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Orphanet J Rare Dis. 2019 May 6;14(1):100. doi: 10.1186/s13023-019-1071-z.

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

Author information

1
Neurology department, Neuromuscular disorders Unit, 12 de Octubre Hospital, Madrid, Spain.
2
Research Institute i+12, 12 de Octubre Hospital, Madrid, Spain.
3
Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
4
Neuropathology, Pathology Department, Neuromuscular disorders Unit, 12 de Octubre Hospital, Madrid, Spain.
5
Pathological Anatomic Department, Neuromuscular Disorders Unit, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío, CSIC, Universidad de Sevilla, Sevilla, Spain.
6
Neumology department, Neuromuscular disorders Unit, 12 de Octubre Hospital, Madrid, Spain.
7
Neurology Department, Neuromuscular disorders Unit, Hospital de Donostia, San Sebastian, Spain.
8
Mitochondrial and Neuromuscular Diseases Laboratory, Research Institute of Hospital '12 de Octubre' ('i+12'), Madrid, Spain.
9
Neurology Department, Hospital de Albacete, Albacete, Spain.
10
Neurology Department, Neuromuscular disorders Unit, Hospital Central de Asturias, Oviedo, Spain.
11
Pathological Anatomy Department, Neuromuscular disorders unit, IDIBELL-Hospital de Bellvitge, Barcelona, Spain.
12
Neurology department, Neuromuscular disorders unit, Hospital Universitari Son Espases, Palma, Spain.
13
Neurology department, Neuromuscular disorders unit, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain.
14
Respiratory Department, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío, CSIC, CIBERES, Universidad de Sevilla, Sevilla, Spain.
15
Rehabilitation Department, Hospital Virgen del Rocio, Sevilla, Spain.
16
Neuromuscular Unit, Neurology Department, Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, Barcelona, Spain.
17
Research group on Neuromuscular and Mitochondrial Diseases, Valld'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.
18
Department of Neurology, H. Houston Merritt Center, Columbia University Medical Center, New York, New York, USA.
19
Neurology Department, Neuromuscular Disorders Unit, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío, CSIC, Universidad de Sevilla, Avd. Manuel Siurot s/n, 41013, Sevilla, Spain. cparadas@us.es.
20
Biomedical Network Research Centre on Neurodegenerative Diseases (CIBERNED), Madrid, Spain. cparadas@us.es.

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.

KEYWORDS:

Mitochondrial myopathy; Multiple deletions; TK2 deficiency

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