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Mutations in the Optic Atrophy 1 gene ( OPA1 ) were first identified in 2000 as the main cause of Dominant Optic Atrophy, a disease specifically affecting the retinal ganglion cells and the optic nerve. Since then, an increasing number of symptoms involving the central, peripheral and autonomous nervous systems, with considerable variations of age of onset and severity, have been reported in OPA1 patients. This variety of phenotypes is attributed to differences in the effects of OPA1 mutations, to the mode of inheritance, which may be mono- or bi-allelic, and eventually to somatic mitochondrial DNA mutations. The diversity of the pathophysiological mechanisms involved in OPA1 -related disorders is linked to the crucial role played by OPA1 in the maintenance of mitochondrial structure, genome and function. The neurological expression of these disorders highlights the importance of mitochondrial dynamics in neuronal processes such as dendritogenesis, axonal transport, and neuronal survival. Thus, OPA1 -related disorders may serve as a paradigm in the wider context of neurodegenerative syndromes, particularly for the development of novel therapeutic strategies against these diseases. [ABSTRACT FROM AUTHOR]

Abstract: Charcot–Marie–Tooth (CMT) disease represents a large group of clinically and genetically heterogeneous disorders leading to inherited peripheral neuropathies affecting motor and sensory neurons. Mutations in the ganglioside-induced differentiation-associated-protein 1 gene (GDAP1), which encodes a protein anchored to the mitochondrial outer membrane, are usually associated with the recessive forms of CMT disease and only rarely with the autosomal dominant forms. The function of GDAP1 is not fully understood but it plays a role in mitochondrial dynamics by promoting fission events. We present an overview of GDAP1 and the corresponding protein together with the complete spectrum of the 41 gene mutations described so far. We examine the relationship between the genotype and the phenotype in the various forms of CMT disease related to GDAP1 mutations, and discuss the pathophysiological hypotheses that link peripheral neuropathies to mitochondrial dysfunction and GDAP1 mutations. The meta-analysis of the literature reveals the great heterogeneity of phenotypic presentations and shows that the recessive forms of CMT disease, i.e. CMT4A and AR-CMT2, are far more severe than the dominant form, i.e. CMT2K. Among patients with recessive forms of the disease, those carrying truncating mutations are more seriously affected, often becoming wheelchair-bound before the end of the third decade. At the neuronal level, GDAP1 mutations may lead to perturbed axonal transport and impaired energy production as in other neurodegenerative diseases due to mutations in genes involved in mitochondrial dynamics. [ABSTRACT FROM AUTHOR]