P.70 - Mitochondrial disorders in adults: clinical and genetic correlations in ten patients with nuclear DNA mutations

Abstract

Mitochondrial diseases are multisystem heterogeneous disorders caused by dysfunction of the mitochondrial respiratory chain. They can be related to mutations in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). The diagnosis is essential for both genetic counseling as well as further treatment. Among 30 patients with multiple mtDNA deletions, nDNA mutations were confirmed in 8 patients. Additionally, 2 relatives of the already diagnosed patients were included in the study. Patients were assessed clinically, electrophysiologically and morphologically. The POLG and C10orf2 genes coding sequences analyses were performed. Different clinical syndromes were identified in examined patients: progressive external ophthalmoplegia (PEO) in 5, progressive external ophthalmoplegia plus proximal myopathy (PEO+) in 2, sensory ataxic neuropathy, dysarthria and ophthalmoparesis syndrome (SANDO) in 2 and myoclonic epilepsy in one. Electromyography studies presented myopathic pattern in 2 patients (with PEO and PEO+), in other it was normal. Ragged-red fibers were detected in 6 biopsies. Fibers devoid of cytochrome c oxidase activity were present in 3 of 6 investigated cases. Genetic analysis of POLG gene revealed following mutations in PEO: p.[Arg309Leu];[Gln968Glu], p.[Ala518Thr];[=] and p.[Trp748Ser];[Ser998Pro]. In PEO+ mutations: p.[Thr251Ile; Pro587Leu];[Thr251Ile;Pro587Leu] and p.[Thr251Ile;Pro587Leu];[Lys1191Asn] were present. In patients with SANDO syndrome the mutation p.[Arg290Cys];[Arg309Cys] was confirmed. And in patient with myoclonic epilepsy the mutation p.[Trp748Ser];[Trp748Ser] was detected. Additionally the analysis of the C10orf2 gene proved the mutation p.[Arg374Gln];[=] in two patients with PEO. Identification of nuclear genes mutations in adults is important for the evaluation of clinical spectrum and natural history of mitochondrial disorders.