Mitochondrial Depletion Syndromes

Abstract

Abstract Mitochondrial DNA (mtDNA) depletion syndromes (MDDSs) are a clinically and molecularly heterogeneous group of mitochondrial disorders characterised by severely reduced mtDNA copy number in affected tissues. Phenotypically, MDDSs manifest as Alpers‐Huttenlocher disease (AHD), mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), infantile‐onset spinocerebellar ataxia (IOSCA), hepatocerebral MDDS, encephalomyopathic MDDS or myopathic MDDS. Genotypically, MDDSs are due to mutations in nine genes (POLG1, C10orf2/PEO1, DGUOK, MPV17, TK2, RRM2B, SUCLA2, SUCLG1, TYMP). Except for AHD and IOSCA, MDDSs are genetically heterogeneous. The diagnosis is established upon clinical and instrumental investigations and demonstration of depleted mtDNA in affected tissues, such as muscle, liver, brain or intestines. Treatment is symptomatic in the vast majority of the cases and can substantially relief clinical manifestations. A causal therapeutic approach with allogeneic, hematopoietic stem‐cell transplantation is available for MNGIE. MDDSs have a poor prognosis in the majority of the cases. The outcome is usually better the later the onset of the MDDSs. Key Concepts Paediatric and adult neurologist must be aware of multisystem mitochondrial depletion syndromes (MDDSs). MDDSs predominantly manifest in the brain, muscle, liver, kidneys and intestines. In addition to mutations in one of the nine classical genes associated with MDDS, it may be caused by mutations in other genes as well. MDDSs are diagnosed by demonstration of mtDNA depletion upon biopsy of the most affected tissues. mtDNA copy number may be normal in tissues hardly phenotypically affected. Clinical severity of MDDS depends on the amount of the residual mtDNA copy number. MDDSs may rarely also occur in adults due to mutations in nuclear genes other than the nine classical ones.