https://www.cell.com/cell-metabolism/pdf/S1550-4131(05)00375-X.pdf

Mitochondrial medicine: a metabolic perspective on the pathology of oxidative phosphorylation disorders.

Rewiring of Glutamine Metabolism Is a Bioenergetic Adaptation of Human Cells with Mitochondrial DNA Mutations

Leigh syndrome: Resolving the clinical and genetic heterogeneity paves the way for treatment options

Hereditary spastic paraplegias are heterogeneous neurological disorders characterized by a pyramidal syndrome with symptoms predominantly affecting the lower limbs. Some limited pyramidal involvement also occurs in patients with an autosomal recessive neurocutaneous syndrome due to ALDH18A1 mutations. ALDH18A1 encodes delta-1-pyrroline-5-carboxylate synthase (P5CS), an enzyme that catalyses the first and common step of proline and ornithine biosynthesis from glutamate. Through exome sequencing and candidate gene screening, we report two families with autosomal recessive transmission of ALDH18A1 mutations, and predominant complex hereditary spastic paraplegia with marked cognitive impairment, without any cutaneous abnormality. More interestingly, we also identified monoallelic ALDH18A1 mutations segregating in three independent families with autosomal dominant pure or complex hereditary spastic paraplegia, as well as in two sporadic patients. Low levels of plasma ornithine, citrulline, arginine and proline in four individuals from two families suggested P5CS deficiency. Glutamine loading tests in two fibroblast cultures from two related affected subjects confirmed a metabolic block at the level of P5CS in vivo. Besides expanding the clinical spectrum of ALDH18A1-related pathology, we describe mutations segregating in an autosomal dominant pattern. The latter are associated with a potential trait biomarker; we therefore suggest including amino acid chromatography in the clinico-genetic work-up of hereditary spastic paraplegia, particularly in dominant cases, as the associated phenotype is not distinct from other causative genes.

/pdf/alteration-of-ornithine-metabolism-leads-to-dominant-and-19ma3gglmd.pdf

Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia.

Leigh Syndrome (OMIM 256000) is a heterogeneous neurologic disorder due to damage in mitochondrial energy production that usually starts in early childhood. The first description given by Leigh pointed out neurological symptoms in children under 2 years and premature death. Following cases brought some hypothesis to explain the cause due to similarity to other neurological diseases and led to further investigation for metabolic diseases. Biochemical evaluation and specific metabolic profile suggested impairment in energy production (OXPHOS) in mitochondria. As direct approach to involved tissues is not always possible or safe, molecular analysis is a great cost-effective option and, besides biochemical results, is required to confirm the underlying cause of this syndrome face to clinical suspicion. The Next Generation Sequencing (NGS) advance represented a breakthrough in molecular biology allowing simultaneous gene analysis giving short-time results and increasing the variants underlying this syndrome, counting over 75 monogenic causes related so far. NGS provided confirmation of emerging cases and brought up diagnosis in atypical presentations as late-onset cases, which turned Leigh into a heterogeneous syndrome with variable outcomes. This review highlights clinical presentation in both classic and atypical phenotypes, the investigation pathway throughout confirmation emphasizing the underlying genetic heterogeneity and increasing number of genes assigned to this syndrome as well as available treatment.

/pdf/molecular-basis-of-leigh-syndrome-a-current-look-1tsqtys643.pdf

Molecular basis of Leigh syndrome: a current look

hypocitrullinaemia (\\10 kmol/L) is one of the main biochemical characterSevere istics of two clinical situations : the disorders of mitochondrial urea-cycle enzymes (N-acetylglutamate synthase, carbamoylphosphate synthetase I (CPS-I) and ornithine carbamoyltransferase (OCT)) and the deÐciency of pyrroline-5-carboxylate synthetase and Kamoun Hypocitrullinaemia was also associated with (Rabier 1995). Pearson syndrome et al Here we report a new situation in which (Ribes 1993). hypocitrullinaemia was observed in 5 patients with mt ATP6 NARP T 8993 G mutation. The NARP 8993 mutation impairs the function of the subunit a or ATPase 6 of the Fo segment of the complex V. This ATPase 6 polypeptide is involved in proton translocation through the inner mitochondrial membrane.

Persistent hypocitrullinaemia as a marker for mtDNA NARP T 8993 G mutation

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Persistent hypocitrullinaemia as a marker for mtDNA NARP T 8993 G mutation