Navajo Neurohepatopathy Is Caused by a Mutation in the MPV17 Gene

Abstract

Navajo neurohepatopathy (NNH) is an autosomal recessive disease that is prevalent among Navajo children in the southwestern United States. The major clinical features are hepatopathy, peripheral neuropathy, corneal anesthesia and scarring, acral mutilation, cerebral leukoencephalopathy, failure to thrive, and recurrent metabolic acidosis with intercurrent infections. Infantile, childhood, and classic forms of NNH have been described. Mitochondrial DNA (mtDNA) depletion was detected in the livers of two patients, suggesting a primary defect in mtDNA maintenance. Homozygosity mapping of two families with NNH suggested linkage to chromosome 2p24. This locus includes the MPV17 gene, which, when mutated, causes a hepatocerebral form of mtDNA depletion. Sequencing of the MPV17 gene in six patients with NNH from five families revealed the homozygous R50Q mutation described elsewhere. Identification of a single missense mutation in patients with NNH confirms that the disease is probably due to a founder effect and extends the phenotypic spectrum associated with MPV17 mutations.

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.…”

“…Of note, among those confirmed cases are individuals with Navajo neurohepatopathy who were found to have homozygous p.Arg50Gln mutations in MPV17. Navajo neurohepatopathy, a disorder prevalent in the Native American Navajo population, has the manifestations of MPV17-related hepatocerebral MDS, as well as painless fractures, acral mutilation, and corneal anesthesia, ulceration, and scarring [60].…”

“…Infancy is the typical age of onset; however, individuals homozygous for the p.Arg50Gln mutation may present later in childhood [60]. In the vast majority of affected individuals, liver disease progresses to liver failure typically during infancy or early childhood.…”

“…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].…”

Adult-Onset Fatal Neurohepatopathy in a Woman Caused by MPV17 Mutation

“…Mutations in MPV17 are known to cause Navajo neurohepatopathy (OMIM #256810), a recessive, rapidly progressive mitochondrial DNA depletion syndrome of liver failure and neurologic deterioration with onset in the first year of life (Karadimas et al 2006;El-Hattab et al 2010;AlSaman et al 2012). More recently, mutations in this gene have been identified in an older child (El-Hattab et al 2010) and two adults (Blakely et al 2012;Garone et al 2012) with subacute onset of many of the same symptoms seen in the infantile form, including peripheral neuropathy, liver dysfunction or failure, progressive white matter disease, and lactic acidosis.…”