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 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 beta-hydroxybutyrate (beta-HOB) and also a high systemic ratio beta-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.

[Plasma chitotriosidase activity in Argentinian patients with Gaucher disease, various lysosomal diseases and other inherited metabolic disorders]. / Actividad de la chitotriosidasa plasmática en pacientes argentinos con enfermedad de Gaucher, diversas l'isosomopatías y en otras metabolopatías genéticas.

The striking and apparent specific elevation of the activity of chitotriosidase found in plasma from patients with Gaucher disease (GD) Type 1 (Mc Kusick 230800) is considered a new diagnostic hallmark of GD and should prove useful in assessing clinical manifestations and monitoring enzyme supplementation therapy. Further data have suggested that the increased levels of chitotriosidade activity in plasma from patients with unexplained diseases may be indicative of a lysosomal storage disorder. We present here an experience of the plasmatic chitotriosidase in an Argentinean population consisting of three groups: a) 25 healthy controls; b) subjects related with GD: 3 patients Type 1, 3 obligated heterocygotes and 1 patient with an atypical variant of GD; c) 42 patients with a precise nosologycal definition of inherited error of metabolism (IEM) and 5 patients presumably affected by a lysosomal pathology but without enzymatic confirmation. Methylumbellypheryl-tri-N-acetyl chitotrioside hydrolase activity was markedly increased: the mean activity being > 600 times and > 100 times the mean value in plasma of our healthy control (mean 17 nmol/min/ml, range 6-60.4 nmol/min/ml) in the plasma of the patients of Gaucher Type 1 disease and an atypical variant of GD, respectively. In the two more affected patients the elevated levels of chitotriosidase activity ran parallel to the severity of the disease and also as a response to the supplementation enzymatic therapy with a decrease of 50% of its activity at 10 months of therapy at a dose of 30 u/kg/month. Moreover, no increase of chitotriosidase activity was found in the 3 obligated heterozygotes of Gaucher Type 1 and Type 2 disease or in any other of the IEM. Chitotriosidase activity was absent in plasma of 2 control subjects and in 4 patients with exact diagnosis of an IEM. The physiological role of the human chitinase still has to be established and warrants further investigation and the natural consequence of the high frequency of a genetic deficiency in man. Meanwhile, reports on the purification and characterization of human chitotriosidase with chitinolytic activity toward chitin-containing pathogens and on the cloning of cDNA encoding chitinase will be crucial to obtain a better insight into this new chapter of medical genetics.