Abstract
BackgroundTK2 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.MethodsWe describe 18 patients with mitochondrial myopathy due to mutations in the TK2 gene with absence of clinical symptoms until the age of 12.ResultsThe 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.ConclusionsThe 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.
Highlights
TK2 gene encodes for mitochondrial thymidine kinase, which phosphorylates the pyrimidine nucleosides thymidine and deoxycytidine
One of the ‘myopathic forms’ of the mitochondrial depletion/multiple deletions syndromes is caused by mutations in the TK2 gene which encodes for mitochondrial thymidine kinase, which phosphorylates the Domínguez-González et al Orphanet Journal of Rare Diseases (2019) 14:100 pyrimidine nucleosides thymidine and deoxycytidine [1, 6]
TK2 deficiency was initially described by Saada, et al in 2001 [6] in four children with a severe myopathy associated with depletion of the mitochondrial DNA (mtDNA)
Summary
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. One of the ‘myopathic forms’ of the mitochondrial depletion/multiple deletions syndromes is caused by mutations in the TK2 gene which encodes for mitochondrial thymidine kinase, which phosphorylates the Domínguez-González et al Orphanet Journal of Rare Diseases (2019) 14:100 pyrimidine nucleosides thymidine (dT) and deoxycytidine (dC) [1, 6]. Recessive mutations in the TK2 gene (MIM# 609560) are responsible for diverse clinical presentations mainly characterized by progressive muscle weakness, dysphagia and respiratory involvement with a wide spectrum severity and of age of onset. The natural history of patients with late onset TK2 deficiency has not been defined in detail
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