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MPV17 encodes a putative channel-forming protein of the inner mitochondrial membrane and is involved in mitochondrial deoxynucleotide homeostasis. MPV17 mutations were first reported in patients with Navajo neurohepatopathy, an autosomal recessive mitochondrial DNA depletion syndrome, characterized by early-onset liver failure, failure to thrive as well as central and peripheral neurological involvement. Recently, two patients with juvenile-onset peripheral sensorimotor neuropathy associated with an MVP17 c.122G>A (p.Arg41Gln) variant have been reported. Here, we describe five additional patients from two unrelated families with sensorimotor axonal neuropathy without hepatocerebral affection caused by homozygous MPV17 variants. Patients of the first family carried the known c.122G>A variant and affected individuals of the second family had a novel c.376-9T>G near-splice variant, which was shown to result in an in-frame deletion of 11 amino acids. This report provides further evidence that MPV17 mutations should be considered in patients with pure, non-syndromic axonal neuropathy.

MPV17-related mitochondrial neurohepatopathy is a rare genetic disorder worldwide. We report on a novel pathogenic variant in the MPV17 gene in 24 unrelated neurohepatopathic infants of non-consanguineous Black South African heritage. Exome sequencing identified homozygosity for a c.106C>T nonsense variant in exon 3 of the human MPV17 gene in 2 unrelated index patients. mRNA analysis revealed transcripts both with and without exon 3, indicating both reduced splice efficiency and premature termination as mechanisms for disease. Carrier frequency in this population was found to be 1 in 68 (95% CI; 1/122-1/38) with an estimated newborn incidence of 1 in 18 496 (95% CI; 1/59 536-1/5776). Affected infants all presented with infantile onset neurohepatopathy with none surviving beyond infancy. This description of a relatively common pathogenic variant underlying a previously uncharacterized severe neurohepatopathy in South Africa will engender increased awareness, earlier diagnosis and possibly improve outcome if preventative or specific therapeutic options can be found.

Mitochondrial DNA (mtDNA) depletion syndromes (MDDSs) are a clinically and molecularly heterogeneous group of mitochondrial disorders characterised by severely reduced mtDNA copy number in affected tissues. Phenotypically, MDDSs manifest as Alpers-Huttenlocher disease (AHD), mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), infantile-onset spinocerebellar ataxia (IOSCA), hepatocerebral MDDS, encephalomyopathic MDDS or myopathic MDDS. Genotypically, MDDSs are due to mutations in nine genes (POLG1, C10orf2/PEO1, DGUOK, MPV17, TK2, RRM2B, SUCLA2, SUCLG1, TYMP). Except for AHD and IOSCA, MDDSs are genetically heterogeneous. The diagnosis is established upon clinical and instrumental investigations and demonstration of depleted mtDNA in affected tissues, such as muscle, liver, brain or intestines. Treatment is symptomatic in the vast majority of the cases and can substantially relief clinical manifestations. A causal therapeutic approach with allogeneic, hematopoietic stem-cell transplantation is available for MNGIE. MDDSs have a poor prognosis in the majority of the cases. The outcome is usually better the later the onset of the MDDSs. Key Concepts Paediatric and adult neurologist must be aware of multisystem mitochondrial depletion syndromes (MDDSs). MDDSs predominantly manifest in the brain, muscle, liver, kidneys and intestines. In addition to mutations in one of the nine classical genes associated with MDDS, it may be caused by mutations in other genes as well. MDDSs are diagnosed by demonstration of mtDNA depletion upon biopsy of the most affected tissues. mtDNA copy number may be normal in tissues hardly phenotypically affected. Clinical severity of MDDS depends on the amount of the residual mtDNA copy number. MDDSs may rarely also occur in adults due to mutations in nuclear genes other than the nine classical ones. Keywords: mitochondrial DNA; depletion; copy number; mitochondrial syndromes; mitochondrial disorders

This study reports clinical, biochemical and histopathological findings associated with a novel homozygous MPV17 mutation in four patients with mitochondrial depletion syndrome. The severe course of the disease, which started in the first weeks of life, was dominated by a failure to thrive, hypotonia and liver dysfunction, with relatively mild neurological involvement. All affected infants died by 1 year of age. Laboratory findings included progressive liver failure (hypertransaminasaemia, icterus, and coagulopathy), recurrent hypoglycaemia, lactic acidaemia, hyperferritinaemia, and increased transferrin saturation. Histological and ultrastructural analyses uncovered significant lipid accumulation in hepatocytes and myocytes. A severe decrease in the mitochondrial/nuclear DNA (mtDNA/nDNA) ratio was found post-mortem in the livers (and in one muscle specimen) of both examined patients. Oxidative phosphorylation system (OXPHOS) Western blotting revealed low levels of complexes I, III and IV subunits. The highlights of our findings are as follows: (i) The novel p.Pro64Arg mutation is the second recurrent MPV17 mutation reported. The phenotype associated with the p.Pro64Arg mutation differs from the phenotype of the relatively common p.Arg50Gln mutation, suggesting the existence of a genotype-phenotype correlation. (ii) Tissues collected from patients during autopsy may be useful for both mtDNA/nDNA ratio assessment and OXPHOS Western blotting.

Mitochondrial DNA depletion syndromes (MDSs) form a group of autosomal recessive disorders characterized by profoundly decreased mitochondrial DNA copy numbers in affected tissues. Three main clinical presentations are known: myopathic, encephalomyopathic and hepatocerebral. The first is associated with mutations in thymidine kinase 2 (TK2) and p53-induced ribonucleotide reductase B subunit (RRM2B); the second with mutations in succinate synthase A (SUCLA2) and B (SUCLG1); the third with mutations in Twinkle (PEO1), pol-gammaA (POLG1), deoxyguanosine kinase (DGUOK) and MPV17 (MPV17). In this work, we review the MDS-associated phenotypes and present our own experience of 32 MDS patients, with the aim of defining the mutation frequency of the known genes, the clinical spectrum of the diseases, and the genotype-phenotype correlations. Five of our patients carried previously unreported mutations in one of the eight MDS genes.

Objective Mitochondrial DNA (mtDNA) depletion syndrome (MDS) is a clinically and genetically heterogeneous group of autosomal recessive diseases characterized by a reduction in mtDNA copy number. Several nuclear genes have been shown to account for these severe oxidative phosphorylation disorders, but the disease-causing mutations remain largely unknown. Methods By virtue of homozygosity mapping, we tested candidate genes involved in mtDNA maintenance in patients born to consanguineous parents. Results We found homozygosity for microsatellite markers flanking the PEO1 gene, encoding the mitochondrial Twinkle helicase, in two sibs presenting a hepatocerebral form of MDS. Sequencing the PEO1 gene showed a homozygous mutation at a conserved position of the protein in the two patients (T457I). The modeling of the Twinkle protein showed that T457 is located in the interface between two monomers of the hexameric enzyme. Finally, using purified recombinant protein, we demonstrated that the T457I mutant Twinkle has a defective helicase activity. Interpretation Although dominant Twinkle mutations have been previously reported in patients with autosomal dominant progressive external ophthalmoplegia and multiple mtDNA deletions, we report here the first recessive Twinkle mutation in patients with hepatocerebral form of MDS. Identifying other Twinkle mutations in MDS and/or autosomal dominant progressive external ophthalmoplegia and studying their impact on the isolated proteins should help in understanding why some mutations are recessive and others are dominant. Ann Neurol 2007

Mitochondrial DNA depletion syndrome is a clinically heterogeneous group of disorders characterized by a reduction in mitochondrial DNA copy number. The recent discovery of mutations in the deoxyguanosine kinase (dGK) gene in patients with the hepatocerebral form of mitochondrial DNA depletion syndrome prompted us to screen 21 patients to determine the frequency of dGK mutations, further characterize the clinical spectrum, and correlate genotypes with phenotypes. We detected mutations in three patients (14%). One patient had a homozygous GATT duplication (nucleotides 763-766), and another had a homozygous GT deletion (nucleotides 609-610); both mutations lead to truncated proteins. The third patient was a compound heterozygote for two missense mutations (R142K and E227K) that affect critical residues of the protein. These mutations were associated with variable phenotypes, and their low frequencies suggests that dGK is not the only gene responsible for mitochondrial DNA depletion in liver. The patient with the missense mutations had isolated liver failure and responded well to liver transplantation, which may be a therapeutic option in selected cases.

Alpers' syndrome is a fatal neurogenetic disorder first described more than 70 years ago. It is an autosomal recessive, developmental mitochondrial DNA depletion disorder characterized by deficiency in mitochondrial DNA polymerase γ (POLG) catalytic activity, refractory seizures, neurodegeneration, and liver disease. In two unrelated pedigrees of Alpers' syndrome, each affected child was found to carry a homozygous mutation in exon 17 of the POLG locus that led to a Glu873Stop mutation just upstream of the polymerase domain of the protein. In addition, each affected child was heterozygous for the G1681A mutation in exon 7 that led to an Ala467Thr substitution in POLG, within the linker region of the protein. Ann Neurol 2004