Lethal hepatopathy and leukodystrophy caused by a novel mutation in MPV17 gene: Description of an alternative MPV17 spliced form

Navarro-Sastre, Aleix; Martín‐Hernández, Elena; Campos, Yolanda; Quintana, Ester; Medina, Enrique; Heras, Rogelio Simón de las; Lluch, Montserrat; Múñoz, Alberto; Hoyo, Pilar del; Martin, R. Llamas; Gort, Laura; Briones, Paz; Ribes, Antònia

doi:10.1016/j.ymgme.2008.01.012

Cited by 45 publications

(32 citation statements)

References 22 publications

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“…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.…”

Section: Mpv17-related Hepatocerebral Mdsmentioning

confidence: 99%

“…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].…”

Section: Mpv17-related Hepatocerebral Mdsmentioning

confidence: 99%

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Mitochondrial DNA Depletion Syndromes: Review and Updates of Genetic Basis, Manifestations, and Therapeutic Options

2013

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Mitochondrial DNA (mtDNA) depletion syndromes (MDS) are a genetically and clinically heterogeneous group of autosomal recessive disorders that are characterized by a severe reduction in mtDNA content leading to impaired energy production in affected tissues and organs. MDS are due to defects in mtDNA maintenance caused by mutations in nuclear genes that function in either mitochondrial nucleotide synthesis (TK2, SUCLA2,

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Section: Mpv17-related Hepatocerebral Mdsmentioning

confidence: 99%

Section: Mpv17-related Hepatocerebral Mdsmentioning

confidence: 99%

Mitochondrial DNA Depletion Syndromes: Review and Updates of Genetic Basis, Manifestations, and Therapeutic Options

2013

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“…1,2 In the limited available reports of MPV17-MDS, the MR imaging findings have been described as normal (most commonly), "nonspecific white matter abnormalities," "cytotoxic edema" involving the deep and subcortical white matter of the cerebrum, or "atrophy," with only a few reports of specific regional abnormalities. 1,[3][4][5]7 We reviewed the available images in these clinical reports and found only 1 with dorsal brain stem involvement, which we opine is localized within the reticular formation. 3 Thus, the incidence of involvement of the reticular formation or reticulospinal tracts in MPV17-MDS is unknown.…”

Section: Spinazzola Et Al (2006)mentioning

confidence: 97%

MR Imaging Findings in the Reticular Formation in Siblings withMPV17-Related Mitochondrial Depletion Syndrome

Merkle

Nascene²,

McKinney³

2011

AJNR Am J Neuroradiol

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SUMMARY:Hepatocerebral MPV17-MDS is quite rare (Ͻ30 confirmed cases), with limited findings described on MR imaging. We report 2 siblings having abnormalities within the reticular formation of the lower brain stem and within the reticulospinal tracts at the cervicocranial junction on T2WI. The presence of these MR imaging findings (relative to previous reports) raises the possibility that they represent subtle but characteristic findings corresponding to clinically observed abnormalities of tone encountered with this recently described disorder. ABBREVIATIONS:1 H-MR spectroscopy ϭ proton MR spectroscopy; MDS ϭ mitochondrial depletion syndrome; MPV17-MDS ϭ MPV17-related mitochondrial depletion syndrome; T1WI ϭ T1-weighted imaging; T2WI ϭ T2-weighted imaging M PV17-related hepatocerebral MDS is a rare congenital autosomal recessive disorder typically characterized by hepatic failure, failure to thrive, and neurologic findings (dependent on the age of onset), such as hypotonia and dystonic movements.1,2 It is 1 of several described MDSs recently confirmed by dedicated laboratory and genetic testing.2 Presentation usually occurs in the first months of life, with the life span typically limited to months.1,2 The MR imaging literature describing MPV17-MDS is sparse and nonspecific, but the variable findings that have been reported range from normal-todiffuse white matter abnormalities, which may resemble a leukodystrophy or hypomyelination.1 Particular regions noted in case reports include the cerebellar white matter, middle cerebellar peduncles, substantia nigra, and a single patient with subtle involvement of the dorsal brain stem.2-4 Herein, we describe 2 infant siblings with MPV17-MDS exhibiting nearly identical involvement on T2WI at the cervicomedullary junction and within the lower dorsal brain stem. Case Reports Case 1A 3-month-old male infant with no significant perinatal/neonatal history presented with progressive deficiencies in feeding, jaundice, failure to thrive, and mild hypotonia; elevated liver enzymes were subsequently detected. Thereafter, a 1.5T MR imaging at 5 months of age demonstrated mild moderately delayed myelination, as represented on T1WI by limited hyperintensity within the anterior limb of the internal capsule, the corpus callosum splenium and lack of significant occipital white matter hyperintensity. There were hyperintense abnormalities on T2WI bilaterally within the reticular formation of the lower dorsal brain stem and the reticulospinal tracts of the cervicomedullary junction (Fig 1), without reduced diffusion. Findings of point-resolved 1 H-MR spectroscopy of the basal ganglia and periventricular white matter appeared normal for his age, without a lactate peak and with equivalent N-acetylaspartate and choline peaks. A head CT at 6.5 months of age did not demonstrate any significant abnormalities or overt atrophy. Hepatomegaly was clinically apparent and confirmed by CT. Muscle biopsies were performed but were negative for the more common mitochondrial disorders. The patient died at ...

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“…Hepatic and neurologic manifestations appear to be the most characteristic findings. All early-onset patients studied presented with liver dysfunction, comprising cholestasis, jaundice and coagulopathy (see Karadimas et al, 2006;Spinazzola et al, 2006Spinazzola et al, , 2008Wong et al, 2007;Navarro-Sastre et al, 2008;Kaji et al, 2009;Parini et al, 2009;El-Hattab et al, 2010;Merkle et al, 2012;Uusimaa et al, 2013). Patients developing cirrhosis or hepatocellular carcinoma were described less frequently (see Karadimas et al, 2006;El-Hattab et al, 2010).…”

Section: Human Mpv17-related Diseasementioning

confidence: 99%

The role of the Mpv17 protein mutations of which cause mitochondrial DNA depletion syndrome (MDDS): lessons from homologs in different species

Löllgen

Weiher

2014

Biological Chemistry

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Mitochondrial DNA depletion syndromes (MDDS) are severe pediatric diseases with diverse clinical manifestations. Gene mutations that underlie MDDS have been associated with alterations in the mitochondrial DNA (mtDNA) replication machinery or in mitochondrial deoxyribonucleoside triphosphate pools. However, the nuclear gene MPV17, whose mutated forms are associated with hepatocerebral MDDS in humans, plays a so-far unknown role in mtDNA maintenance. A high degree of conservation has been determined between MPV17 and its mouse (Mpv17), zebrafish (tra) and yeast (SYM1) homologs, respectively, whereby mutants in these cause very different phenotypes. While dysfunction in this gene in humans causes fatal liver disease, kidney pathology is induced in mice. Moreover, in zebrafish inactivation of the Mpv17 homolog was detected as a viable dyscolouration mutant. Knock out of the yeast ortholog results in a temperature-sensitive metabolic growth phenotype. Detailed analyses on common denominators between these different phenotypes strengthen the hypothesis that the Mpv17 protein forms a channel in the inner mitochondrial membrane, allowing small molecules -in vertebrates probably nucleotides, and in yeast probably intermediates of the tricarboxylic acid cycle -to pass. Moreover, a function modifying the pathologic manifestations of MPV17-related disease in mice has been identified. This signaling pathway remarkably involves the non-mitochondrial catalytic subunit of DNA-dependent protein kinase (PRKDC), important in double-strand break repair resistance against reactive oxygen-induced genotoxic stress.

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Lethal hepatopathy and leukodystrophy caused by a novel mutation in MPV17 gene: Description of an alternative MPV17 spliced form

Cited by 45 publications

References 22 publications

Mitochondrial DNA Depletion Syndromes: Review and Updates of Genetic Basis, Manifestations, and Therapeutic Options

Mitochondrial DNA Depletion Syndromes: Review and Updates of Genetic Basis, Manifestations, and Therapeutic Options

MR Imaging Findings in the Reticular Formation in Siblings withMPV17-Related Mitochondrial Depletion Syndrome

The role of the Mpv17 protein mutations of which cause mitochondrial DNA depletion syndrome (MDDS): lessons from homologs in different species

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