Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities

Summary

Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities (MONDO:0015003) is a disease caused by MECR (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MECR (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 20
• Phenotypes (HPO): 31

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		7	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

31 HPO clinical features (Orphanet curated; top 31 by frequency):

HPO ID	Term	Frequency
HP:0001260	Dysarthria	Very frequent (80-99%)
HP:0001332	Dystonia	Very frequent (80-99%)
HP:0031206	Striatal T2 hyperintensity	Very frequent (80-99%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0000648	Optic atrophy	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0002451	Limb dystonia	Frequent (30-79%)
HP:0007663	Reduced visual acuity	Frequent (30-79%)
HP:0012179	Craniofacial dystonia	Frequent (30-79%)
HP:0100660	Dyskinesia	Frequent (30-79%)
HP:0001336	Myoclonus	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0002059	Cerebral atrophy	Occasional (5-29%)
HP:0002072	Chorea	Occasional (5-29%)
HP:0002315	Headache	Occasional (5-29%)
HP:0002530	Axial dystonia	Occasional (5-29%)
HP:0008314	Decreased activity of mitochondrial complex II	Occasional (5-29%)
HP:0008347	Decreased activity of mitochondrial complex IV	Occasional (5-29%)
HP:0011923	Decreased activity of mitochondrial complex I	Occasional (5-29%)
HP:0011968	Feeding difficulties	Occasional (5-29%)
HP:0012707	Elevated brain lactate level by MRS	Occasional (5-29%)
HP:0025312	Esophoria	Occasional (5-29%)
HP:0032005	Hemidystonia	Occasional (5-29%)
HP:0000649	Abnormality of visual evoked potentials	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001257	Spasticity	Occasional (5-29%)
HP:0001272	Cerebellar atrophy	Occasional (5-29%)
HP:0001324	Muscle weakness	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities
Mondo ID	MONDO:0015003
OMIM	617282
Orphanet	508093
DOID	DOID:0081419
UMLS	C4310634
MedGen	934601
GARD	0013488
Is cancer (heuristic)	no

Also known as: dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities · dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities; DYTOABG · DYTOABG

Data availability: 20 ClinVar variants · 2 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 › inherited lipoic acid biosynthesis defect › dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities

Related subtypes (5): pyruvate dehydrogenase E3 deficiency, lipoic acid synthetase deficiency, lipoyl transferase 1 deficiency, spasticity-ataxia-gait anomalies syndrome, fatal multiple mitochondrial dysfunctions syndrome

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

20 retrieved; paginated sample, class counts are floors:

6 uncertain significance, 4 pathogenic, 3 benign, 3 likely pathogenic, 3 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1173961	NM_016011.5(MECR):c.910G>T (p.Asp304Tyr)	MECR	Pathogenic	no assertion criteria provided
374878	NM_016011.5(MECR):c.695G>A (p.Gly232Glu)	MECR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
374879	NM_016011.5(MECR):c.855T>G (p.Tyr285Ter)	MECR	Pathogenic	criteria provided, multiple submitters, no conflicts
374881	NM_016011.5(MECR):c.854A>G (p.Tyr285Cys)	MECR	Pathogenic/Likely pathogenic	no assertion criteria provided
374883	NM_016011.5(MECR):c.247_250del (p.Asn83fs)	MECR	Pathogenic	criteria provided, multiple submitters, no conflicts
449055	NM_016011.5(MECR):c.830+2dup	MECR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
807442	NC_000001.11:g.29203234del	MECR	Pathogenic	criteria provided, single submitter
3583631	NM_016011.5(MECR):c.176+1G>A	MECR	Likely pathogenic	criteria provided, single submitter
4277683	NM_016011.5(MECR):c.410C>T (p.Thr137Ile)	MECR	Likely pathogenic	criteria provided, single submitter
4292104	NM_016011.5(MECR):c.831-2_831-1insT	MECR	Likely pathogenic	criteria provided, single submitter
374882	NM_016011.4(MECR):c.772C>T (p.Arg258Trp)	MECR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029421	NM_016011.5(MECR):c.161C>T (p.Pro54Leu)	MECR	Uncertain significance	criteria provided, single submitter
2067908	NM_016011.5(MECR):c.583G>A (p.Gly195Arg)	MECR	Uncertain significance	criteria provided, multiple submitters, no conflicts
3251976	NM_016011.5(MECR):c.534C>G (p.Phe178Leu)	MECR	Uncertain significance	criteria provided, single submitter
3256916	NM_016011.5(MECR):c.406G>A (p.Gly136Arg)	MECR	Uncertain significance	criteria provided, single submitter
489272	NM_016011.5(MECR):c.965-11A>G	MECR	Uncertain significance	criteria provided, multiple submitters, no conflicts
522856	NC_000001.11:g.29230945C>G	MECR	Uncertain significance	criteria provided, single submitter
1251778	NM_016011.5(MECR):c.597A>G (p.Ala199=)	MECR	Benign	criteria provided, multiple submitters, no conflicts
1257057	NM_016011.5(MECR):c.286T>C (p.Phe96Leu)	MECR	Benign	criteria provided, multiple submitters, no conflicts
1321161	NM_016011.5(MECR):c.176+19G>A	MECR	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 2 · 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
MECR	Strong	Autosomal recessive	dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MECR	Orphanet:508093	MEPAN syndrome
MECR	Orphanet:98676	Autosomal recessive isolated optic atrophy

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MECR	HGNC:19691	ENSG00000116353	Q9BV79	Enoyl-[acyl-carrier-protein] reductase, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MECR	Enoyl-[acyl-carrier-protein] reductase, mitochondrial	Catalyzes the NADPH-dependent reduction of trans-2-enoyl thioesters in mitochondrial fatty acid synthesis (fatty acid synthesis type II).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MECR	Other/Unknown	no		GroES-like_sf, ADH-like_C, ADH-like_N

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
gastrocnemius	1
hindlimb stylopod muscle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MECR	261	ubiquitous	marker	apex of heart, hindlimb stylopod muscle, gastrocnemius

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MECR	2,353

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MECR	Q9BV79	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 1 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
Beta oxidation of decanoyl-CoA to octanoyl-CoA-CoA	1	1903.3×	0.002	MECR
mitochondrial fatty acid beta-oxidation of saturated fatty acids	1	1631.4×	0.002	MECR
Mitochondrial Fatty Acid Beta-Oxidation	1	380.7×	0.005	MECR
Fatty acid metabolism	1	131.3×	0.011	MECR
Metabolism of lipids	1	31.6×	0.038	MECR
Metabolism	1	11.6×	0.086	MECR

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
ceramide biosynthetic process	1	421.3×	0.005	MECR
fatty acid biosynthetic process	1	351.1×	0.005	MECR
intracellular iron ion homeostasis	1	244.2×	0.005	MECR
fatty acid metabolic process	1	193.7×	0.005	MECR

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
MECR	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	MECR

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MECR	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.