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Barth's syndrome-like disorder: A new phenotype with a maternally inherited A3243G substitution of mitochondrial DNA (MELAS mutation)

Dodelson De Kremer, Raquel ORCID:, Paschini Capra, Ana, Bacman, Sandra ORCID:, Argaraña, Carlos ORCID:, Civallero, Gabriel, Kelley, Richard I. ORCID:, Guelbert, Norberto ORCID:, Latini, Alexandra ORCID:, Noher de Halac, Inés ORCID:, Giner Ayala, Alicia, Johnston, Jennifer and Proujansky, Roy (2001) Barth's syndrome-like disorder: A new phenotype with a maternally inherited A3243G substitution of mitochondrial DNA (MELAS mutation). American Journal of Medical Genetics, 99 (2). pp. 83-93. ISSN 0148-7299

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An Argentine male child died at 4.5 years of age of a lethal mitochondrial disease associated with a MELAS mutation and a Barth syndrome-like presentation. The child had severe failure to thrive from the early months and for approximately two years thereafter. In addition, the patient had severely delayed gross motor milestones, marked muscle weakness, and dilated cardiomyopathy that progressed to congestive heart failure. He also had persistently elevated urinary levels of 3-methylglutaconic and 2-ethylhydracrylic acids and low blood levels of cholesterol. Detailed histopathologic evaluation of the skeletal muscle biopsy showed high activity of succinate dehydrogenase, a generalized decrease of COX activity, and abundant ragged-red fibers. Electron microscopic studies revealed multiple mitochondrial abnormalities in lymphocytes and monocytes, in the striated muscle, and in the postmortem samples (muscle, heart, liver, and brain). Biochemical analysis showed a pronounced and constant lactic acidosis, and abnormal urinary organic acid excretion (unchanged in the fasting and postprandial states). In addition, in CSF there was a marked increase of lactate and β-hydroxybutyrate (β-HOB) and also a high systemic ratio β-HOB/acetoacetate. Enzymatic assay of the respiratory chain in biopsied muscle showed 10% of complex I activity and 24% of complex IV activity compared with controls. Molecular studies of the mitochondrial genome revealed an A to G mutation at nucleotide pair 3243 in mitochondrial DNA, a well-known pathogenetic mutation (MELAS mutation) in all the patient's tissues and also in the blood specimens of the probands mother and sibs (4 of 5). The diagnosis of MELAS mutation was reinforced by the absence of an identifiable mutation in the X-linked G4.5 gene of the propositus. The present observation gives additional evidence of the variable clinical expression of mtDNA mutations in humans and demonstrates that all clinical variants deserve adequate investigation to establish a primary defect. It also suggests adding Barth-like syndrome to the list of phenotypes with the MELAS mutation.

Tipo de documento: Artículo
Palabras clave: 3-methylglutaconic aciduria. Barth syndrome. Cardiomyopathy. Inborn errors of metabolism. MELAS. Mitochondrial cytopathy. Ragged-red fibers. Respiratory chain defects.
Temas: R Medicina > R Medicina (General)
Unidad académica: Universidad Católica de Córdoba > Facultad de Ciencias de la Salud
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