Myopathic mtDNA Depletion Syndrome Due to Mutation in TK2 Gene

Abstract

Whole-exome sequencing (WES) was used to identify the disease gene(s) in a Spanish girl with failure to thrive, muscle weakness, mild facial weakness, elevated creatine kinase (CK), deficiency of mitochondrial complex III and depletion of mtDNA. With WES data, it was possible to get the whole mtDNA sequencing and discard any pathogenic variant in this genome. The analysis of whole exome uncovered a homozygous pathogenic mutation in Thymidine kinase 2 gene (TK2; NM_004614.4:c.323C>T, p.T108M). TK2 mutations have been identified mainly in patients with the myopathic form of mtDNA depletion syndromes (MDS). This patient presents an atypical TK2 related-myopathic form of MDS, because despite having a very low content of mtDNA (<20%), she presents a slower and less severe evolution of the disease. In conclusion, our data confirm the role of TK2 gene in MDS and expanded the phenotypic spectrum.

Metrics of progression and prognosis in untreated adults with thymidine kinase 2 deficiency: An observational study

“…mtDNA maintenance disorders are characterized by presenting mtDNA depletion and/or multiple mtDNA deletions in muscle samples [ 2 , 3 , 5 , 38-42 ]. In most patients, early-onset cases have predominantly mtDNA depletion (mtDNA falls below 30%) [43] , while late-onset cases have multiple mtDNA deletions [ 44 , 45 ], but some patients with childhood-or juvenile-onset TK2d have both mtDNA deletions and depletion, as demonstrated in our study where 70% of the 10 patients evaluated had mtDNA levels > 30% and all 10 had multiple mtDNA deletions. In a large natural history study, mtDNA copy number < 30% in approximately 81% (21/26) of early-onset cases, 77% (24/31) of childhood-onset cases, and 7% (1/14) of later-onset cases [3] ; Domínguez-González et al ( 2019) reported multiple mtDNA deletions in 100% of the 14 patients for whom this parameter was evaluated, but only 2 patients (of 9 in whom copy number was evaluated) had mtDNA depletion [4] .…”

TK2-related Myopathic Mitochondrial Depletion Syndrome

“…We read with interest the article by Martin-Hernandez et al about a 7-year-old female patient with mitochondrial depletion syndrome due to a mutation in the TK2 gene who manifested clinically solely with myopathy. 1 We have the following comments and concerns.…”

“…The patient obviously also had hyperuricemia and hyperaminoacidurea. 1 Was hyperuricemia due to an alimentary or a genetic cause? Did the TK2 mutation manifest in the kidneys?…”