3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome

Summary

3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MONDO:0013875) is a disease caused by SERAC1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SERAC1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 323

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		67	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome
Mondo ID	MONDO:0013875
OMIM	614739
Orphanet	352328
DOID	DOID:0110001
SNOMED CT	711409002
UMLS	C4040739
MedGen	873604
GARD	0012963
Is cancer (heuristic)	no

Also known as: 3-methylglutaconic aciduria caused by mutation in SERAC1 · 3-methylglutaconic aciduria type VI · 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome · 3-methylglutaconic aciduria with deafness-encephalopathy-Leigh-like syndrome · 3-MGCA type IV (formerly) · 3-MGCA-4 (formerly) · MEGDEL · MEGDEL syndrome · MGCA6 · SERAC1 3-methylglutaconic aciduria · SERAC1 defect

Data availability: 323 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome

Related subtypes (13): oxoglutaricaciduria, multiple acyl-CoA dehydrogenase deficiency, inborn mitochondrial myopathy, HSD10 mitochondrial disease, histiocytoid cardiomyopathy, hypotonia-cystinuria syndrome, fumaric aciduria, mitochondrial pyruvate carrier deficiency, mitochondrial oxidative phosphorylation disorder, mitochondrial membrane transport disorder, inherited lipoic acid biosynthesis defect, pyruvate dehydrogenase deficiency, OPA1-related optic atrophy with or without extraocular features

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

323 retrieved; paginated sample, class counts are floors:

113 likely benign, 110 uncertain significance, 27 pathogenic, 17 conflicting classifications of pathogenicity, 17 benign, 15 benign/likely benign, 15 likely pathogenic, 8 pathogenic/likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
2427078	NC_000006.11:g.(?158532398)(162868359_?)del	ACAT2	Pathogenic	criteria provided, single submitter
1184550	NM_032861.4(SERAC1):c.1850_1851insA (p.Pro618fs)	SERAC1	Pathogenic	no assertion criteria provided
120184	NM_032861.4(SERAC1):c.202C>T (p.Arg68Ter)	SERAC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1329462	NM_032861.4(SERAC1):c.1504CTT[1] (p.Leu503del)	SERAC1	Pathogenic	no assertion criteria provided
1430677	NM_032861.4(SERAC1):c.625G>T (p.Glu209Ter)	SERAC1	Pathogenic	criteria provided, single submitter
1456235	NM_032861.4(SERAC1):c.1403+1G>A	SERAC1	Pathogenic	criteria provided, single submitter
1804045	NM_032861.4(SERAC1):c.1211G>A (p.Gly404Glu)	SERAC1	Pathogenic	criteria provided, single submitter
1957954	NM_032861.4(SERAC1):c.777T>G (p.Tyr259Ter)	SERAC1	Pathogenic	criteria provided, single submitter
1961244	NM_032861.4(SERAC1):c.1266dup (p.Pro423fs)	SERAC1	Pathogenic	criteria provided, single submitter
208610	NM_032861.4(SERAC1):c.262_265dup (p.Gly89fs)	SERAC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2136486	NM_032861.4(SERAC1):c.310A>T (p.Lys104Ter)	SERAC1	Pathogenic	criteria provided, single submitter
215142	NM_032861.4(SERAC1):c.1126C>T (p.Gln376Ter)	SERAC1	Pathogenic	criteria provided, multiple submitters, no conflicts
215148	NM_032861.4(SERAC1):c.1628_1629dup (p.Val544fs)	SERAC1	Pathogenic	criteria provided, single submitter
2584436	NM_032861.4(SERAC1):c.1339C>T (p.Arg447Ter)	SERAC1	Pathogenic	criteria provided, multiple submitters, no conflicts
2705467	NM_032861.4(SERAC1):c.116C>G (p.Ser39Ter)	SERAC1	Pathogenic	criteria provided, single submitter
2759584	NM_032861.4(SERAC1):c.698_699delinsAGTGATA (p.Leu233Ter)	SERAC1	Pathogenic	criteria provided, single submitter
2782312	NM_032861.4(SERAC1):c.236_237del (p.Thr79fs)	SERAC1	Pathogenic	criteria provided, multiple submitters, no conflicts
280568	NM_032861.4(SERAC1):c.227_228dup (p.Val77fs)	SERAC1	Pathogenic	criteria provided, multiple submitters, no conflicts
2916178	NM_032861.4(SERAC1):c.134_137del (p.Ser45fs)	SERAC1	Pathogenic	criteria provided, single submitter
35556	NM_032861.4(SERAC1):c.442C>T (p.Arg148Ter)	SERAC1	Pathogenic	criteria provided, multiple submitters, no conflicts
35558	NM_032861.4(SERAC1):c.1167_1170del	SERAC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
35559	NM_032861.4(SERAC1):c.1432CTT[1] (p.Leu479del)	SERAC1	Pathogenic	no assertion criteria provided
3642297	NM_032861.4(SERAC1):c.289G>T (p.Glu97Ter)	SERAC1	Pathogenic	criteria provided, single submitter
420150	NM_032861.4(SERAC1):c.1822_1828+10delinsACCAACAGG	SERAC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
430608	NM_032861.4(SERAC1):c.1643_1646dup (p.Leu550fs)	SERAC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
430610	NM_032861.4(SERAC1):c.1403+1G>C	SERAC1	Pathogenic	criteria provided, single submitter
445812	NM_032861.4(SERAC1):c.1159C>T (p.Arg387Ter)	SERAC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
452315	NM_032861.4(SERAC1):c.1102C>T (p.Arg368Ter)	SERAC1	Pathogenic	criteria provided, multiple submitters, no conflicts
4807929	NM_032861.4(SERAC1):c.733C>T (p.Gln245Ter)	SERAC1	Pathogenic	criteria provided, single submitter
587693	NM_032861.4(SERAC1):c.92-239G>C	SERAC1	Pathogenic	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
SERAC1	Definitive	Autosomal recessive	3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SERAC1	Orphanet:352328	MEGDEL 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
SERAC1	HGNC:21061	ENSG00000122335	Q96JX3	Protein SERAC1	gencc,clinvar
ACAT2	HGNC:94	ENSG00000120437	Q9BWD1	Acetyl-CoA acetyltransferase, cytosolic	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SERAC1	Protein SERAC1	Facilitates the transport of serine from the cytosol to the mitochondria by interacting with and stabilizing Sideroflexin-1 (SFXN1), a mitochondrial serine transporter, playing a fundamental role in the one-carbon cycle responsible for the…
ACAT2	Acetyl-CoA acetyltransferase, cytosolic	Involved in the biosynthetic pathway of cholesterol.

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)
SERAC1	Other/Unknown	no		ARM-like, ARM-type_fold, AB_hydrolase_fold
ACAT2	Enzyme (other)	yes	2.3.1.9	Thiolase, Thiolase-like, Thiolase_AS

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
endothelial cell	1
epithelial cell of pancreas	1
islet of Langerhans	1
adrenal tissue	1
ganglionic eminence	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SERAC1	214	ubiquitous	marker	epithelial cell of pancreas, endothelial cell, islet of Langerhans
ACAT2	283	ubiquitous	marker	ventricular zone, ganglionic eminence, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACAT2	2,250
SERAC1	885

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ACAT2	Q9BWD1	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SERAC1	Q96JX3	78.66

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
Cholesterol biosynthesis	1	1142.0×	0.003	ACAT2
Lanosterol biosynthesis	1	761.3×	0.003	ACAT2
Metabolism of steroids	1	137.6×	0.012	ACAT2
Metabolism of lipids	1	31.6×	0.040	ACAT2
Metabolism	1	11.6×	0.086	ACAT2

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
farnesyl diphosphate biosynthetic process, mevalonate pathway	1	2808.7×	0.002	ACAT2
phosphatidylglycerol acyl-chain remodeling	1	936.2×	0.004	SERAC1
intracellular cholesterol transport	1	648.1×	0.004	SERAC1
phospholipid biosynthetic process	1	337.0×	0.005	SERAC1
fatty acid metabolic process	1	96.8×	0.014	ACAT2
extracellular matrix organization	1	61.1×	0.019	SERAC1
lipid metabolic process	1	45.8×	0.022	ACAT2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SERAC1	0	0
ACAT2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ACAT2	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ACAT2	2.3.1.9	acetyl-CoA C-acetyltransferase

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	ACAT2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SERAC1

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)
SERAC1	0	—
ACAT2	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.