Congenital muscular dystrophy

Gene: TK2

Green List (high evidence)

Comment on list classification: There are numerous patients reported in literature with biallelic variants in TK2 and mitochondrial myopathy. More than 25 cases have been reported with rapidly progressive infantile-onset (<1year of age) muscle weakness, usually leading to respiratory failure before age 3. Based on available evidence TK2 should be promoted to Green for Congenital muscular dystrophy at the next GMS update.

Created: 15 Dec 2025, 12:08 p.m. | Last Modified: 15 Dec 2025, 12:08 p.m.

Panel Version: 6.4

PMID: 18819985 Gotz et al., 2008
Reported 7 patients with rapidly progressive myopathy / encephalomyopathy, leading to respiratory failure within first 3 years of life. Myopathy onset reported at 3-18 months old. Elevated CK and COX-negatvie fibers were noted.
Patients were homozygous or compound het for Scandinavian founder mutations: p.R172W (NM_004614.5(TK2):c.388C>T (p.Arg130Trp)) & R225W (NM_004614.5(TK2):c.547C>T (p.Arg183Trp)).

PMID: 38544965 Ceballos et al., 2024
Cohort of 53 Spanish patients with biallelic variants in TK2 diagnosed with mitochondrial myopathy. 40% of patients presented with disease before 12yo; 4 patients (7.5%) presented with disease within the first year of life.

PMID: 40098049 Li et al., 2025
Female patient with early-onset lipid storage myopathy (onset at 8 months old); compound het variants in TK2: c.311G > A (p.Arg104His) and a deletion spanning TK2 exons 5-10 (g.66545871_66565372del); COX negative fibers and accumulation of lipid droplets noted on biceps biopsy; detected decrease in TK2 protein and mtDNA copy number in patient muscle samples. Patient passed at 13 months due to respiratory distress.

Based on literature review of 50 TK2-related myopathy cases, authors note that the same TK2 variant may cause variable onset and severity of disease between patients. Variable presentation of limb girdle muscle weakness, ptosis, respiratory failure, and facial weakness; range of congenital to adult disease onset. 15/50 cases in the review had onset under 1yo.

TK2 is associated with AR Mitochondrial DNA depletion syndrome 2 (myopathic type), MIM:609560 and putatively associated with AR Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3, MIM:617069 (OMIM accessed 15th Dec 2025).

Created: 15 Dec 2025, 12:03 p.m. | Last Modified: 15 Dec 2025, 12:03 p.m.

Panel Version: 6.4

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Mitochondrial DNA depletion syndrome 2 (myopathic type), OMIM:609560; mitochondrial DNA depletion syndrome, myopathic form, MONDO:0012301

Publications

• 18819985
• 38544965
• 40098049

Green List (high evidence)

Sources: NHS GMS, TK2 is on a mitochondrial panel however, it causes a muscle predominant phenotype and should be present on congenital muscular dystrophy, LGMD and as a consequence other rare neuromuscular disorders and hypotonic infant

Created: 3 Dec 2025, 10:15 a.m. | Last Modified: 3 Dec 2025, 10:17 a.m.

Panel Version: 6.1

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Congenital muscular dystrophy; mitochondrial disease; limb girdle muscular dystrophy

Publications

• 11687801 18021809 19736010 16831967 36146520

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Variants in this GENE are reported as part of current diagnostic practice