Late-onset thymidine kinase 2 deficiency: a review of 18 cases

Abstract

Background TK2 gene encodes for mitochondrial thymidine kinase, which phosphorylates the pyrimidine nucleosides thymidine and deoxycytidine. Recessive mutations in the TK2 gene are responsible for the ‘myopathic form’ of the mitochondrial depletion/multiple deletions syndrome, with a wide spectrum of severity. Methods We describe 18 patients with mitochondrial myopathy due to mutations in the TK2 gene with absence of clinical symptoms until the age of 12. Results The mean age of onset was 31 years. The first symptom was muscle limb weakness in 10/18, eyelid ptosis in 6/18, and respiratory insufficiency in 2/18. All patients developed variable muscle weakness during the evolution of the disease. Half of patients presented difficulty in swallowing. All patients showed evidence of respiratory muscle weakness, with need for non-invasive Mechanical Ventilation in 12/18. Four patients had deceased, all of them due to respiratory insufficiency. We identified common radiological features in muscle magnetic resonance, where the most severely affected muscles were the gluteus maximus, semitendinosus and sartorius. On muscle biopsies typical signs of mitochondrial dysfunction were associated with dystrophic changes. All mutations identified were previously reported, being the most frequent the in-frame deletion p.Lys202del. All cases showed multiple mtDNA deletions but mtDNA depletion was present only in two patients. Conclusions The late-onset is the less frequent form of presentation of the TK2 deficiency and its natural history is not well known. Patients with late onset TK2 deficiency have a consistent and recognizable clinical phenotype and a poor prognosis, due to the high risk of early and progressive respiratory insufficiency.

Clinical, pathological and genetic spectrum in 89 cases of mitochondrial progressive external ophthalmoplegia

“…TK2 gene encodes thymidine kinase 2 and displays a recessive inheritance, with a continuum clinical phenotype comprising mild to severe forms. Cases of infantile onset are caused by mtDNA depletion and show a rapidly fatal course,13 while late-onset forms with MultDels present myopathy with early diaphragmatic weakness and variable rate of progression 14–16. Five of the patients included in this series carried the inframe deletion p.K202del, specific to Spanish/Hispanic population14 15 and apparently exclusive of late-onset forms.…”

Growth Differentiation Factor 15 is a potential biomarker of therapeutic response for TK2 deficient myopathy

“…The 26 patients included span the spectrum of phenotypes associated with TK2 deficiency 4 . Pretreatment data are summarized in Table 1.…”

“…Group 2 consisted of nine patients (seven female and two male) and included one patient with childhood-onset (P22) and eight patients with late-onset forms (P16 to P21 and P23 to P24). To assess disease progression, patients were compared with other patients with similar clinical phenotypes based on previous publications 2,4,9 . The follow-up time ranged from 1 to 49 months for patients in group 1 and from 1 to 46 months for patients in group 2.…”

“…www.nature.com/scientificreports www.nature.com/scientificreports/ Mitochondrial DNA depletion and deletion syndrome 2 (MTDPS2) is caused by mutations in the nuclear gene TK2 that encodes thymidine kinase 2 (TK2) which is necessary for mitochondrial DNA replication and maintenance 1 . TK2 deficiency manifests predominantly as a myopathy and includes extremely severe and rapidly progressive early-onset forms with survival of less than two years, to milder forms with late or very late-onset, and a slower rate of progression, but with almost invariable respiratory involvement than shortens life expectancy [2][3][4] .…”

Infantile and early childhood onset of mitochondrial myopathy due to mutations in the TK2 gene with a phenotype of spinal muscular atrophy 5q: the first cases in Russia

“…Наши данные не позволили выявить МРТ паттерн в виде поражения больших ягодичных, полусухожильных и портняжных мышц, описанного Domínguez-González и соавт. в 2019 г. при взрослой форме заболевания [16]. У наших лежачих больных выявлены отек и незначительная атрофия мышц голеней (см.…”