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

An Argentine male child died at 4.5 years of age of a lethal mitochondrial disease associated with a MELAS mutation and a Earth syndrome-like presenta tion. The child had severe failure to thrive from the early months and for approximately two years thereafter. In addition, the patient had severely d elayed gross motor milestones, marked muscle weakness, and dilated cardiomy opathy that progressed to congestive heart failure. He also had persistentl y elevated urinary levels of S-methylglutaconic and 2-ethylhydracrylic acid s and low blood levels of cholesterol, Detailed histopathologic evaluation of the skeletal muscle biopsy showed high activity of succinate dehydrogena se, 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 postmorte m 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, i n CSF there was a marked increase of lactate and P-hydroxybutyrate (P-HOE) and also a high systemic ratio HOB/acetoacetate, Enzymatic assay of the res piratory chain in biopsied muscle showed 10% of complex I activity and 24% of compiler IV activity compared with controls. Molecular studies of the mi tochondrial genome revealed an A to G mutation at nucleotide pair 3243 in m itochondrial DNA, a well-known pathogenetic mutation (MELAS mutation in all the patient's tissues and also in the blood specimens of the probands moth er 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 propo situs. The present observation gives additional evidence of the variable cl inical expression of mtDNA mutations in humans and demonstrates that all cl inical variants deserve adequate investigation to establish a primary defec t. It also suggests adding Earth-like syndrome to the list of phenotypes wi th the MELAS mutation. (C) 2001 Wiley-Liss, Inc.