Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies

Gene: TK2

Green List (high evidence)

Comment on list classification: There are numerous individuals reported in literature with biallelic TK2 variants and mitochondrial myopathy. Affected individuals may present with disease of variable severity and age of onset. The phenotype range includes progressive muscle weakness, ptosis, chronic progressive external ophthalmoplegia (CPEO), and respiratory failure. Based on available evidence, this gene should be promoted to Green for Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies.

Created: 15 Dec 2025, 10:56 a.m. | Last Modified: 15 Dec 2025, 10:56 a.m.

Panel Version: 5.25

PMID: 24198295 Alston et al., 2013
A 74-year-old woman with sensorineural hearing loss, progressive muscle weakness and rapidly progressive respiratory failure. Compound het TK2 variants c.103C>T (p.Gln35*) and c.582G>T (p.Lys194Asn).

PMID: 35280287 Manini et al., 2022
55yo Italian woman; ptosis and dysphonia with onset at 8yo, dysphagia at 20yo, slowly progressive limb weakness reported in adulthood; compound het TK2 mutations: c.278A>G, p.Asn93Ser and c.543del, p.Leu182Phefs*11; mtDNA depletion demonstrated by qPCR in muscle tissue.

PMID: 37527940 Morganroth et al., 2023
Report of a 40yo male patient with muscle weakness (limb girdle weakness, chronic progressive external ophthalmoplegia, dysphagia) and respiratory failure; developed limb girdle weakness at 21yo; homozygous for TK2 c.604_606del (p.K202del). Mother confirmed to be a heterozygous carrier.

PMID: 38544965 Ceballos et al., 2024
Cohort of 53 Spanish patients with biallelic variants in TK2. 40% of patients presented with disease before 12yo. 50/53 patients had a diagnosis of mitochondrial myopathy based on muscle biopsy findings.

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.
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.

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, 10:45 a.m. | Last Modified: 15 Dec 2025, 10:56 a.m.

Panel Version: 5.25

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

• 24198295
• 35280287
• 37527940
• 38544965
• 40098049

Green List (high evidence)

This is already green in mitochondrial disease. It causes limb girdle muscular dystrophy and should be on this panel and the wider related panel other rare neuromuscular
Sources: NHS GMS

Created: 3 Dec 2025, 10:31 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

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

Publications

• 22345218 23303857 24198295 31092255 25948719