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Título

Mitochondrial Myopathy caused by TK2 deficiency.

Resumo

Background and Objectives:
The nuclear gene TK2 encodes the mitochondrial thymidine kinase, an enzyme involved in the phosphorylation of deoxycytidine and deoxythymidine nucleosides. Biallelic TK2 mutations lead to mitochondrial DNA instability and are associated with a wide clinical spectrum of disease (TK2d). Current classification includes infantile (≤ 1 year), childhood- (1-12 years), and late-onset (≥12 years) forms. These forms differ for progression and life expectancy. Deoxynucleosides reposition were shown to be effective to disease controls in a compassionate use. Here we report the clinical findings and mutational spectrum of a series of Brazilian cases presenting infantile and childhood-onset TK2d. This report characterized patients with TK2-deficiency enhancing the importance of a clinical recognition of patients with a severe, potentially lethal, and potentially treatable condition.
Methods and results: Patients with TK2d were evaluated in a Terciary Center. We presented clinical and molecular findings from 8 patients (6 families) harboring pathogenic variants in TK2 gene. Four patients presented the early-onset infantile form. Of those, three passed away still in their first decade of life. P5 was 2 years old in the last evaluation, he had normal motor development until the age 11 months, when a weakness started. After 5 months of the beginning of symptoms he had lost his gait, head support and started on night-time non-invasive ventilatory support at age of 18. At 23 months he was hypotonic, had generalized weakness and was requiring ventilation also for a couple of hours during the day. Five patients presented the childhood form (mean of age average of 32 +- 8 years old). Despite the slow disease progression, all of them noticed first symptoms in their first decade of life, they had difficulties gaining weight and frequent episodes of diarrhea. They had severe proximal and axial weakness and started on NIVS around 20 years old. Four of them used NIVS night-time only and one used for 15 hours/day.
Discussion: With the advent of a specific treatment and given the severity of TK2d, clinicians need to know how to recognize this disorder. The mortality rates are high mainly among the infantile presentation; however, childhood-onset are also a debilitating condition. Ptosis and hypoacusis were not found in our series. But all patients had proximal and axial weakness, global hypotrophy, dysphagia and respiratory involvement.

Palavras Chave

TK2 deficiency, mitochondrial myopathy, deoxynucleosides