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

Cristina Domínguez-González,
Aurelio Hernández-Laín,
Eloy Rivas,
Ana Hernández-Voth,
Javier Sayas Catalán,
Roberto Fernández-Torrón,
Carmen Fuiza-Luces,
Jorge García García,
Germán Morís,
Montse Olivé,
Frances Miralles,
Jordi Díaz-Manera,
Candela Caballero,
Bosco Méndez-Ferrer,
Ramon Martí,
Elena García Arumi,
María Carmen Badosa,
Jesús Esteban,
Cecilia Jimenez-Mallebrera,
Alberto Blazquez Encinar,
Joaquín Arenas,
Michio Hirano,
Miguel Ángel Martin and
Carmen ParadasEmail author

Orphanet Journal of Rare Diseases201914:100

https://doi.org/10.1186/s13023-019-1071-z

Received: 5 February 2019
Accepted: 17 April 2019
Published: 6 May 2019

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.