mitochondrial DNA depletion syndrome, myopathic form

Summary

mitochondrial DNA depletion syndrome, myopathic form (MONDO:0012301) is a disease caused by TK2 (GenCC Definitive), with 1 cohort gene and 5 clinical trials. Top therapeutic interventions include doxribtimine and doxecitine.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TK2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 138
• Phenotypes (HPO): 39
• Clinical trials: 5

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		45	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

39 HPO clinical features (Orphanet curated; top 39 by frequency):

HPO ID	Term	Frequency
HP:0003198	Myopathy	Obligate (100%)
HP:0001290	Generalized hypotonia	Very frequent (80-99%)
HP:0001324	Muscle weakness	Very frequent (80-99%)
HP:0002093	Respiratory insufficiency	Very frequent (80-99%)
HP:0002333	Motor deterioration	Very frequent (80-99%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001265	Hyporeflexia	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001531	Failure to thrive in infancy	Frequent (30-79%)
HP:0002098	Respiratory distress	Frequent (30-79%)
HP:0002197	Generalized-onset seizure	Frequent (30-79%)
HP:0002376	Developmental regression	Frequent (30-79%)
HP:0002460	Distal muscle weakness	Frequent (30-79%)
HP:0002747	Respiratory insufficiency due to muscle weakness	Frequent (30-79%)
HP:0002878	Respiratory failure	Frequent (30-79%)
HP:0003202	Skeletal muscle atrophy	Frequent (30-79%)
HP:0003324	Generalized muscle weakness	Frequent (30-79%)
HP:0003546	Exercise intolerance	Frequent (30-79%)
HP:0003698	Difficulty standing	Frequent (30-79%)
HP:0006532	Recurrent pneumonia	Frequent (30-79%)
HP:0007105	Infantile encephalopathy	Frequent (30-79%)
HP:0008872	Feeding difficulties in infancy	Frequent (30-79%)
HP:0009073	Progressive proximal muscle weakness	Frequent (30-79%)
HP:0012432	Chronic fatigue	Frequent (30-79%)
HP:0000590	Progressive external ophthalmoplegia	Occasional (5-29%)
HP:0000597	Ophthalmoparesis	Occasional (5-29%)
HP:0001260	Dysarthria	Occasional (5-29%)
HP:0001283	Bulbar palsy	Occasional (5-29%)
HP:0001488	Bilateral ptosis	Occasional (5-29%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0003326	Myalgia	Occasional (5-29%)
HP:0005946	Ventilator dependence with inability to wean	Occasional (5-29%)
HP:0008610	Infantile sensorineural hearing impairment	Occasional (5-29%)
HP:0008625	Severe sensorineural hearing impairment	Occasional (5-29%)
HP:0030319	Weakness of facial musculature	Occasional (5-29%)
HP:0100543	Cognitive impairment	Occasional (5-29%)
HP:0002650	Scoliosis	Very rare (<1-4%)
HP:0007269	Spinal muscular atrophy	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial DNA depletion syndrome, myopathic form
Mondo ID	MONDO:0012301
MeSH	C563698
OMIM	609560
Orphanet	254875
DOID	DOID:0080120
ICD-11	294556832
SNOMED CT	703527003
UMLS	C3149750
MedGen	461100
GARD	0017228
Is cancer (heuristic)	no

Also known as: mitochondrial DNA depletion syndrome 2 (myopathic type) · mitochondrial DNA depletion syndrome type 2 · mtDNA depletion syndrome, myopathic form · MTDPS2 · thymidine kinase 2 deficiency

Data availability: 138 ClinVar variants · 4 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › mitochondrial oxidative phosphorylation disorder › mitochondrial DNA depletion syndrome › mitochondrial DNA depletion syndrome, myopathic form

Related subtypes (20): Sengers syndrome, mitochondrial DNA depletion syndrome 1, mitochondrial DNA depletion syndrome 4b, mitochondrial DNA depletion syndrome 11, mitochondrial DNA deletion syndrome with progressive myopathy, mitochondrial DNA depletion syndrome 12B (cardiomyopathic type), autosomal recessive, mitochondrial DNA depletion syndrome 14B (cardioencephalomyopathic type), mitochondrial DNA depletion syndrome 15 (hepatocerebral type), mitochondrial DNA depletion syndrome 12A (cardiomyopathic type), autosomal dominant, mitochondrial DNA depletion syndrome, encephalomyopathic form, mitochondrial dna depletion syndrome 16B (neuroophthalmic type), mitochondrial DNA depletion syndrome 20 (mngie type), mitochondrial DNA depletion syndrome 16 (hepatic type), mitochondrial DNA depletion syndrome 17, mitochondrial DNA depletion syndrome 18, mitochondrial DNA depletion syndrome 19, mitochondrial DNA depletion syndrome, hepatocerebral form, AFG3L2-related optic atrophy and/or spastic ataxia spectrum, mitochondrial dna depletion syndrome 21, mitochondrial dna depletion syndrome 14A (encephalomyopathic type)

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

138 retrieved; paginated sample, class counts are floors:

64 uncertain significance, 21 conflicting classifications of pathogenicity, 17 pathogenic, 15 benign, 9 pathogenic/likely pathogenic, 5 likely pathogenic, 5 likely benign, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
38972	NM_001040138.2(CKLF):c.-7863_-2035delins[AC010542.7:g.65062_65110]	LOC130059156	Pathogenic	no assertion criteria provided
1190844	NM_004614.5(TK2):c.623A>G (p.Tyr208Cys)	TK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12708	NM_004614.5(TK2):c.361C>A (p.His121Asn)	TK2	Pathogenic	criteria provided, multiple submitters, no conflicts
12709	NM_004614.5(TK2):c.635T>A (p.Ile212Asn)	TK2	Pathogenic	criteria provided, multiple submitters, no conflicts
12710	NM_004614.5(TK2):c.323C>T (p.Thr108Met)	TK2	Pathogenic	criteria provided, multiple submitters, no conflicts
1323691	NM_004614.5(TK2):c.441del (p.Tyr148fs)	TK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1410181	NM_004614.5(TK2):c.415G>A (p.Ala139Thr)	TK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1496034	NM_004614.5(TK2):c.1A>T (p.Met1Leu)	TK2	Pathogenic	criteria provided, multiple submitters, no conflicts
1686262	NM_004614.5(TK2):c.414C>A (p.Ser138Arg)	TK2	Pathogenic	criteria provided, single submitter
1962979	NM_004614.5(TK2):c.536_538+8del	TK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265614	NM_004614.5(TK2):c.372_373delinsCT (p.Gln125Ter)	TK2	Pathogenic	criteria provided, multiple submitters, no conflicts
3581130	NM_004614.5(TK2):c.544del (p.Leu182fs)	TK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
38971	NM_004614.4:c.-270+2561delins;7287-7335inv	TK2	Pathogenic	no assertion criteria provided
38973	NM_004614.5(TK2):c.129_132del (p.Lys43fs)	TK2	Pathogenic	criteria provided, multiple submitters, no conflicts
38974	NM_004614.5(TK2):c.133C>T (p.Gln45Ter)	TK2	Pathogenic	criteria provided, multiple submitters, no conflicts
38978	NM_004614.5(TK2):c.173A>G (p.Asn58Ser)	TK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
38979	NM_004614.5(TK2):c.191C>T (p.Thr64Met)	TK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
38986	NM_004614.5(TK2):c.360_361delinsAA (p.His121Asn)	TK2	Pathogenic	criteria provided, multiple submitters, no conflicts
38988	NM_004614.5(TK2):c.388C>T (p.Arg130Trp)	TK2	Pathogenic	criteria provided, multiple submitters, no conflicts
38990	NM_004614.5(TK2):c.416C>T (p.Ala139Val)	TK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
38992	NM_004614.5(TK2):c.547C>T (p.Arg183Trp)	TK2	Pathogenic	criteria provided, multiple submitters, no conflicts
38994	NM_004614.5(TK2):c.575G>A (p.Arg192Lys)	TK2	Pathogenic	criteria provided, multiple submitters, no conflicts
38995	NM_004614.5(TK2):c.604_606del (p.Lys202del)	TK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39416	NM_004614.5(TK2):c.8dup (p.Trp4fs)	TK2	Pathogenic	criteria provided, single submitter
972912	NM_004614.5(TK2):c.144_145del (p.Lys50fs)	TK2	Pathogenic	criteria provided, multiple submitters, no conflicts
972914	NM_004614.5(TK2):c.328C>T (p.Gln110Ter)	TK2	Pathogenic	criteria provided, multiple submitters, no conflicts
12711	NM_004614.5(TK2):c.159C>G (p.Ile53Met)	TK2	Likely pathogenic	criteria provided, single submitter
2585339	NM_004614.5(TK2):c.402G>T (p.Arg134Ser)	TK2	Likely pathogenic	criteria provided, single submitter
3767180	NM_004614.5(TK2):c.124G>A (p.Asp42Asn)	TK2	Likely pathogenic	criteria provided, single submitter
3897043	NM_004614.5(TK2):c.643C>A (p.Leu215Ile)	TK2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
TK2	Definitive	Autosomal recessive	mitochondrial DNA depletion syndrome, myopathic form	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TK2	Orphanet:254875	Mitochondrial DNA depletion syndrome, myopathic form
TK2	Orphanet:254886	Autosomal recessive progressive external ophthalmoplegia

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
TK2	HGNC:11831	ENSG00000166548	O00142	Thymidine kinase 2, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TK2	Thymidine kinase 2, mitochondrial	Phosphorylates thymidine, deoxycytidine, and deoxyuridine in the mitochondrial matrix.

Protein-family classification

Druggable: 1 · 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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TK2	Kinase	yes	2.7.1.21	DCK/DGK, P-loop_NTPase, DNK_dom

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
adrenal tissue	1
calcaneal tendon	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TK2	280	ubiquitous	marker	calcaneal tendon, sural nerve, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TK2	2,031

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TK2	O00142	85.01

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Nucleotide salvage	1	1142.0×	0.002	TK2
Pyrimidine salvage	1	1038.2×	0.002	TK2
Metabolism of nucleotides	1	300.5×	0.004	TK2
Metabolism	1	11.6×	0.086	TK2

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
deoxycytidine metabolic process	1	16852.0×	2e-04	TK2
pyrimidine nucleoside salvage	1	8426.0×	2e-04	TK2
thymidine metabolic process	1	8426.0×	2e-04	TK2
DNA biosynthetic process	1	802.5×	0.002	TK2
nucleobase-containing compound metabolic process	1	526.6×	0.002	TK2

Therapeutics

Drug target analysis

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

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

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
TK2	SORIVUDINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TK2	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SORIVUDINE	4	TK2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
TK2	17	Binding:17

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TK2	2.7.1.21	thymidine kinase

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

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)
SORIVUDINE	4	TK2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TK2
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	2
PHASE3	1
PHASE1/PHASE2	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04581733	PHASE3	WITHDRAWN	A Study of the Efficacy and Safety of MT1621 in Thymidine Kinase 2 (TK2) Deficiency (Treatment naïve)
NCT03639701	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Treatment of TK2 Deficiency With Thymidine and Deoxycytidine
NCT03845712	PHASE2	ACTIVE_NOT_RECRUITING	An Open-Label Study of Continuation Treatment With Combination Pyrimidine Nucleosides in Patients With TK2 Deficiency
NCT06754098	PHASE2	RECRUITING	Doxecitin and Doxribthymine in Adult Subjects With Thymidine Kinase 2 (TK2) Deficiency
NCT05017818	Not specified	COMPLETED	A Retrospective Study of Subjects With Thymidine Kinase 2 Deficiency

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DOXRIBTIMINE	2	3
DOXECITINE	2	2
CHEMBL211174	0	1