Biomedical subjects
Publications and source records attributed to P Divry.
The authors report two cases of citrullinemia in siblings which add to 68 observations from the literature. They overview the clinical presentation, diagnosis and therapeutic management of the disease. The prognosis of severe neonatal form remains poor but an early adequate management may contribute to an acceptable outcome.
OBJECTIVE: Mevalonic aciduria is a consequence of the deficiency of mevalonate kinase, the first enzyme after 3-hydroxy-3-methylglutaryl-coenzyme A reductase in the biosynthesis of cholesterol and nonsterol isoprenes. To establish the clinical and biochemical phenotype of mevalonic aciduria, the authors assembled their experience with 11 patients including attempts at therapeutic interventions. METHODS: Mevalonic acid in body fluids was determined by stable isotope dilution gas chromatography/mass spectroscopy with selected ion monitoring, ubiquinone-10 concentrations by reversed-phase high-pressure liquid chromatography. RESULTS: Varying degrees of severity of clinical illness were observed despite uniform, virtual absence of residual activity of the enzyme. The most severely affected patients have had profound developmental delay, dysmorphic features, cataracts, hepatosplenomegaly, lymphadenopathy, and anemia, as well as diarrhea and malabsorption, and have died in infancy. Less severely affected patients have had psychomotor retardation, hypotonia, myopathy, and ataxia. All patients have had recurrent crises in which there was fever, lymphadenopathy, increase in size of liver and spleen, arthralgia, edema, and a morbilliform rash. Neuroimaging studies revealed selective and progressive atrophy of the cerebellum. Mevalonic acid concentrations were found to be grossly elevated in body fluids of all patients. Concentrations of plasma cholesterol were normal or only slightly reduced. Concentrations of ubiquinone-10 in plasma were found to be decreased in most patients. Abnormalities such as hypoglycemia, metabolic acidosis, or lactic acidemia, the usual concomitants of disorders of organic acid metabolism, were conspicuously absent. CONCLUSIONS: These observations establish the broad range of clinical symptoms and biochemical findings in mevalonic aciduria. It is concluded that although patients with mevalonic aciduria have a recognizable phenotype of serious clinical manifestations, some patients are likely to remain undiagnosed and may be found in a variety of subspecialty clinics, including neurology, gastroenterology, cardiology, and genetics.
Medium chain acyl-CoA dehydrogenase (MCAD) and long chain acyl-CoA dehydrogenase (LCAD) deficiency are defects of mitochondrial beta-oxidation. The method of choice to measure specifically acyl-CoA dehydrogenase activity in human tissues uses purified electron transfer flavoprotein (ETF). We describe a simple and optimized method of purification allowing isolation of ETF with a degree of purity never reported so far. An assay for acyl-CoA dehydrogenase activity in cultured skin fibroblasts was developed using microquantities of electron transfer flavoprotein and substrate. MCAD deficiency was demonstrated in fibroblasts from nine patients and LCAD deficiency in fibroblasts from two patients.
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Regarding a case of beta-ketothiolase deficiency revealed by ketoacidosis with hyperglycinemia, the authors show the way to diagnose and to treat this disease. Ketoacidosis without hyperglycemia or lactacidemia suggested this diagnosis. Gas chromatography-mass-spectrography revealed unusual urinary excretion of metabolic products of isoleucine. The enzymological study of fibroblasts confirmed the diagnosis. The treatment of acute episodes consisted of acidosis control and exclusive glucides intake before diagnosis. Afterwards, a controlled proditic diet and L-carnitine must be given and fasting must be avoided.
A defect in intracellular uptake of carnitine has been identified in patients with severe carnitine deficiency. To define the clinical manifestations of this disorder, the presenting features of 15 affected infants and children were examined. Progressive cardiomyopathy, with or without chronic muscle weakness, was the most common presentation (median age of onset, 3 years). Other patients presented with episodes of fasting hypoglycemia during the first 2 years of life before cardiomyopathy had become apparent. A defect in carnitine uptake was demonstrable in fibroblasts and leukocytes from patients. The defect also appears to be expressed in muscle and kidney. Concentrations of plasma carnitine and rates of carnitine uptake in parents were intermediate between affected patients and normal control subjects, consistent with recessive inheritance. Early recognition and treatment with high doses of oral carnitine may be life-saving in this disorder of fatty acid oxidation.
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Lysine is an important amino acid: it is incorporated to collagene, one of the most important component of conjonctive tissue and, though, necessary for growth. It is also important for carnitine synthesis. Its intestinal absorption requires two transport systems that lysine shares with ornithine, arginine and cystine for the former and with ornithine and arginine for the latter. The same transport systems are present in the hepatocytes, were lysine is extensively catabolized, and in renal tubular cells. The main catabolic pathway for lysine, via saccharopine, is a mitochondrial pathway leading to acetyl-CoA. The peroxisomal pathway, via pipecolic acid is of less physiological importance and is mainly active in brain. The existence of the two minor pathways, the acetyllysine pathway and the lysine-urea cycle, remains to be demonstrated.
A wide variety of inborn errors of lysine catabolism have been described. They include: abnormalities of the mitochrondrial catabolism via the "saccharopine pathway", abnormalities of the peroxisomal catabolism via the pipecolic pathway, and "lysine intolerance with periodic ammonia intoxication" linked to urea cycle pathway. These inborn errors are associated with a wide variety of clinical symptoms and biochemical profiles as persistent hyperlysinemia, saccharopinuria, "amino and ketoadipic aciduria, and glutaric aciduria.
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Urinary excretion of an abnormal amount of N-acetylaspartic acid has been evident in a 17-month-old child with an infantile picture of Canavan-van Bogaert disease. This observation makes it possible to consider the possibility of a simple biological diagnosis and confirms the existence of metabolic abnormalities which will probably permit to make rapid progress in the physiopathologic study of this disease.
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