2 research outputs found

    Genetic and phenotypic characterization of NKX6ā€2ā€related spastic ataxia and hypomyelination

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    Background and purpose Hypomyelinating leukodystrophies are a heterogeneous group of genetic disorders with a wide spectrum of phenotypes and a high rate of genetically unsolved cases. Biā€allelic mutations in NKX6ā€2 were recently linked to spastic ataxia 8 with hypomyelinating leukodystrophy. Methods Using a combination of homozygosity mapping, exome sequencing, and detailed clinical and neuroimaging assessment a series of new NKX6ā€2 mutations in a multicentre setting is described. Then, all reported NKX6ā€2 mutations and those identified in this study were combined and an inā€depth analysis of NKX6ā€2ā€related disease spectrum was provided. Results Eleven new cases from eight families of different ethnic backgrounds carrying compound heterozygous and homozygous pathogenic variants in NKX6ā€2 were identified, evidencing a high NKX6ā€2 mutation burden in the hypomyelinating leukodystrophy disease spectrum. Our data reveal a phenotype spectrum with neonatal onset, global psychomotor delay and worse prognosis at the severe end and a childhood onset with mainly motor phenotype at the milder end. The phenotypic and neuroimaging expression in NKX6ā€2 is described and it is shown that phenotypes with epilepsy in the absence of overt hypomyelination and diffuse hypomyelination without seizures can occur. Conclusions NKX6ā€2 mutations should be considered in patients with autosomal recessive, very early onset of nystagmus, cerebellar ataxia with hypotonia that rapidly progresses to spasticity, particularly when associated with neuroimaging signs of hypomyelination. Therefore, it is recommended that NXK6ā€2 should be included in hypomyelinating leukodystrophy and spastic ataxia diagnostic panels

    MPV17Ć¢ related mitochondrial DNA maintenance defect: New cases and review of clinical, biochemical, and molecular aspects

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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 infantileĆ¢ onset hepatocerebral mtDNA depletion syndrome and Navajo neurohepatopathy. To date, 75 individuals with MPV17Ć¢ 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 earlyĆ¢ 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 lateĆ¢ 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.MPV17 is a mitochondrial inner membrane protein involved in importing deoxynucleotides into the mitochondria. To date, 75 individuals with MPV17Ć¢ related mitochondrial DNA (mtDNA) maintenance defect have been reported with 39 different MPV17 pathogenic variants. In this report, we present an additional 25 affected individuals with 9 novel MPV17 pathogenic variants. The vast majority of affected individuals presented with an earlyĆ¢ onset encephalohepatopathic disease. Rarely, MPV17 deficiency can cause a lateĆ¢ onset neuromyopathic disease with no or minimal liver involvement.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142478/1/humu23387_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142478/2/humu23387.pd
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