Hepatocerebral Form of Mitochondrial DNA Depletion Syndrome

Abstract

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.

The Channel-Forming Sym1 Protein Is Transported by the TIM23 Complex in a Presequence-Independent Manner

“…Seven of eight genes that have been linked to MDDS were found to play a direct role in mitochondrial DNA maintenance (13,19,41,54,62). The depletion of the mitochondrial DNA phenotype and the concomitant decrease of respiratory activity were recapitulated in MPV17 knockout mice.…”

“…Mutations in human MPV17 lead to the hepatocerebral form of mitochondrial DNA depletion syndrome (MDDS) (62). Seven of eight genes that have been linked to MDDS were found to play a direct role in mitochondrial DNA maintenance (13,19,41,54,62).…”

Mitochondrial DNA Depletion Syndromes: Review and Updates of Genetic Basis, Manifestations, and Therapeutic Options

“…Approximately 30 affected individuals have been reported with MPV17-related hepatocerebral MDS [59][60][61][62][63][64][65][66][67][68]. Of note, among those confirmed cases are individuals with Navajo neurohepatopathy who were found to have homozygous p.Arg50Gln mutations in MPV17.…”

“…Less frequent manifestations include renal tubulopathy, hypoparathyroidism, and gastrointestinal dysmotility that manifests as gastroesophageal reflux, cyclic vomiting, and diarrhea. Corneal anesthesia and ulcers were reported in individuals homozygous for the mutation p.Arg50Gln [59][60][61][62][63][64][65][66][67][68].…”

“…In addition, uncooked cornstarch may reduce symptomatic hypoglycemia in individuals with DGUOK and MPV17-related hepatocerebral MDS [54,65]. Furthermore, cornstarch use may slow the progression of the liver disease in MPV17-related hepatocerebral MDS [63,65].…”