.
  diagnosis_term:
    preferred_term: magnetic resonance imaging procedure
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  results: Reduced white matter may progress to global atrophy without major structural anomalies.
  evidence:
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      microcephaly but no major structural anomalies
    explanation: The figure description summarizes the characteristic MRI pattern.
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      displayed reduced white matter, that further developed into global atrophy
      with wide sulci
    explanation: Serial imaging directly supports progression from white-matter reduction to atrophy.
- name: Ophthalmologic examination
  description: Ophthalmologic assessment evaluates retinal pigment changes, refractive error, and nystagmus.
  results: Visual dysfunction with retinal pigment abnormalities supports the syndrome.
  evidence:
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hypermetropia and mild nystagmus were noticed upon ophthalmological
      investigation.
    explanation: The clinical examination directly defines the ocular findings.
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      retinal pigment changes observed in all patients who had undergone
      ophthalmological examination.
    explanation: The cohort supports retinal pigment assessment as a diagnostic evaluation.
treatments:
- name: Symptomatic antiseizure therapy
  description: >-
    Multiple antiseizure drugs, ACTH, and ketogenic diet were attempted in the
    index case, but seizures remained daily and intractable. This documents
    symptomatic management and poor response, not an effective disease-specific therapy.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Epileptic encephalopathy
    term:
      id: HP:0200134
      label: Epileptic encephalopathy
  - preferred_term: Infantile spasms
    term:
      id: HP:0012469
      label: Infantile spasms
  evidence:
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Despite the use of multiple anti-epileptic drugs, including ACTH and a
      ketogenic diet, seizures remained intractable and occurred daily.
    explanation: The detailed case documents treatment attempts and persistent seizures.
progression:
- phase: Early infancy
  notes: Irritability and jitteriness can appear in the first weeks, followed by infantile spasms and severe epilepsy.
  evidence:
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      which developed into infantile spasms and severe epileptic activity on
      multiple electroencephalograms
    explanation: The index case establishes early-infantile onset and evolution.
- phase: Infancy and early childhood
  notes: Severe developmental impairment persists while microcephaly and cerebral atrophy progress; early mortality is common in the reported cohort.
  evidence:
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ten of these individuals passed away early, with the majority before the
      age of 3.5 years.
    explanation: The cohort documents substantial early mortality.
experimental_models:
- name: UGP2-engineered and patient-derived neural stem-cell models
  description: >-
    CRISPR knockout and recurrent-variant knock-in human embryonic stem cells,
    together with patient iPSC-derived neural stem cells and long-isoform rescue,
    model the neural-lineage-specific biochemical and differentiation defects.
  experimental_model_type: IPSC_DERIVED_MODEL
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: neural stem cell
    term:
      id: CL:0000047
      label: neural stem cell
  conditions:
  - UGP2 knockout
  - recurrent UGP2 variant knock-in
  - patient-derived iPSC neural differentiation
  - long-isoform rescue
  cell_source: Engineered human embryonic stem cells and patient-derived induced pluripotent stem cells
  culture_system: In-vitro neural stem-cell differentiation
  publication: PMID:31820119
  modeled_mechanisms:
  - target: Reduced UDP-glucose synthesis in neural-lineage cells
    relationship: RECAPITULATES
    evidence:
    - reference: PMID:31820119
      reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: |-
        KO NSCs showed a severely reduced ability to pro-
        duce UDP-glucose
      explanation: The model directly measures reduced UGP2-dependent substrate production.
  - target: Impaired glycogen synthesis
    relationship: RECAPITULATES
    evidence:
    - reference: PMID:31820119
      reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        KI NSCs showed a more severe reduction in PAS staining compared to the
        ESC state
      explanation: PAS staining directly demonstrates the modeled glycogen defect.
  - target: Protein hypoglycosylation
    relationship: RECAPITULATES
    evidence:
    - reference: PMID:31820119
      reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We found that KO NSCs show hypoglycosylation of LAMP2 that is rescued by
        the overexpression of both WT and mutant long isoform
      explanation: LAMP2 directly reports the modeled glycosylation defect.
  - target: Protein hypoglycosylation
    relationship: FAILS_TO_RECAPITULATE
    limitations: >-
      The patient-genotype knock-in neural stem cells retained residual UGP2
      because the in-vitro isoform switch was incomplete and therefore did not
      reproduce the complete-knockout LAMP2 glycosylation defect.
    evidence:
    - reference: PMID:31820119
      reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The absence of changes in LAMP2 glycosylation in KI cells is likely
        explained by a non-complete isoform switch upon in vitro NSC
        differentiation, resulting in residual UGP2 levels
      explanation: The patient-genotype knock-in arm fails to reproduce the knockout glycosylation phenotype.
  - target: Neural stem-cell ER stress and unfolded-protein response
    relationship: RECAPITULATES
    evidence:
    - reference: PMID:31820119
      reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        This indicates that NSCs having UGP2 levels under a certain threshold are
        more prone to ER stress and UPR.
      explanation: UPR-marker measurements directly support this modeled mechanism.
  - target: Premature neuronal differentiation
    relationship: RECAPITULATES
    evidence:
    - reference: PMID:31820119
      reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        altered glycogen metabolism, upregulated unfolded protein response and
        premature neuronal differentiation
      explanation: The model directly demonstrates the differentiation phenotype.
  evidence:
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Similar expression changes were observed in NSCs differentiated from
      induced pluripotent stem cells (iPSCs) that we had generated from family 1
    explanation: Patient-derived neural stem cells reproduce the engineered-model changes.
animal_models:
- name: ugp2a/ugp2b-deficient zebrafish
  species: Danio rerio
  genotype: CRISPR-generated ugp2a and ugp2b double-mutant larvae
  description: >-
    Double-mutant larvae have reduced Ugp2 activity, reduced eye movements, and
    increased movement responses after convulsant exposure. The model supports
    susceptibility rather than full recapitulation of the human syndrome.
  genes:
  - preferred_term: UGP2
    term:
      id: hgnc:12527
      label: UGP2
  associated_phenotypes:
  - Visual disturbance
  - Increased seizure susceptibility after 4-aminopyridine
  modeled_mechanisms:
  - target: Reduced UDP-glucose synthesis in neural-lineage cells
    relationship: PARTIALLY_RECAPITULATES
    limitations: >-
      Reduced enzyme activity and behavioral susceptibility are reproduced,
      but the zebrafish does not establish the full human neural-lineage or
      clinical syndrome.
    evidence:
    - reference: PMID:31820119
      reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        showing reduced Ugp2 enzyme activity in double mutant zebrafish
      explanation: The zebrafish biochemical assay reproduces reduced Ugp2 activity.
  evidence:
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      velocity compared to controls, which might indicate an increased seizure
      susceptibility
    explanation: Convulsant challenge demonstrates increased seizure susceptibility.
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      severely reduced Ugp2a/Ugp2b levels result in a behavior defect with
      reduced eye movements
    explanation: The zebrafish model directly supports the eye-movement phenotype.
datasets:
- accession: geo:GSE137129
  title: RNA-seq of UGP2 mutant human embryonic stem cells and in vitro differentiated neural stem cells
  description: >-
    Transcriptomic profiles from engineered UGP2 knockout, recurrent-variant
    knock-in, wild-type, and rescue human stem-cell models used to identify
    neural-lineage transcriptional consequences of UGP2 deficiency.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  conditions:
  - UGP2 knockout
  - recurrent variant knock-in
  - wild-type control
  - long-isoform rescue
  genes:
  - preferred_term: UGP2
    term:
      id: hgnc:12527
      label: UGP2
  publication: PMID:31820119
  evidence:
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      RNA-Seq of in vitro studies is publicly available through the National
      Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO)
      under accession number GSE137129.
    explanation: The paper's data-availability statement identifies the accession.
discussions:
- discussion_id: mismatch_ugp2_knockin_lamp2_glycosylation
  prompt: Does the recurrent patient-genotype start-loss allele cause protein hypoglycosylation in a model with a complete brain-like isoform switch?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Protein hypoglycosylation
  rationale: >-
    Complete-knockout NSCs show rescued LAMP2 hypoglycosylation, but the
    patient-genotype knock-in model retains residual UGP2 and shows no LAMP2
    glycosylation change. A model completing the fetal-brain isoform switch is
    needed to determine whether this branch applies to the human genotype.
  evidence:
  - reference: PMID:31820119
    reference_title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The absence of changes in LAMP2 glycosylation in KI cells is likely
      explained by a non-complete isoform switch upon in vitro NSC
      differentiation, resulting in residual UGP2 levels
    explanation: The figure legend explicitly records the patient-genotype model's negative LAMP2 result and its proposed technical explanation.
references:
- reference: PMID:31820119
  title: "Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases."
review_notes: >-
  This review deliberately limits DEE83 to the recurrent isoform-specific
  short-transcript start-loss syndrome reported in 22 individuals from 15
  families; it does not generalize these findings to every possible biallelic
  UGP2 disorder. The sole disease-specific primary publication supplies a rich
  clinical cohort, engineered and patient-derived neural models, zebrafish
  modeling, and public RNA-seq dataset GSE137129. No matching GeneReviews chapter
  or repository deep-research artifact was found. Mechanism nodes were atomized
  and all serialized causal edges retain evidence calibrated to their source.
  The disease-defining and visual endpoints are linked through explicitly
  unknown intermediates; other phenotypes remain unwired where the study offers
  only biologic plausibility. Cohort-wide frequencies for many additional HPO
  annotations reside in supplementary material that is not present in the
  cached main text, so those frequency claims are intentionally not imported;
  the main-text-quotable nystagmus, hypermetropia, hyperreflexia, infant feeding
  difficulty, sloping forehead, bitemporal narrowing, high hairline, and arched
  eyebrow findings are retained without fabricated cohort frequency bands. The
  main text says foveal hypopigmentation, not the
  HPOA near-neighbor foveal hypoplasia, so that term is not promoted. The
  complete-knockout glycosylation result and
  patient-genotype knock-in null result are both retained, and the contradicted
  hypoglycosylation-to-UPR dependency was removed. Treatment evidence is
  limited to unsuccessful symptomatic seizure management; no disease-modifying
  therapy or disorder-specific clinical trial is established.
📚

References & Deep Research

References

1
PMID:31820119
Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases.
No top-level findings curated for this source.