Mitochondrial myopathy-lactic acidosis-deafness syndrome

Summary

Mitochondrial myopathy-lactic acidosis-deafness syndrome (MONDO:0016825) is a disease caused by PNPLA8 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PNPLA8 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 35
• Phenotypes (HPO): 9

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

9 HPO clinical features (Orphanet curated; top 9 by frequency):

HPO ID	Term	Frequency
HP:0000407	Sensorineural hearing impairment	Very frequent (80-99%)
HP:0001942	Metabolic acidosis	Very frequent (80-99%)
HP:0003198	Myopathy	Very frequent (80-99%)
HP:0003202	Skeletal muscle atrophy	Very frequent (80-99%)
HP:0003348	Hyperalaninemia	Very frequent (80-99%)
HP:0003457	EMG abnormality	Very frequent (80-99%)
HP:0003737	Mitochondrial myopathy	Very frequent (80-99%)
HP:0004320	Vaginal fistula	Very frequent (80-99%)
HP:0001250	Seizure	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial myopathy-lactic acidosis-deafness syndrome
Mondo ID	MONDO:0016825
MeSH	C537476
OMIM	251950
Orphanet	2597
UMLS	C1855033
MedGen	343245
GARD	0003682
Is cancer (heuristic)	no

Also known as: metabolic myopathy associated with chronic lactic acidemia, growth failure, and nerve deafness · mitochondrial myopathy with lactic acidosis · mitochondrial myopathy-lactic acidosis-hearing loss syndrome · MMLA

Data availability: 35 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › skeletal muscle disorder › myopathy › congenital myopathy › congenital structural myopathy › inborn mitochondrial myopathy › mitochondrial myopathy-lactic acidosis-deafness syndrome

Related subtypes (23): myopathy, lactic acidosis, and sideroblastic anemia, mitochondrial encephalomyopathy, progressive external ophthalmoplegia, mitochondrial myopathy with a defect in mitochondrial-protein transport, Barth syndrome, mitochondrial myopathy with diabetes, mitochondrial myopathy with reversible cytochrome C oxidase deficiency, lethal infantile mitochondrial myopathy, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, mitochondrial trifunctional protein deficiency, adenosine monophosphate deaminase deficiency, congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome, autosomal dominant mitochondrial myopathy with exercise intolerance, fatal infantile encephalocardiomyopathy, mitochondrial neurogastrointestinal encephalomyopathy, adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy, maternally-inherited progressive external ophthalmoplegia, mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy, mitochondrial complex II deficiency, nuclear type, mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome, X-linked recessive mitochondrial myopathy, mitochondrial complex I deficiency, nuclear type 1, COX deficiency, benign infantile mitochondrial myopathy

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

35 retrieved; paginated sample, class counts are floors:

10 uncertain significance, 10 pathogenic, 8 likely pathogenic, 3 conflicting classifications of pathogenicity, 2 benign, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1332796	NM_001256007.3(PNPLA8):c.517G>T (p.Glu173Ter)	PNPLA8	Pathogenic	criteria provided, single submitter
190127	NM_001256007.3(PNPLA8):c.634_637del (p.Asn212fs)	PNPLA8	Pathogenic	criteria provided, single submitter
190128	NM_001256007.3(PNPLA8):c.2275_2276del (p.Leu759fs)	PNPLA8	Pathogenic	criteria provided, multiple submitters, no conflicts
2442058	NM_001256007.3(PNPLA8):c.524del (p.Ser175fs)	PNPLA8	Pathogenic	criteria provided, single submitter
2581318	NM_001256007.3(PNPLA8):c.870dup (p.Leu291fs)	PNPLA8	Pathogenic	criteria provided, multiple submitters, no conflicts
2632596	NM_001256007.3(PNPLA8):c.86delinsAA (p.Leu29fs)	PNPLA8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2992245	NM_001256007.3(PNPLA8):c.1048C>T (p.Arg350Ter)	PNPLA8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3777697	H625R	PNPLA8	Pathogenic	no assertion criteria provided
3777698	NM_001256007.3(PNPLA8):c.2269del (p.Thr757fs)	PNPLA8	Pathogenic	no assertion criteria provided
3777699	NM_001256007.3(PNPLA8):c.1231C>T (p.Arg411Ter)	PNPLA8	Pathogenic	no assertion criteria provided
3777700	NM_001256007.3(PNPLA8):c.1559T>A (p.Val520Asp)	PNPLA8	Pathogenic	no assertion criteria provided
4291772	NM_001256007.3(PNPLA8):c.620dup (p.Leu207fs)	PNPLA8	Pathogenic	criteria provided, single submitter
1050814	NM_001256007.3(PNPLA8):c.944_945del (p.Lys314_Tyr315insTer)	PNPLA8	Likely pathogenic	criteria provided, single submitter
1328387	NM_001256007.3(PNPLA8):c.1637del (p.Gly546fs)	PNPLA8	Likely pathogenic	no assertion criteria provided
2584537	NM_001256007.3(PNPLA8):c.1614_1615insGG (p.Asn539fs)	PNPLA8	Likely pathogenic	criteria provided, single submitter
3065896	NM_001256007.3(PNPLA8):c.1748_1749del (p.Tyr583fs)	PNPLA8	Likely pathogenic	criteria provided, single submitter
3896954	NM_001256007.3(PNPLA8):c.1056+1G>A	PNPLA8	Likely pathogenic	criteria provided, single submitter
4077436	NM_001256007.3(PNPLA8):c.1045C>T (p.Gln349Ter)	PNPLA8	Likely pathogenic	criteria provided, single submitter
4846897	NM_001256007.3(PNPLA8):c.1532C>G (p.Ser511Ter)	PNPLA8	Likely pathogenic	criteria provided, single submitter
804406	NM_001256007.3(PNPLA8):c.1580G>A (p.Trp527Ter)	PNPLA8	Likely pathogenic	criteria provided, single submitter
2231916	NM_001256007.3(PNPLA8):c.1996G>C (p.Asp666His)	PNPLA8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3255561	NM_001256007.3(PNPLA8):c.692G>A (p.Arg231Gln)	PNPLA8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
634462	NM_001256007.3(PNPLA8):c.559C>T (p.Arg187Cys)	PNPLA8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1031939	NM_001256007.3(PNPLA8):c.373C>T (p.Arg125Cys)	PNPLA8	Uncertain significance	criteria provided, multiple submitters, no conflicts
1328386	NM_001256007.3(PNPLA8):c.1904C>T (p.Pro635Leu)	PNPLA8	Uncertain significance	no assertion criteria provided
1330216	NM_001256007.3(PNPLA8):c.1874A>G (p.His625Arg)	PNPLA8	Uncertain significance	criteria provided, single submitter
1805799	NM_001256007.3(PNPLA8):c.929T>C (p.Val310Ala)	PNPLA8	Uncertain significance	criteria provided, multiple submitters, no conflicts
1806132	NM_001256007.3(PNPLA8):c.1844T>A (p.Phe615Tyr)	PNPLA8	Uncertain significance	criteria provided, single submitter
2442089	NM_001256007.3(PNPLA8):c.1441G>A (p.Gly481Ser)	PNPLA8	Uncertain significance	criteria provided, single submitter
2627572	NM_001256007.3(PNPLA8):c.1452A>C (p.Thr484=)	PNPLA8	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 0 · 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
PNPLA8	Strong	Autosomal recessive	mitochondrial myopathy-lactic acidosis-deafness syndrome	3

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
PNPLA8	HGNC:28900	ENSG00000135241	Q9NP80	Calcium-independent phospholipase A2-gamma	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PNPLA8	Calcium-independent phospholipase A2-gamma	Calcium-independent and membrane-bound phospholipase, that catalyzes the esterolytic cleavage of fatty acids from glycerophospholipids to yield free fatty acids and lysophospholipids, hence regulating membrane physical properties and the r…

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)
PNPLA8	Other/Unknown	no		PNPLA_dom, Acyl_Trfase/lysoPLipase, PNPLA8-like

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
endothelial cell	1
epithelial cell of pancreas	1
tibialis anterior	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PNPLA8	259	ubiquitous	marker	endothelial cell, epithelial cell of pancreas, tibialis anterior

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PNPLA8	1,217

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PNPLA8	Q9NP80	66.84

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Acyl chain remodelling of PC	1	423.0×	0.003	PNPLA8
Acyl chain remodelling of PE	1	393.8×	0.003	PNPLA8

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
cardiolipin metabolic process	1	8426.0×	0.001	PNPLA8
phosphatidylethanolamine catabolic process	1	4213.0×	0.001	PNPLA8
phosphatidylcholine catabolic process	1	1296.3×	0.002	PNPLA8
regulation of cellular response to oxidative stress	1	1296.3×	0.002	PNPLA8
prostaglandin biosynthetic process	1	1123.5×	0.002	PNPLA8
linoleic acid metabolic process	1	702.2×	0.002	PNPLA8
arachidonate secretion	1	702.2×	0.002	PNPLA8
arachidonate metabolic process	1	481.5×	0.003	PNPLA8
triglyceride homeostasis	1	481.5×	0.003	PNPLA8
lipid homeostasis	1	337.0×	0.004	PNPLA8
fatty acid metabolic process	1	193.7×	0.006	PNPLA8
intracellular signal transduction	1	38.1×	0.026	PNPLA8

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PNPLA8	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PNPLA8	1	Binding:1

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	PNPLA8

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)
PNPLA8	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.