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CPEO DUE TO TK2 MUTATION, A RARE AND ORPHAN DISEASE – CASE REPORT

RESUMO

CASE REPORT: female patient, 32 years old, previously healthy, with proximal limb weakness since childhood, described as incapacity to jump, difficulty to run and frequent falls. In adulthood, she had progression of the weakness associated with pain in proximal limbs. There were no diplopia, dysphagia, cervical weakness or systemic complaints. No fluctuation of symptoms was noted. Patient denied similar cases in family and consanguinity. Neurological examination showed bilateral, symmetrical and proximally appendicular weakness with myopathic gait associated with facial diparesis and paresis of the bilaterally superior rectus muscles. Complementary investigation showed a slight increase in hepatic transaminases associated with significant increase in CK (1.341 UI/L) and lactate levels. Electroneuromyography evidenced polyphasic motor unit potentials with reduced amplitude and short duration in the right deltoid muscle. Muscle biopsy showed marked variation in the diameter of fibers, single or multiples internal nuclei, some degenerating fibers and evidence of post-necrosis regeneration, derangement of the intermyofibrillar cytoarchitecture without inflammatory infiltrates and also substantial number of “ragged-red” and “ragged-blue” fibers with COX-negative and fiber hyperintensity in the NADH-TR and SDH reactions. Genetic panel revealed a homozygous pathogenic variant in the TK2 gene (c.323C>T, p.Thr108Met). DISCUSSION: TK2 is a nuclear gene that encodes the mitochondrial thymidine kinase (TK), an enzyme involved in the maintenance of the deoxynucleotides of the mitochondria and crucial in the biosynthesis of the mitochondrial genome. Bi-allelic mutations in the TK2 gene relates with diverse clinical presentations, mainly with a severe myopathy, which is rapidly progressive, or with chronic progressive external ophthalmoplegia (CPEO) associated with limb muscle weakness and dysphagia, both with premature death. Although not approved by FDA yet, deoxynucleosides therapis for TK2 deficiency are under research with positive results, mainly in early-onset cases. FINAL COMMENTS: In clinical practice, from molecular point of view, CPEO is a diagnostic challenging. This case report illustrates that testing CPEO in genetic panels is worthwhile. Considering the tragic natural history of the disease, it is essential to identify the TK2 patients, not only for diagnosis, but also to offer these promising therapies.

Palavras Chave

CPEO; myopathy; genetic panel; TK2 gene.

Área

Neurogenética