mitochondrial DNA depletion syndrome 7 (hepatocerebral type)

Summary

mitochondrial DNA depletion syndrome 7 (hepatocerebral type) (MONDO:0010060) is a disease caused by TWNK (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TWNK (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 104
• Phenotypes (HPO): 7

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		29	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

7 HPO clinical features (Orphanet curated; top 7 by frequency):

HPO ID	Term	Frequency
HP:0000365	Hearing impairment	Very frequent (80-99%)
HP:0000602	Ophthalmoplegia	Very frequent (80-99%)
HP:0000648	Optic atrophy	Very frequent (80-99%)
HP:0001251	Ataxia	Very frequent (80-99%)
HP:0001315	Reduced tendon reflexes	Very frequent (80-99%)
HP:0002270	Abnormality of the autonomic nervous system	Very frequent (80-99%)
HP:0100022	Abnormality of movement	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial DNA depletion syndrome 7 (hepatocerebral type)
Mondo ID	MONDO:0010060
MeSH	C535523
OMIM	271245
Orphanet	1186
DOID	DOID:0050556, DOID:0080126
SNOMED CT	724227000
UMLS	C1849096
MedGen	338613
GARD	0004062
Is cancer (heuristic)	no

Also known as: autosomal recessive degenerative and progressive cerebellar ataxia caused by mutation in TWNK · IOSCA · mitochondrial DNA depletion syndrome 7 (hepatocerebral type) · mitochondrial DNA depletion syndrome type 7 · MTDPS7 · OHAHA syndrome · Ohaha syndrome · ophthalmoplegia - hypotonia - ataxia - hypoacusis - athetosis · ophthalmoplegia, hypotonia, ataxia, hypacusis, and athetosis · ophthalmoplegia-hypotonia-ataxia-hypoacusis-athetosis syndrome · SCA8 (formerly) · spinocerebellar ataxia 8 · spinocerebellar ataxia 8 (formerly) · spinocerebellar ataxia infantile with sensory neuropathy · TWNK autosomal recessive degenerative and progressive cerebellar ataxia

Data availability: 104 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › autosomal recessive cerebellar ataxia › autosomal recessive degenerative and progressive cerebellar ataxia › mitochondrial DNA depletion syndrome 7 (hepatocerebral type)

Related subtypes (6): early-onset cerebellar ataxia with retained tendon reflexes, Marinesco-Sjogren syndrome, congenital cataracts-facial dysmorphism-neuropathy syndrome, early-onset progressive encephalopathy-spastic ataxia-distal spinal muscular atrophy syndrome, Friedreich ataxia, FLVCR1-related retinopathy with or without ataxia

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

104 retrieved; paginated sample, class counts are floors:

43 uncertain significance, 34 conflicting classifications of pathogenicity, 7 likely pathogenic, 6 pathogenic, 6 benign, 5 pathogenic/likely pathogenic, 2 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1120050	NM_014889.4(PITRM1):c.2236-1dup	PITRM1	Pathogenic	no assertion criteria provided
162049	NM_021830.5(TWNK):c.1754A>G (p.Asn585Ser)	TWNK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1708153	NM_021830.5(TWNK):c.1729_1732del (p.Ala577fs)	TWNK	Pathogenic	criteria provided, single submitter
214183	NM_021830.5(TWNK):c.967C>T (p.Arg323Ter)	TWNK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
225837	NM_021830.5(TWNK):c.333del (p.Leu112fs)	TWNK	Pathogenic	no assertion criteria provided
4623	NM_021830.5(TWNK):c.1001G>A (p.Arg334Gln)	TWNK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4626	NM_021830.5(TWNK):c.1370C>T (p.Thr457Ile)	TWNK	Pathogenic	no assertion criteria provided
4627	NM_021830.5(TWNK):c.1523A>G (p.Tyr508Cys)	TWNK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4630	NM_021830.5(TWNK):c.952G>A (p.Ala318Thr)	TWNK	Pathogenic	criteria provided, single submitter
620159	NM_021830.5(TWNK):c.853C>T (p.Arg285Ter)	TWNK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
694436	NM_021830.5(TWNK):c.49del (p.Leu17fs)	TWNK	Pathogenic	criteria provided, single submitter
1956760	NM_021830.5(TWNK):c.1060C>T (p.Arg354Cys)	TWNK	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3382359	NM_021830.5(TWNK):c.1399C>T (p.Gln467Ter)	TWNK	Likely pathogenic	criteria provided, single submitter
3897973	NM_021830.5(TWNK):c.595C>T (p.Arg199Ter)	TWNK	Likely pathogenic	criteria provided, single submitter
4619	NM_021830.5(TWNK):c.1422G>A (p.Trp474Ter)	TWNK	Likely pathogenic	criteria provided, single submitter
638300	NM_021830.5(TWNK):c.1441C>G (p.Leu481Val)	TWNK	Likely pathogenic	criteria provided, single submitter
694431	NM_021830.5(TWNK):c.1199G>T (p.Arg400Leu)	TWNK	Likely pathogenic	criteria provided, single submitter
694434	NM_021830.5(TWNK):c.1314C>G (p.Asn438Lys)	TWNK	Likely pathogenic	criteria provided, single submitter
136587	NM_021830.5(TWNK):c.639C>T (p.Gly213=)	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
136594	NM_021830.5(TWNK):c.1735-14C>A	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1497932	NM_021830.5(TWNK):c.1618G>A (p.Gly540Arg)	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1683933	NM_021830.5(TWNK):c.1958C>T (p.Ser653Phe)	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214177	NM_021830.5(TWNK):c.1697A>G (p.Lys566Arg)	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214178	NM_021830.5(TWNK):c.1975G>A (p.Ala659Thr)	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214180	NM_021830.5(TWNK):c.2045G>A (p.Arg682His)	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214185	NM_021830.5(TWNK):c.1196A>G (p.Asn399Ser)	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
225838	NM_021830.5(TWNK):c.904C>T (p.Arg302Trp)	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
279715	NM_021830.5(TWNK):c.241C>G (p.Leu81Val)	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
279716	NM_021830.5(TWNK):c.2050A>C (p.Lys684Gln)	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
281415	NM_021830.5(TWNK):c.384C>T (p.Ser128=)	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 6 · 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
TWNK	Strong	Autosomal recessive	mitochondrial DNA depletion syndrome 7 (hepatocerebral type)	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TWNK	Orphanet:1186	Infantile-onset spinocerebellar ataxia
TWNK	Orphanet:254892	Autosomal dominant progressive external ophthalmoplegia
TWNK	Orphanet:363534	Mitochondrial DNA depletion syndrome, hepatocerebrorenal form
TWNK	Orphanet:642945	Perrault syndrome type 1
TWNK	Orphanet:642976	Perrault syndrome type 2
TWNK	Orphanet:70595	Sensory ataxic neuropathy-dysarthria-ophthalmoparesis 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
TWNK	HGNC:1160	ENSG00000107815	Q96RR1	Twinkle mtDNA helicase	gencc,clinvar
PITRM1	HGNC:17663	ENSG00000107959	Q5JRX3	Presequence protease, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TWNK	Twinkle mtDNA helicase	Mitochondrial helicase involved in mtDNA replication and repair.
PITRM1	Presequence protease, mitochondrial	Metalloendopeptidase of the mitochondrial matrix that functions in peptide cleavage and degradation rather than in protein processing.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Protease	1	18.3×	0.108
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TWNK	Enzyme (other)	yes	3.6.4.12	DNA_helicase_DnaB-like_C, Twinkle-like, P-loop_NTPase
PITRM1	Protease	yes	3.4.24.56	Peptidase_M16_C, Metalloenz_LuxS/M16, Pept_M16_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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	1
male germ line stem cell (sensu Vertebrata) in testis	1
tendon of biceps brachii	1
adrenal tissue	1
apex of heart	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TWNK	211	ubiquitous	yes	male germ line stem cell (sensu Vertebrata) in testis, tendon of biceps brachii, gastrocnemius
PITRM1	292	ubiquitous	marker	apex of heart, adrenal tissue, right adrenal gland cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PITRM1	1,862
TWNK	1,390

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PITRM1	Q5JRX3	8
TWNK	Q96RR1	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Strand-asynchronous mitochondrial DNA replication	1	571.0×	0.007	TWNK
Transcriptional activation of mitochondrial biogenesis	1	102.0×	0.016	TWNK
Mitochondrial protein import	1	84.0×	0.016	PITRM1
Mitochondrial protein degradation	1	57.1×	0.017	TWNK

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
mitochondrial transcription	1	1203.7×	0.003	TWNK
mitochondrial DNA replication	1	766.0×	0.003	TWNK
protein hexamerization	1	702.2×	0.003	TWNK
obsolete protein targeting to mitochondrion	1	290.6×	0.005	PITRM1
DNA-templated DNA replication	1	280.9×	0.005	TWNK
protein processing	1	85.1×	0.014	PITRM1
proteolysis	1	17.1×	0.058	PITRM1

Therapeutics

Drug target analysis

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

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
PITRM1	1	3
TWNK	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TALABOSTAT	3	PITRM1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
PITRM1	15	Binding:15

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TWNK	3.6.4.12	DNA helicase
PITRM1	3.4.24.56	insulysin

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

1 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.

Compound	Max phase	Cohort target (bioactivity)
TALABOSTAT	3	PITRM1

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	1	PITRM1
C	Druggable family + PDB, no drug	1	TWNK
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
TWNK	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.