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Biomedical subjects

A Munnich

Publications and source records attributed to A Munnich.

At least 523 records · Page 29Linked to original sources
PubMed1982

Congenital lactic acidosis, alpha-ketoglutaric aciduria and variant form of maple syrup urine disease due to a single enzyme defect: dihydrolipoyl dehydrogenase deficiency.

A 6-month-old girl with vomiting, hypotonia and motor retardation was found to have elevated blood lactate, pyruvate, and branched chain amino acids associated with ketoglutaric aciduria. The combination of a congenital lactic acidosis with a variant form of maple syrup urine disease and ketoglutaric aciduria suggested a defect of a single component, common to pyruvate dehydrogenase, to branched chain ketoacid dehydrogenase, and to alpha-ketoglutarate dehydrogenase. Dihydrolipoyl dehydrogenase is the common component (E3). The three enzyme activities and the E3 component activity were found to be reduced in liver and cultured fibroblasts, thus confirming that a single defect of this component can result in a multiple deficiency involving several oxidative decarboxylation reactions.

Acidosis↗
PubMed1982

[Heterogeneity of leucinosis. Correlations between clinical manifestations, protein tolerance and enzyme deficiency].

Maple syrup urine disease (MSUD) is an inborn error of branched-chain aminoacid (BCAA) catabolism due to a defect of BC ketoacid decarboxylation. Beside the classical form of the disease, general variant forms have been recently reported. From our personal experience in 21 patients consisting of 14 patients with classical MSUD and 7 patients with "variant" forms (1 intermittent, 2 subacute forms, 1 lipoamide dehydrogenase deficiency and 3 composite heterozygotes), we tried to correlate clinical features with protein tolerance and enzyme activity. All classical forms share an acute neonatal presentation, with a low leucine tolerance (m +/- SD = 465 +/- 88 mg per day), and a very low enzyme activity (m +/- SD = 2.5 +/- 1.5% of controls), mild variations being consistent with a possible polyallelism within this group. All "variant" forms share a late onset with a reasonable leucine tolerance (2-3 grams per day) and a fair enzyme activity, ranging from 7 to 20% of controls. However, no strict correlation could be found between the severity of the outcome and the extent of the residual enzyme activity, since acute episodes or chronic deterioration occurred even in "variants", irrespective of the level of their enzyme activity. Finally, our data suggest that variant forms could result from a composite heterozygotism, combining heterozygotism for the gene of classical MSUD and heterozygotism for a "petite" mutation, undetectable when isolated. The occurrence of classical MSUD and "variant" forms of the disease within a single family of our series further supports this hypothesis.

Adolescent↗
PubMed1982

[Double deficiency of sulfite and xanthine oxidase causing encephalopathy and due to a hereditary anomaly in the metabolism of molybdenum].

The clinical features and biological results in a second patient with a metabolic defect of the molybdenum cofactor are described. The first case was reported in 1978 by Duran et al. Their clinical description was similar with early encephalopathy and myoclonial and dislocation of the lens. Biologically, this condition is characterised by secondary hypo-uricemia and hypo-uricuria due to xanthine oxidase deficiency and by sulphituria, resulting from sulphite oxidase deficiency. These two enzymes have a common hepatic molybdenum cofactor, the structure and metabolism of which are only partially known.

Brain Diseases, Metabolic↗
PubMed1981

Biotin dependent multiple carboxylase deficiency presenting as a congenital lactic acidosis.

Two patients presented in early childhood with (i) alopecia, skin rashs, and dermatitis, (ii) severe hypotonia, ataxia and motor retardation, (iii) frequent episodes of ketoacidosis with hyperlactacidemia. Propionic and methylcrotonic aciduria only appeared on high protein diet. Mitochondrial biotin-dependent carboxylase activities were decreased in the liver and leukocytes, but were similar to control values in fibroblasts cultured in a biotin-free medium. In addition, the plasma biotin was found to be significantly lower than in control subjects. These disorders responded to biotin administration, pointing to biotin-dependent multiple carboxylase deficiencies (MCD). Our report stresses the polymorphism of MCD and suggests that MCD could be of two types: impaired vitamin metabolism (absorption, plasma transport), might result in low plasma biotin with generalized MCD involving acetyl CoA carboxylase. Defective mitochondrial holocarboxylase synthetase might lead to a pure mitochondrial MCD, with fibroblastic deficiency and presumably normal biotin metabolism.

Acidosis↗
PubMed1981

[Multiple biotin-dependent carboxylase deficiencies (author's transl)].

Two patients presented in early childhood with: 1) alopecia, skin rashs, and candida dermatitis; 2) severe hypotonia, ataxia and motor retardation; 3) frequent episodes of ketoacidosis with hyperlactacidemia. Propionic and methylcrotonic aciduria only appeared on hyperprotidic diet. Mitochondrial biotin-dependent carboxylase activities were decreased in the liver and leukocytes, but were paradoxically normal in cultured fibroblasts whatever the biotin content of the medium. These disorders responded to biotin administration, pointing to multiple biotin-dependent carboxylase deficiencies (MCD). Our report stresses the polymorphism of MCD: major discrepancies concern predominance of carboxylase deficiency, expression of MCD in cultured fibroblasts, and possible involvement of a cytoplasmic biotin enzyme, acetyl CoA carboxylase (ACC). Finally, we suggest that MCD could be of two types: impaired biotin metabolism (absorption, transport, activation) might result in generalization MCD involving ACC. Defective holocarboxylase synthetase might lead to a pure mitochondrial MCD with fibroblastic deficiency and presumably skin integrity.

Acetyl-CoA Carboxylase↗
PubMed1980

[Alopecia, chronic candidodis, mental retardation and repeated ketoacidosic comas curable by biotin administration: multiple carboxylases deficiency (author's transl)].

Multiple carboxylases deficiency, a recently identified metabolic disease in infants, can be cured by the administration of biotine, a cofactor of the carboxylases: pyruvate, propionyl coenzyme A (CoA), methylcrotonyl CoA, and acetyl CoA. The disorder presents as alopecia, associated with chronic candidosis, psychomotor retardation, and frequent episodes of ketoacidosis coma which responded to biotine treatment. Biological signs, related to the deficiency of the individual enzymes, are observed as hyperlactacidemia, propionic aciduria, and methylcrotonylglycinuria. The metabolic basis of this vitamin-dependent size is still obscure, but the research stimulated by this new disease should clarify the still poorly understood physiological role of this vitamin in humans.

Acidosis↗
PubMedDate not supplied

Expression of respiratory chain deficiencies in human cultured cells.

The expression of respiratory chain deficiencies was studied in cultured skin fibroblasts and B lymphoblastoid cell lines from patients with mitochondrial disorders. The genotype and phenotype of the cells were found to be dramatically different depending on the cell type and metabolic environment. In all cases, respiratory chain deficiencies gradually disappeared during the cell proliferation. However, in the presence of uridine, deficiencies were maintained in cultured skin fibroblasts. Accordingly, in cells harbouring a population of deleted mtDNA, the addition of uridine in the culture medium maintained the proportion of deleted mtDNA. In Epstein-Barr virus transformed lymphocytes, while a normal respiratory chain activity could be measured, deleted mtDNA was still present in high proportions (> 60% of the total mtDNA). The persistence of the deleted mtDNA was observed under all metabolic conditions tested, even when energy production from glycolysis was restricted. Finally, prenatal diagnosis of such a respiratory chain deficiency (cytochrome c oxidase deficiency) was performed in three cases. In all of them, a normal cytochrome c oxidase activity was measured in the cultured amniocytes. The children were born and are presenting no sign of an eventual affection.

B-Lymphocytes↗