Abstract
Mitochondrial DNA (mtDNA) depletion syndromes are autosomal-recessive diseases characterized by a severe decrease in mtDNA content leading to organ dysfunction due to insufficient amount of respiratory chain components. They are phenotypically heterogeneous and classified as myopathic, encephalomyopathic, or hepatocerebral. The latter group has been associated with mutations in TWINKLE, POLG1, DGUOK genes, and recently with mutations in the MPV17 gene. MPV17 encodes a mitochondrial inner membrane protein and plays as yet a poorly understood role in the maintenance of mtDNA integrity. MPV17-associated hepatocerebral mtDNA depletion syndrome presents in infancy with liver dysfunction that progress to liver failure in most of the affected individuals. Cholestasis, hepatomegaly, liver cirrhosis, and hepatocellular carcinoma can develop. The vast majority of the affected individuals exhibit neurological manifestations, including developmental delay, hypotonia, muscle weakness, motor and sensory peripheral neuropathy, and leukodystrophy. Other common manifestations include failure-to-thrive, lactic acidosis, and hypoglycemia. The diagnosis is based on clinical presentation, demonstration of liver mtDNA depletion, and identification of MPV17 mutations. The prognosis is unfavorable with half of affected individuals died in infancy. Liver transplant remains the only option with half of the transplanted individuals not surviving posttransplantation. Till date, 20 different mutations have been reported in MPV17 gene with clustering of mutations in the region of the putative protein kinase C phosphorylation site. About half of those mutations are missense. The p.R50Q mutation, which occurs in a CpG dinucleotide, is the most common MPV17 mutation and, till date, has only been found in the homozygous state. In contrast to most MPV17 gene mutations that are associated with death in infancy or early childhood, the p.R50Q mutation is associated with longer survival and better posttransplant outcomes.
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El-Hattab, A.W. (2013). MPV17-Associated Hepatocerebral Mitochondrial DNA Depletion Syndrome. In: Wong, LJ. (eds) Mitochondrial Disorders Caused by Nuclear Genes. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-3722-2_6
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DOI: https://doi.org/10.1007/978-1-4614-3722-2_6
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