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Background: A hemolytic-uremic syndrome associated with methylmalonic aciduria and homocystinuria is seen during the first weeks of life. A molecular defect in the CbIC mutation has been found. This report describes a new case with this association., Case Report: A girl, the second in this family, was born at term: her birth weight was 2,100 g, height was 47 cm and head circumference 31.5 cm. She was admitted at 32 days of age with hemolytic anemia and fragmencytosis, renal failure and thrombocytopenia. The renal failure required peritoneal dialysis followed by hemofiltration. The signs of pancytopenia of central origin and liver failure seen at that time raised the possibility of an intracellular defect of B12 metabolism. Chromatography of the amino acids and organic acids in the urine and plasma revealed homocystinemia, hypomethioninemia, homocystinuria and methylmalonic aciduria. The deficient B12 metabolism was confirmed in fibroblasts which showed deficits in both methyl and adenosyl-cobalamin synthesis. The metabolic disturbances were completely resolved after intravenous administration of hydroxy-cobalamin (2,000 micrograms per day) and folinic acid (25 mg per day) for 5 days. But the neurological abnormalities persisted, with retinitis pigmentosa and major leukodystrophic changes seen by MRI, and the infant died one month later., Conclusion: This new case emphasizes the importance of systematically screening all cases of neonatal hemolytic-uremic syndrome for this autosomal recessive disorder.

Background: Neonates with classic maple syrup urine disease (MSUD) undergo rapid neurological deterioration by the end of the first week of life. Exchange transfusion and peritoneal dialysis are the usual emergency treatment. Continuous arteriovenous hemofiltration (CAVHF) appears to be safe and more rapidly effective., Case Report: Martin was born at the 37th week from a normal pregnancy. Abnormal movements of legs and lethargy appeared on the 7th day of life. Progressive brain dysfunction with coma led to intubation on the 13th day. A diagnosis of MSUD was immediately made and CAVHF was initiated and continued for 19 hours. The plasma leucine, valine and isoleucine levels fell from 2,248 to 275, 640 to 91 and 298 to 13 mumol/l, respectively. Neurologic improvement was dramatic, except for moderate hypertonia which lasted for the 2 following days., Conclusion: CAVHF is an appropriate treatment for very young patients with inborn errors of metabolism. It appears safer and more rapidly effective for eliminating branched-chain amino acids than other techniques, such as peritoneal dialysis with or without exchange transfusions. It also permits more rapid introduction of the specific diet.

In 14 patients with methylmalonic acidemia we studied the correlations between clinical severity (considered in terms of survival and number of acute episodes), daily tolerance to proteins (amounts of leucine, valine, methionine, threonine compatible with good health and a methylmalonic acid excretion below 4 mmol/24h), the in vivo response to vitamin B12 and the nature of the enzymatic defect. This study showed that 2 groups of patients with congenital methylmalonic acidemia may be delineated with respect to prognosis. In patients with complete methylmalonyl CoA mutase deficiency, unresponsive to vitamin B12 in vitro and in vivo, the disease begins most often in the neonatal period and evolution is severe, with frequent acute episodes. Their tolerance to precursor aminoacids is similar to the minimal need (10-15 moles i.e. a total proteic intake of 6-9 g/24 h). None of the 8 patients of this group survived for more than 3 years. Conversely, in the second group (patients with normal in vitro MMCoA mutase activity in the presence of vitamin B12 in excess) the disease begins later, evolution is less severe and tolerance to protein intake is normal or subnormal. However, in this group, in vivo response to vitamin B12 is not constant.

Carnitine Palmitoyl Transferase (CPT) deficiencies are found in 2 different clinical forms: muscular and hepatic. The study of fibroblasts of 2 patients corresponding to each of these situations showed that these phenotypes are associated with different abnormalities of CPT, CPT I in the hepatic type and CPT II in the muscular type. The functional consequences of both abnormalities are different. In the hepatic type, CPT I deficiency induces a lack of long chain fatty acid (LCFA) oxidation in fibroblasts as well as, probably, in the patient's liver. In the muscular type, CPT II deficiency has no functional consequences in the fibroblast, contrary to what is observed in the patient's muscle. It is postulated that control of the mitochondrial LCFA oxidation in the liver and in the fibroblasts depends on CPT I, while it depends on CPT II in the muscle.

Thirty-three children presenting with "primitive" cardiomyopathy observed from January 1984 to December 1985 underwent a protocol of investigations consisting of histo-enzymatic study of the deltoid muscle, metabolic studies (glucose, free fatty acids, lactate, pyruvate, 3-hydroxybutyrate, aceto-acetate, carnitine, amino-acids blood levels after a 15 hour-fast; urinary organic acids chromatography) and a study of the fatty acids oxidation in cultured fibroblasts. In all children cardiac involvement was predominant and had been the cause for hospitalization. Cardiomyopathies of the hypertrophic type have an early onset, most often are part of a complex picture of extra-cardiac involvement and frequently have a lethal evolution. On the contrary, hypokinetic dilated cardiomyopathies are most often isolated, have a later onset and a less severe course. In 2 cases, an early hypokinetic dilated cardiomyopathy evolved toward hypertrophy. Peripheral muscular involvement is very frequent (lipidosis, mitochondrial aggregates or specific aspects) (60% of cases) in dilated as well as hypertrophic types. A precise etiological diagnosis or a strong presumption was possible in 12 of 33 cases: 2 with hereditary deficiency of the fatty acids beta-oxidation, 1 carnitine systemic deficiency, 1 Friedreich ataxia, 1 central core disease, 1 coxsackie B1 myocarditis, 6 strong suspicions of respiratory chain deficiency.

One should henceforth systematically search for hypertyrosinemia which, too often, goes unrecognized for years, in patients presenting chronic keratitis associated with palmar and plantar hyperkeratosis. As a matter of fact, this highly crippling disease may be cured with an appropriate diet and the diagnosis, once suspected, is easily confirmed by simple investigations.

The indications and effects of exchange transfusion, peritoneal dialysis, osmotic diuresis and early feeding have been studied in 28 children with inborn errors of aminoacid metabolism presenting in the neonatal period. Exchange-transfusion has only a transitory and incomplete effect but it is simple and quick. Peritoneal dialysis has a remarkable and often life-saving effect because the blood levels of toxic metabolites are reduced very effectively in organic acidaemias. However the rate of removal may decline if plasma concentrations fall below a critical level (1.2 mmol/L foor leucine). If the dialysis is prolonged for more than 36 hours it may cause hypoprotidaemia. Osmotic diuresis increases the 45 ml/min. However it is of little elimination of methylmalonic acid because the renal clearance is between 15 and 45 ml/min. However it is of little value in maple syrup urine disease, propionic acidaemia or isovaleric acidaemia because the renal clearance of the toxic metabolites is so low. The early re-introduction of low protein high calorie of a low protein and high calorie diet by continuous intragastric feeding is very important. The authors propose a protocol for the treatment of babies presenting inborn errors of aminoacid metabolism in the neonatal period. Peritoneal dialysis should be started as soon as the diagnosis is considered and continued for 24 to 36 hours. An exchange of transfusion shold be undertaken before and after the dialysis, together with an osmotic diuresis if appropriate. Continuous enteral feeding should be given, the quantity being adjusted to the baby's requirements.

The occurrence in a previously healthy infant of sudden febrile encephalopathy with shock and metabolic acidosis associated with liver and renal failure and bloody watery diarrhea has been reported by several authors in recent years. We report the same association in a 3 1/2 month-old infant. We discuss the similarities between this clinical picture and malignant hyperthermia and Reye syndrome.

Lysinuric protein intolerance is an autosomal recessive disease, due to a defect in intestinal, renal and hepatic dibasic amino acid transport. Two new cases in the same family are reported. The disease appears progressively during the first months of life with failure to thrive, anorexia, vomiting, diarrhea, hepatosplenomegaly, muscular weakness, osteoporosis, anemia, leukothrombocytopenia, hyperammonemia and orotic aciduria after a high-protein intake. Hyperdibasicamino-aciduria was associated with subnormal plasma concentrations of the same aminoacids. Oral l-arginine, l-ornithine, l-lysine, and lysyl-glycine loads confirmed the diagnosis. The supplementation of the diet with l-citrulline resulted in normal levels of blood ammonia. However, hepatosplenomegaly, muscular weakness, osteoporosis remained unchanged and growth was not improved. These may be due to lysine 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.

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.