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MPV17-related hepatocerebral mitochondrial DNA depletion syndrome (MPV17-NNH) revisited.

ABSTRACT: MPV17-related hepatocerebral mitochondrial DNA depletion syndrome (previously known as Navajo neurohepatopathy) was discovered in children in the Four Corner's region of New Mexico approximately 40 years ago. This disease is associated with a single missense mutation in exon 2 in the MPV17 gene. The syndrome has now been recognized world-wide. We find that huge quantities of neurotoxins were present in archived nervous tissues from such patients. Arsenic was increased 18 ×, cadmium ~ 10 ×, cobalt 2.5 × and manganese 2.3 ×; the largest increase was in mercury content 16,000 × compared to contemporaneous fresh-frozen normal nervous tissues. In the Four Corner's region of NM the life span is reduced compared to other parts of the United States and in our patients with MPV17-NNH the average life span was 5.4 years ± 2.7 (SE) years. We now live in the Anthropocene an epoch characterized by large additions to the biosphere of neurotoxins. The effects of such toxic loads on human health and disease remain to be assessed. We speculate how such high neurotoxin content in tissues, which is likely to increase during the Anthropocene, may have influenced MPV17-NNH and similar phenotypes in different parts of the world. Our results imply that selenium supplementation to the diet in the Four Corner's region of NM might be beneficial to normal people and in the management of patients with MPV17-NNH syndrome.

SUBMITTER: Qualls C

PROVIDER: S-EPMC5818138 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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MPV17-related hepatocerebral mitochondrial DNA depletion syndrome (MPV17-NNH) revisited.

Qualls Clifford C Kornfeld Mario M Joste Nancy N Ali Abdul-Mehdi AM Appenzeller Otto O

eNeurologicalSci 20160128

MPV17-related hepatocerebral mitochondrial DNA depletion syndrome (previously known as Navajo neurohepatopathy) was discovered in children in the Four Corner's region of New Mexico approximately 40 years ago. This disease is associated with a single missense mutation in exon 2 in the <i>MPV17</i> gene. The syndrome has now been recognized world-wide. We find that huge quantities of neurotoxins were present in archived nervous tissues from such patients. Arsenic was increased 18 ×, cadmium ~ 10 × ...[more]

PMID: 29473055

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Project description:BackgroundAlthough Mitochondrial DNA depletion syndrome (MDS) can be classified into three forms: myopathic, encephalomyopathic and hepatocerebral form, it is difficult to identify its form due to its clinical heterogeneity. Therefore, it is very important to conduct molecular genetic analysis on suspected patients. This study presented a male 38 weeks and 5 days infant with liver cytolysis and leukodystrophy.Case presentationA male infant proband was admitted to the department of NICU for feeding intolerance, irregular rhythm of respiration, hypoglycemia, lactic acidosis, liver cytolysis and neurological abnormalities. He was onset of mild jaundice with leukodystrophy and high lactate and phenylderivatives for urine organic acids on the 7th day. Whole exome sequencing (WES) and Sanger sequencing were performed to screen and confirm the suspicious pathogenic mutations. The results revealed this proband carried two compound heterozygous mutations in TWNK: c.1186 C > T / p.Pro396Ser and c.1844 G > C / p.Gly615Ala inherited by an autosomal recessive form from his parents, of which protein conservative analysis and structural modeling supported the pathogenicity of the two mutations. Unfortunately, the conditions described above were not improved until he was discharged from the hospital on the 23rd day and died at 4 months of age.ConclusionsIn this study, we investigated a Chinese family with the hepatocerebral form of MDS and conducted WES and Sanger sequencing to explore the causative mutations for this proband born from non-consanguineous and healthy parents. We identified two novel TWNK c.1186 C > T/ c.1844 G > C compound heterozygous mutations which were probably the disease-causing mutations of hepatocerebral form of MDS and described the clinical manifestations of the proband, which expanded the phenotypic spectrum of MDS caused by variants in TWNK. This study also emphasized WES technology can provide the genetic diagnosis of Mendelian genetic disease.

Dataset Information

MPV17-related hepatocerebral mitochondrial DNA depletion syndrome (MPV17-NNH) revisited.

Publications

MPV17-related hepatocerebral mitochondrial DNA depletion syndrome (MPV17-NNH) revisited.

Similar Datasets

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