Mitochondrial Parkinsonism: A Practical Guide to Genes and Clinical Diagnosis

BackgroundPrimary mitochondrial diseases (PMDs) are the most common inborn errors of energy metabolism, with a combined prevalence of 1 in 4300. They can result from mutations in either nuclear DNA (nDNA) or mitochondrial DNA (mtDNA). These disorders are multisystemic and mainly affect high energy-demanding tissues, such as muscle and the central nervous system (CNS). Among many clinical features of CNS involvement, parkinsonism is one of the most common movement disorders in PMDs.MethodsThis review provides a pragmatic educational overview of the most recent advances in the field of mitochondrial parkinsonism, from pathophysiology and genetic etiologies to phenotype and diagnosis.ResultsmtDNA maintenance and mitochondrial dynamics alterations represent the principal mechanisms underlying mitochondrial parkinsonism. It can be present in isolation, alongside other movement disorders or, more commonly, as part of a multisystemic phenotype. Mutations in several nuclear-encoded genes (ie, POLG, TWNK, SPG7, and OPA1) and, more rarely, mtDNA mutations, are responsible for mitochondrial parkinsonism. Progressive external opthalmoplegia and optic atrophy may guide genetic etiology identification.ConclusionA comprehensive deep-phenotyping approach is needed to reach a diagnosis of mitochondrial parkinsonism, which lacks distinctive clinical features and exemplifies the intricate genotype-phenotype interplay of PMDs.