UGP2-related developmental and epileptic encephalopathy 83 is an autosomal recessive isoform-specific UDP-glucose pyrophosphorylase disorder. A recurrent homozygous start-loss variant disrupts the shorter UGP2 isoform that is predominant in brain while sparing enough long-isoform function for organismal viability. Neural stem cells therefore have reduced functional UGP2 enzyme, reduced UDP-glucose production, altered glycogen metabolism, abnormal protein glycosylation/proteostasis stress, and premature neuronal differentiation, producing severe intractable epilepsy, developmental delay, progressive microcephaly, and visual disturbance.
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name: UGP2-related developmental and epileptic encephalopathy 83
creation_date: "2026-07-06T06:04:18Z"
description: >-
UGP2-related developmental and epileptic encephalopathy 83 is an autosomal
recessive isoform-specific UDP-glucose pyrophosphorylase disorder. A recurrent
homozygous start-loss variant disrupts the shorter UGP2 isoform that is
predominant in brain while sparing enough long-isoform function for organismal
viability. Neural stem cells therefore have reduced functional UGP2 enzyme,
reduced UDP-glucose production, altered glycogen metabolism, abnormal protein
glycosylation/proteostasis stress, and premature neuronal differentiation,
producing severe intractable epilepsy, developmental delay, progressive
microcephaly, and visual disturbance.
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: >-
Classified as a multiple-glycosylation-pathway disorder because UGP2
produces UDP-glucose, a donor/precursor for glycogen metabolism and
protein glycosylation pathways.
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
DEE83 is caused by a homozygous recurrent UGP2 start-loss variant affecting
the shorter brain-predominant isoform.
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 study directly establishes autosomal recessive UGP2-related DEE.
pathophysiology:
- name: Brain-predominant UGP2 isoform loss
description: >-
The recurrent start-loss variant abolishes the shorter UGP2 isoform that is
predominant in brain, reducing functional UDP-glucose pyrophosphorylase in
neural stem cells.
role: trigger
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
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: >-
We show that the absence of the shorter isoform leads to a reduction of
functional UGP2 enzyme in neural stem cells
explanation: >-
In-vitro neural stem cell experiments support reduced functional UGP2 as
the primary defect.
downstream:
- target: UDP-glucose-dependent metabolic and glycosylation stress
description: >-
Reduced functional UGP2 lowers UDP-glucose production in neural stem
cells, affecting glycogen metabolism, glycosylation, and ER proteostasis.
causal_link_type: DIRECT
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: >-
leading to altered glycogen metabolism, upregulated unfolded protein
response and premature neuronal differentiation
explanation: >-
The abstract connects short-isoform loss to metabolic stress and
premature neuronal differentiation.
- name: UDP-glucose-dependent metabolic and glycosylation stress
description: >-
UDP-glucose shortage in brain-lineage cells disrupts glycogen synthesis and
protein glycosylation, with unfolded-protein-response activation.
role: central_effector
biological_processes:
- preferred_term: protein N-linked glycosylation
modifier: ABNORMAL
term:
id: GO:0006487
label: protein N-linked glycosylation
- preferred_term: protein folding in endoplasmic reticulum
modifier: ABNORMAL
term:
id: GO:0034975
label: protein folding in endoplasmic reticulum
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 full text directly links reduced UDP-glucose synthesis to protein
glycosylation defects.
downstream:
- target: Premature neuronal differentiation and epileptic encephalopathy
description: >-
Neural stem cell stress and premature neuronal differentiation impair
brain development and produce the developmental epileptic encephalopathy
phenotype.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- neural stem cell unfolded-protein response
- premature neuronal differentiation
- name: Premature neuronal differentiation and epileptic encephalopathy
description: >-
The brain-restricted isoform loss produces severe intractable epilepsy,
severe developmental delay, progressive microcephaly, and visual
disturbance.
role: consequence
cell_types:
- preferred_term: neuron
term:
id: CL:0000540
label: neuron
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 severe form of intractable epilepsy, severe developmental delay,
progressive microcephaly, visual disturbance and similar minor
dysmorphisms.
explanation: >-
The patient cohort defines the recurrent neurologic phenotype.
phenotypes:
- name: Developmental and epileptic encephalopathy
description: Therapy-resistant epilepsy with developmental encephalopathy is central to DEE83.
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 reports severe intractable epilepsy.
- name: Global developmental delay
description: Severe developmental delay is a core feature.
phenotype_term:
preferred_term: Global developmental delay
term:
id: HP:0001263
label: 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: >-
severe developmental delay, progressive microcephaly, visual disturbance
explanation: The abstract directly reports severe developmental delay.
- name: Progressive microcephaly
description: Progressive microcephaly occurs in the reported syndrome.
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: >-
progressive microcephaly
explanation: The abstract directly reports progressive microcephaly.
genetic:
- name: UGP2
association: Homozygous isoform-specific start-loss variant
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: The cohort identifies the recurrent homozygous UGP2 variant.