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Original Contribution
August 2008

Hepatocerebral Form of Mitochondrial DNA Depletion Syndrome: Novel MPV17 Mutations

Author Affiliations

Author Affiliations: Unit of Molecular Neurogenetics, Pierfranco and Luisa Mariani Center for the Study of Children's Mitochondrial Disorders, “C. Besta” Neurological Institute Foundation, Milan, Italy (Drs Spinazzola and Zeviani); Departments of Pediatrics (Drs Santer and Tsiakas), Pathology (Dr Schaefer), and Neuroradiology (Dr Ding), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Neurology, Columbia University Medical Center, New York, New York (Drs Akman, Karadimas, Shanske, and Di Mauro); and Department of Metabolism and Genetics, University of Pennsylvania School of Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (Dr Ganesh).

Arch Neurol. 2008;65(8):1108-1113. doi:10.1001/archneur.65.8.1108

Background  Autosomal recessive mutations in MPV17 (OMIM *137960) have been identified in the hepatocerebral form of mitochondrial DNA depletion syndrome (MDS).

Objective  To describe the clinical, morphologic, and genetic findings in 3 children with MPV17-related MDS from 2 unrelated families.

Design  Case report.

Setting  Academic research.

Main Outcome Measures  We identified 3 novel pathogenic mutations in 3 children.

Results  Two children were homozygous for nonsense mutation p.W120X. A third child was compound heterozygous for missense mutation p.G24W and for a macrodeletion spanning MPV17 exon 8. All patients demonstrated lactic acidosis, hypoglycemia, hepatomegaly, and progressive liver failure. Neurologic symptoms manifested at a later stage of the disease. Death occurred within the first year of life in all 3 patients.

Conclusions  These data confirm that MPV17 mutations are associated with a 2-stage syndrome. The first symptoms are metabolic and rapidly progress to hepatic failure. This stage is followed by neurologic involvement affecting the central and peripheral systems.