RESUMEN
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.
Asunto(s)
Encefalopatías Metabólicas/genética , Codón sin Sentido/genética , ADN Mitocondrial/genética , Fallo Hepático/genética , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/genética , Proteínas Mitocondriales/deficiencia , Proteínas Mitocondriales/genética , Mutación Missense/genética , Encefalopatías Metabólicas/metabolismo , Encefalopatías Metabólicas/patología , Resultado Fatal , Femenino , Genes Recesivos , Genoma Mitocondrial/genética , Humanos , Lactante , Fallo Hepático/metabolismo , Fallo Hepático/patología , Errores Innatos del Metabolismo/genética , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/metabolismo , Enfermedades Mitocondriales/patología , SíndromeRESUMEN
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.
Asunto(s)
Encefalopatías/genética , Enfermedades de la Córnea/genética , Genes Mitocondriales , Indígenas Norteamericanos/genética , Hepatopatías/genética , Mutación , Enfermedades del Sistema Nervioso Periférico/genética , Adulto , Encefalopatías/etnología , Cromosomas Humanos Par 2/genética , Enfermedades de la Córnea/etnología , Análisis Mutacional de ADN , ADN Mitocondrial/análisis , ADN Mitocondrial/genética , Femenino , Homocigoto , Humanos , Hígado/química , Hepatopatías/etnología , Masculino , Linaje , Enfermedades del Sistema Nervioso Periférico/etnologíaRESUMEN
A 21-year-old woman described proximal muscle weakness since early childhood. At age 16, she developed bilateral ptosis, progressive external ophthalmoplegia, and exercise intolerance. She harbored a heteroplasmic G12315A mutation in the mitochondrial DNA tRNA(Leu(CUN)) gene, which disrupts a highly conserved G-C base pair in the TPsiC stem of the molecule. Mutant mitochondrial DNA was 62% of total in muscle and 17% in blood. The mutation was undetectable in blood, urinary sediment, and hair follicles from the patient's mother. This second patient with G12315A and progressive external ophthalmoplegia confirms the pathogenicity of the mutation and helps to define the correlation between genotype and phenotype.