Hyperinsulinism-hyperammonemia syndrome

Summary

Hyperinsulinism-hyperammonemia syndrome (MONDO:0011717) is a disease caused by GLUD1 (GenCC Definitive), with 2 cohort genes and 3 clinical trials. Top therapeutic interventions include vitamin e.

At a glance

• Prevalence: Unknown (Europe)
• Causal gene: GLUD1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 214
• Phenotypes (HPO): 12
• Clinical trials: 3

Clinical features

Signs & symptoms

Clinical features (HPO)

12 HPO clinical features (Orphanet curated; top 12 by frequency):

HPO ID	Term	Frequency
HP:0008162	Asymptomatic hyperammonemia	Very frequent (80-99%)
HP:0012051	Reactive hypoglycemia	Very frequent (80-99%)
HP:0000825	Hyperinsulinemic hypoglycemia	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001328	Specific learning disability	Frequent (30-79%)
HP:0002121	Generalized non-motor (absence) seizure	Frequent (30-79%)
HP:0002197	Generalized-onset seizure	Frequent (30-79%)
HP:0002342	Intellectual disability, moderate	Frequent (30-79%)
HP:0007018	Attention deficit hyperactivity disorder	Frequent (30-79%)
HP:0008283	Fasting hyperinsulinemia	Frequent (30-79%)
HP:0011198	EEG with generalized epileptiform discharges	Frequent (30-79%)
HP:0012402	Increased urine alpha-ketoglutarate concentration	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperinsulinism-hyperammonemia syndrome
Mondo ID	MONDO:0011717
MeSH	C538375
OMIM	606762
Orphanet	35878
DOID	DOID:0070217
NCIT	C131832
UMLS	C1847555
MedGen	376153
GARD	0009931
Is cancer (heuristic)	no

Also known as: GDH hyperinsulinism · GLUD1 hyperinsulinism · glutamate dehydrogenase 1 hyperinsulinism · HA/hi syndrome · HHF6 · hi/HA syndrome · hyperinsulinemic hypoglycemia familial 6 · hyperinsulinemic hypoglycemia, familial, 6 · hyperinsulinemic hypoglycemia, familial, type 6 · hyperinsulinism hyperammonemia syndrome · hyperinsulinism-hyperammonemia syndrome · hyperinsulinism/hyperammonemia syndrome

Data availability: 214 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › digestive system disorder › pancreas disorder › endocrine pancreas disorder › islet cell adenomatosis › congenital isolated hyperinsulinism › diazoxide-sensitive diffuse hyperinsulinism › hyperinsulinism-hyperammonemia syndrome

Related subtypes (7): hyperinsulinemic hypoglycemia, familial, 4, exercise-induced hyperinsulinism, hyperinsulinism due to HNF4A deficiency, hyperinsulinism due to UCP2 deficiency, autosomal dominant hyperinsulinism due to SUR1 deficiency, autosomal dominant hyperinsulinism due to Kir6.2 deficiency, hyperinsulinism due to HNF1A deficiency

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

214 retrieved; paginated sample, class counts are floors:

101 uncertain significance, 69 likely benign, 17 conflicting classifications of pathogenicity, 9 benign, 8 benign/likely benign, 6 pathogenic, 3 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1072420	NM_005271.5(GLUD1):c.1507A>G (p.Lys503Glu)	GLUD1	Pathogenic	criteria provided, single submitter
16121	NM_005271.5(GLUD1):c.1519C>T (p.His507Tyr)	GLUD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16122	NM_005271.5(GLUD1):c.1493C>T (p.Ser498Leu)	GLUD1	Pathogenic	criteria provided, multiple submitters, no conflicts
16125	NM_005271.5(GLUD1):c.1496G>A (p.Gly499Asp)	GLUD1	Pathogenic	criteria provided, single submitter
16126	NM_005271.5(GLUD1):c.1046A>C (p.Glu349Ala)	GLUD1	Pathogenic	no assertion criteria provided
16128	NM_005271.5(GLUD1):c.820C>T (p.Arg274Cys)	GLUD1	Pathogenic	criteria provided, multiple submitters, no conflicts
16129	NM_005271.5(GLUD1):c.965G>A (p.Arg322His)	GLUD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1802279	NM_005271.5(GLUD1):c.943C>T (p.His315Tyr)	GLUD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
226111	NM_005271.5(GLUD1):c.1496G>T (p.Gly499Val)	GLUD1	Pathogenic	criteria provided, multiple submitters, no conflicts
1685333	NM_005271.5(GLUD1):c.1496G>C (p.Gly499Ala)	GLUD1	Likely pathogenic	criteria provided, single submitter
1338629	NM_005271.5(GLUD1):c.953G>C (p.Arg318Thr)	GLUD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1438940	NM_005271.5(GLUD1):c.1466C>T (p.Pro489Leu)	GLUD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
16124	NM_005271.5(GLUD1):c.1495G>A (p.Gly499Ser)	GLUD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1912578	NM_005271.5(GLUD1):c.1466C>G (p.Pro489Arg)	GLUD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211086	NM_005271.5(GLUD1):c.1498G>A (p.Ala500Thr)	GLUD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2135702	NM_005271.5(GLUD1):c.1358G>A (p.Arg453His)	GLUD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2573541	NM_005271.5(GLUD1):c.1063C>T (p.His355Tyr)	GLUD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
301390	NM_005271.5(GLUD1):c.1557+12G>A	GLUD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
301391	NM_005271.5(GLUD1):c.1515C>T (p.Ile505=)	GLUD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
301392	NM_005271.5(GLUD1):c.1403-11T>C	GLUD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
301393	NM_005271.5(GLUD1):c.1402+10G>A	GLUD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
785322	NM_005271.5(GLUD1):c.393C>G (p.Val131=)	GLUD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
848715	NM_005271.5(GLUD1):c.635A>G (p.Lys212Arg)	GLUD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
878672	NM_005271.5(GLUD1):c.330G>A (p.Lys110=)	GLUD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
880412	NM_005271.5(GLUD1):c.1500A>G (p.Ala500=)	GLUD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
878673	NM_005271.5(GLUD1):c.55C>T (p.Leu19=)	LOC130004255	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
301401	NM_005271.5(GLUD1):c.-44C>T	SHLD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1007983	NM_005271.5(GLUD1):c.1198-11CT[2]	GLUD1	Uncertain significance	criteria provided, single submitter
1030901	NM_005271.5(GLUD1):c.839T>C (p.Ile280Thr)	GLUD1	Uncertain significance	criteria provided, single submitter
1339165	NM_005271.5(GLUD1):c.1111A>G (p.Ile371Val)	GLUD1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
GLUD1	Definitive	Autosomal dominant	hyperinsulinism-hyperammonemia syndrome	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GLUD1	Orphanet:35878	Hyperinsulinism-hyperammonemia syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GLUD1	HGNC:4335	ENSG00000148672	P00367	Glutamate dehydrogenase 1, mitochondrial	gencc,clinvar
SHLD2	HGNC:28773	ENSG00000122376	Q86V20	Shieldin complex subunit 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GLUD1	Glutamate dehydrogenase 1, mitochondrial	Mitochondrial glutamate dehydrogenase that catalyzes the conversion of L-glutamate into alpha-ketoglutarate.
SHLD2	Shieldin complex subunit 2	Component of the shieldin complex, which plays an important role in repair of DNA double-stranded breaks (DSBs).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GLUD1	Enzyme (other)	yes	1.4.1.3	Glu/Leu/Phe/Val/Trp_DH, Glu/Leu/Phe/Val/Trp_DH_C, Glu/Leu/Phe/Val/Trp_DH_dimer
SHLD2	Other/Unknown	no		FAM35A, SHLD2_C, SHLD2_OB1

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
nucleus accumbens	1
right lobe of liver	1
superior vestibular nucleus	1
calcaneal tendon	1
duodenum	1
endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GLUD1	291	ubiquitous	marker	right lobe of liver, nucleus accumbens, superior vestibular nucleus
SHLD2	141	ubiquitous	marker	calcaneal tendon, endometrium, duodenum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GLUD1	3,309
SHLD2	517

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GLUD1	P00367	7
SHLD2	Q86V20	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Glutamate and glutamine metabolism	1	815.7×	0.004	GLUD1
Transcriptional activation of mitochondrial biogenesis	1	203.9×	0.007	GLUD1
Mitochondrial protein degradation	1	114.2×	0.009	GLUD1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
somatic diversification of immunoglobulins involved in immune response	1	2106.5×	0.002	SHLD2
L-glutamate catabolic process	1	2106.5×	0.002	GLUD1
obsolete glutamate biosynthetic process	1	1685.2×	0.002	GLUD1
tricarboxylic acid metabolic process	1	1404.3×	0.002	GLUD1
telomere maintenance in response to DNA damage	1	936.2×	0.003	SHLD2
L-glutamine metabolic process	1	648.1×	0.003	GLUD1
positive regulation of isotype switching	1	648.1×	0.003	SHLD2
regulation of double-strand break repair via homologous recombination	1	495.6×	0.003	SHLD2
positive regulation of double-strand break repair via nonhomologous end joining	1	495.6×	0.003	SHLD2
negative regulation of double-strand break repair via homologous recombination	1	312.1×	0.004	SHLD2
substantia nigra development	1	183.2×	0.006	GLUD1
positive regulation of insulin secretion	1	127.7×	0.008	GLUD1
DNA repair	1	31.9×	0.031	SHLD2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GLUD1	0	0
SHLD2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GLUD1	1.4.1.3	glutamate dehydrogenase [NAD(P)+]

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	GLUD1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SHLD2

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
GLUD1	0	—
SHLD2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04984798	PHASE2	WITHDRAWN	Vitamin E Efficacy in HI/HA
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT03797222	Not specified	COMPLETED	Vitamin E Supplementation in Hyperinsulinism/Hyperammonemia Syndrome

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
VITAMIN E	4	2