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

Mendelsohn, Bryce A.; Mehta, Neil; Hameed, Bilal; Pekmezci, Melike; Packman, Seymour; Ralph, Jeffrey W.

doi:10.1007/8904_2013_267

Cited by 12 publications

(13 citation statements)

References 13 publications

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“…The same mutation has also been reported in the homozygous state in a 21-year-old man presenting with neuropathy and leukoencephalopathy [17] and in a 25-year-old woman presenting with secondary amenorrhea, megaloblastic anemia, lactic acidosis, leukoencephalopathy, peripheral neuropathy and liver cirrhosis [18]. These late-onset cases suggest that this mutation could be a milder allele responsible for attenuated or, at least, delayed phenotypes.…”

Section: Discussionsupporting

confidence: 63%

“…On one hand, except in the Navajo population of the southwestern United States, MPV17 is usually responsible for marked developmental delay, infantile hypotonia, muscle weakness and peripheral neuropathy, leading to severe encephalomyopathy. However, as discussed previously, the specific homozygote mutation identified in our patients has been reported with later onset cases, albeit in only two patients [17], [18]. On the other hand, the p.Leu483Pro mutation in the homozygote state is the most common genotype associated with the subacute neuropathic form (type 3b) of Gaucher disease [19], [20].…”

Section: Discussionsupporting

confidence: 49%

See 1 more Smart Citation

Clinical variability in neurohepatic syndrome due to combined mitochondrial DNA depletion and Gaucher disease

Harvengt

Wanty

Paepe

et al. 2014

Molecular Genetics and Metabolism Reports

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A 1-year-old girl born to consanguineous parents presented with unexplained liver failure, leading to transplantation at 19 months. Subsequent partial splenectomy for persistent cytopenia showed the presence of foamy cells, and Gaucher disease was confirmed by homozygosity for the p.Leu483Pro mutation in the GBA gene. She was treated by enzyme replacement therapy (ERT). Clinical follow-up showed mild developmental delay, strabismus, nystagmus and oculomotor apraxia. Biochemical studies revealed multiple respiratory chain deficiencies and a mosaic pattern of deficient complex IV immunostaining in liver and fibroblast. Molecular analysis identified a mtDNA depletion syndrome due to the homozygous p.Pro98Leu mutation in MPV17. A younger sister unaffected by mtDNA depletion, presented with pancytopenia and hepatosplenomegaly. ERT for Gaucher disease resulted in visceral normalization without any neurological symptom. A third sister, affected by both conditions, had marked developmental delay, strabismus and ophthalmoplegia but no liver cirrhosis. In conclusion, intrafamilal variability occurs in MPV17-related disease. The combined pathological effect of Gaucher and mitochondrial diseases can negatively impact neurological and liver functions and influence the outcome in consanguineous families. The immunocytochemical staining of OXPHOS protein in tissues and cultured cells is a powerful tool revealing mosaic pattern of deficiency pointing to mtDNA-related mitochondrial disorders.

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Section: Discussionsupporting

confidence: 63%

Section: Discussionsupporting

confidence: 49%

Clinical variability in neurohepatic syndrome due to combined mitochondrial DNA depletion and Gaucher disease

Harvengt

Wanty

Paepe

et al. 2014

Molecular Genetics and Metabolism Reports

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“…Pathogenic MPV17 variants are associated with Navajo neurohepatopathy, a severe infantile hepatocerebral MTDPS, often leading to death in the first year of life (OMIM#256810). However, the homozygous MPV17 variant c.293C>T has been described in patients with adult onset of neurohepatopathy and leukoencephalopathy . Patient LP147 showed only mild myopathy and exhibited no psychiatric or neurological symptoms until now, emphasizing the wide spectrum of phenotypical presentations in mitochondriopathies. Patient LP164 had a phenotype consistent with BRIC and CNS with conjugated and unconjugated hyperbilirubinemia (Table ).…”

Section: Discussionmentioning

confidence: 96%

Diagnosis of monogenic liver diseases in childhood by next‐generation sequencing

et al. 2017

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Next-generation sequencing (NGS) has opened up novel diagnostic opportunities for children with unidentified, but suspected inherited diseases. We describe our single-center experience with NGS diagnostics in standard clinical scenarios in pediatric hepatology. We investigated 135 children with suspected inherited hepatopathies, where initially no causative pathogenic variant had been identified, with an amplicon-based NGS panel of 21 genes associated with acute and chronic hepatopathies. In 23 of these patients, we detected pathogenic or likely pathogenic variants in 10 different genes. We present 6 novel variants. A total of 14 of these patients presented with the characteristic phenotype of the related hepatopathy. Nine patients showed only few or atypical clinical symptoms or presented with additional signs. In another 13 out of 135 cases, we detected variants of unknown significance (VUS) in 9 different genes. Only 2 of these patients showed characteristic phenotypes conclusive with the detected variants, whereas 11 patients showed unspecific or atypical phenotypes. Our multi-gene panel is a fast and comprehensive tool to diagnose inherited pediatric hepatopathies. We also illustrate the challenge of dealing with genetic variants and highlight arising clinical questions, especially in patients with atypical phenotypes.

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“…To date, 75 individuals with MPV17 ‐related mtDNA maintenance defect have been reported with 39 different MPV17 pathogenic variants (Al‐Hussaini et al., ; Al‐Jasmi, Penefsky, & Souid, ; AlSaman, Tomoum, Invernizzi, & Zeviani, et al., ; Bijarnia‐Mahay, Mohan, Goyal, & Verma, ; Bitting & Hanson, ; Blakely et al., ; Choi et al., ; El‐Hattab et al., ; Garone et al., ; Kaji et al., ; Karadimas et al., ; Kim et al., ; McKiernan et al., ; Mendelsohn et al., ; Merkle, Nascene, & McKinney, ; Navarro‐Sastre et al., ; Nogueira et al., ; Piekutowska‐Abramczuk et al., ; Sarkhy, Al‐Sunaid, Abdullah, AlFadhel, & Eiyad, ; Spinazzola et al., , ; Uusimaa et al., ; Vilarinho et al., ; Wong et al., ). In this report, we present additional 25 affected individuals and nine novel MPV17 pathogenic variants.…”

Section: Introductionmentioning

confidence: 99%

MPV17-related mitochondrial DNA maintenance defect: New cases and review of clinical, biochemical, and molecular aspects

et al. 2018

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Mitochondrial DNA (mtDNA) maintenance defects are a group of diseases caused by deficiency of proteins involved in mtDNA synthesis, mitochondrial nucleotide supply, or mitochondrial dynamics. One of the mtDNA maintenance proteins is MPV17, which is a mitochondrial inner membrane protein involved in importing deoxynucleotides into the mitochondria. In 2006, pathogenic variants in MPV17 were first reported to cause infantile-onset hepatocerebral mtDNA depletion syndrome and Navajo neurohepatopathy. To date, 75 individuals with MPV17-related mtDNA maintenance defect have been reported with 39 different MPV17 pathogenic variants. In this report, we present an additional 25 affected individuals with nine novel MPV17 pathogenic variants. We summarize the clinical features of all 100 affected individuals and review the total 48 MPV17 pathogenic variants. The vast majority of affected individuals presented with an early-onset encephalohepatopathic disease characterized by hepatic and neurological manifestations, failure to thrive, lactic acidemia, and mtDNA depletion detected mainly in liver tissue. Rarely, MPV17 deficiency can cause a late-onset neuromyopathic disease characterized by myopathy and peripheral neuropathy with no or minimal liver involvement. Approximately half of the MPV17 pathogenic variants are missense. A genotype with biallelic missense variants, in particular homozygous p.R50Q, p.P98L, and p.R41Q, can carry a relatively better prognosis.

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

Abstract: Hepatocerebral mitochondrial DNA depletion syndromes are classically considered diseases of early childhood, typically affecting the liver, peripheral, and central nervous systems with a rapidly progressive course.

Cited by 12 publications

References 13 publications

Clinical variability in neurohepatic syndrome due to combined mitochondrial DNA depletion and Gaucher disease

Clinical variability in neurohepatic syndrome due to combined mitochondrial DNA depletion and Gaucher disease

Diagnosis of monogenic liver diseases in childhood by next‐generation sequencing

MPV17-related mitochondrial DNA maintenance defect: New cases and review of clinical, biochemical, and molecular aspects

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