Chronic cardiomyopathy and weakness or acute coma in children with a defect in carnitine uptake.

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.

[Lysine metabolism in man]. / Le métabolisme de la lysine chez l'homme.

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.

[Inborn errors of lysine metabolism]. / Erreurs innées du métabolisme de la lysine.

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.

Deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase: a cause of lethal myopathy and cardiomyopathy in early childhood.

A child presented in early childhood with episodes of coma and hypoglycemia and a rapidly evolutive myopathy and cardiomyopathy leading to death at 9 mo of age. Ketosis was decreased (blood beta-hydroxybutyrate: 0.07 mmol/L) despite normal plasma levels of fatty acids (0.81 mmol/L). The patient's urine contained excessive amounts of the C6 to C10 dicarboxylic acids present in almost all defects of fatty acid mitochondrial oxidation. More specifically, gas chromatography-mass spectrometry identified an accumulation of medium- and long-chain (C8 to C14) 3-hydroxy-dicarboxylic acids, suggesting a defect of the mitochondrial enzyme that normally dehydrogenates these 3-hydroxyacyl-CoA esters. Biochemical studies in the patient's cultured fibroblasts confirmed the impairment of medium- and long-chain fatty acid oxidation, and allowed the recognition of the deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase. The activities of long-, medium-, and short-chain acyl-CoA dehydrogenases and 3-ketoacyl-CoA thiolase were normal. These results describe a disorder of fatty acid metabolism that affects the liver, skeletal muscles, and myocardium. It is important to point out that long-chain 3-hydroxyacyl-CoA deficiency shares many clinical similarities with systemic carnitine deficiency, as well as with carnitine-palmityl-CoA transferase and long-chain acyl-CoA dehydrogenase deficiencies. The differential diagnosis of this disease relies on the demonstration of long-chain urinary dicarboxylic acids with a hydroxyl group in 3-position and the study of the enzyme activity in cultured fibroblasts.

Antenatal diagnosis of molybdenum cofactor deficiency.

Analysis of uncultured chorionic villus material from a woman at risk of fetus with sulfite oxidase deficiency revealed a deficiency of sulfite oxidase. This was confirmed on termination of the pregnancy.

Spongy degeneration of the neuraxis (Canavan-van Bogaert disease) and N-acetylaspartic aciduria.

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.

[Biotidinase deficiency: a disease with neurologic and cutaneous expression susceptible to biotin]. / Le déficit en biotinidase: une maladie à expression neurologique et cutanée sensible à la biotine.

The authors report 2 familial cases of biotin deficiency. The first neurological signs appeared at the age of 2 years in a boy. The diagnosis was established in his sister in the neonatal period. A review of 41 published cases summarizes the neurologic signs (seizures, ataxia, hypotonia and later, developmental delay and deafness) and the cutaneous signs (rash, alopecia). An early treatment with biotin cures or prevents the clinical signs of the disease in most cases.

[Protein intolerance with lysinuria. Value of orotic aciduria in adjusting treatment with citrulline]. / Intolérance aux protéines avec lysinurie. Intérêt de l'acidurie orotique pour l'adaptation du traitement par la citrulline.

A new case of lysinuric protein intolerance is described in a 14 year-old Maghrebian child who presented with growth failure, vertebral osteoporosis, aversion to proteins and digital hippocratism, rarely described in this disease. Orotic aciduria was studied after a protein load with and without citrulline supplement and during the course of a 11 month-treatment. There was a clear relationship between orotic aciduria, protein intake and citrulline supplementation. Orotic aciduria appears to be very useful to adjust the treatment.

[Genetic heterogeneity of cystinuria. Study of 12 families]. / Hétérogénéité génétique de la cystinurie. Etude de 12 familles.

The authors attempted to predict the genotypes of 15 cystinuric children, from the results of oral lysine loads on the propositus and the urinary excretion rates of cystine, lysine, ornithine and arginine of their parents and siblings. Type I cystinuria is more common, as well in the homozygous state, as in combination to type II or III (compound heterozygous genotypes).

Routine gas chromatographic/mass spectrometric analysis of urinary organic acids. Results over a three-year period.

Organic acidaemias are an important part of inborn errors of metabolism. The biochemical diagnosis is based on gas chromatographic/mass spectrometric identification of urinary organic acids. Since 1973 we have used gas chromatographic analysis of the methyl esters of urinary organic acids. Mass spectral identification was performed only when an abnormal gas chromatographic profile was suspected. In 1983 we introduced routine gas chromatographic/mass spectrometric analysis organic acids. More than 1500 urine samples from 1000 children have been analysed and we encountered more than 40 abnormal profiles: 18 classical organic acidaemias (propionic, methylmalonic, isovaleric, glutaric type I and 3-hydroxy-3-methyl glutaric acidaemias); 6 aminoacidopathies with excretion of branched chain keto acids (leucinosis) or succinylacetone (tyrosinosis type I); 14 massive dicarboxylic acidurias with excretion of suberyl and hexanoyl glycine and deficiency of the medium chain acyl CoA dehydrogenase in four patients. The use of gas chromatography/mass spectrometry routinely allows the identification of abnormal metabolites excreted in small amounts: beta-methyl-crotonyl glycine indicative of biotin deficiency: gamma-hydroxybutyric acid; and 3-methyl-glutaconic + 3-methy-glutaric acid is in a 3-methyl-glutaconic aciduria type II. Abnormal profiles due to metabolites of drugs as valproate, salicylate and barbiturate can be recognized immediately. This simple gas chromatographic/mas spectrometric system can lead to diagnosis, in one day, of rare but severe diseases needing a specific and early treatment.

Hemoglobin J-Baltimore (beta 16(A13)Gly----Asp): interference with the assay of HbA1c.

Three independent cases of Hemoglobin J-Baltimore(beta 16(A13)Gly----Asp) were detected through the assay of HbA1c in diabetic patients. Using chromatography on Bio-Rex 70 resin, one large peak replaced the usually well resolved peaks of HbA1a + b and HbA1c. The species that overlapped the latter fractions was identified as HbJ1c. HbJ-Baltimore itself was identified using HPLC of the beta-chain tryptic peptides. This observation emphasizes the errors that hemoglobin variants may introduce in the assay of HbA1c.

The inborn errors of mitochondrial fatty acid oxidation.

To date, seven inborn errors of mitochondrial fatty acid oxidation have been identified. A total of about 100 patients in the world have been reported. Clinically the beta-oxidation defects are more often characterized by episodic hypoglycaemia leading to a coma mimicking Reye's syndrome. The hypoglycaemia is non-ketotic since the synthesis of ketone bodies is deficient. Periods of decompensation occur when carbohydrate supply is poor, e.g. prolonged fasting, vomiting, or increased caloric requirements, as and when lipid stores are used. Defects in beta-oxidation have also been reported to be one cause of sudden infant death syndrome. The diagnosis of these inborn errors is by biochemical investigation since where symptoms suggest such a defect, the precise aetiology cannot be assessed. The biochemical diagnosis is based firstly on identification of abnormal plasma and of urinary metabolites during acute attacks. Derivatives of the omega-oxidation and omega-1-oxidation of medium chain fatty acids have been identified, as well as acylglycine and acylcarnitine conjugates. These metabolites are nearly always absent when patients are in good clinical condition. Secondly, the diagnosis must be based on the identification of the enzymatic defects: this involves global assays which allow a localization of the 'level' of the defect (i.e. the oxidation of long, medium or short chain fatty acids) and specific measurement of enzyme activities (acyl-CoA dehydrogenases and electron carriers: ETF and ETF-DH). The diagnosis of these disorders is of prime importance because of the severity of the clinical symptoms. These can be prevented, in some cases, by an appropriate diet (a high carbohydrate, low fat diet, sometimes supplemented with L-carnitine). In other cases, genetic counselling can be offered.

[Determination of serum proline iminopeptidase activity using a fluorescent substrate in patients with Paget's disease and prostatic bone metastases. Preliminary results]. / Détermination de l'activité proline imino-peptidase dans le sérum à l'aide d'un substrat fluorescent dans la maladie de Paget et les métastases osseuses condensantes prostatiques. Résultats préliminaires.

Assessment of proline iminopeptidase activity in serum has been performed in 80 control subjects, 14 Paget's diseases and 10 patients with prostatic and osteoblastic bone metastases. In normal subjects, the PIP activity rises with age, mainly (+63%) in women after menopause. In benign or malignant osteoblastic bone diseases PIP activity is elevated and slightly related to urinary hydroxyproline excretion (r = 0.76) which evolution is close to. It is concluded that PIP activity dosage in serum may provide with urinary hydroxyproline, further information for the study of collagen metabolism in osteoblastic bone diseases during treatment.

Gas chromatography--mass spectrometry (GC--MS) diagnosis of two cases of medium chain acyl-CoA dehydrogenase deficiency.

Two patients with hypoketotic hypoglycaemia and dicarboxylic aciduria are described. Studies of their urinary organic acids by gas chromatography-mass spectrometry (GC-MS) showed an excretion of dicarboxylic acids (adipic suberic and sebacic acids), unsaturated dicarboxylic acids (cis-octenedioic and decenedioic acids),5-hydroxyhexanoic acid, hexanoyl-glycine and suberylglycine. Deficiency of the medium chain acyl-CoA dehydrogenase (MCAD) in fibroblasts was documented for both children. Despite a similar presentation (hypoglycaemic coma), organic acid profile (dicarboxylic aciduria and suberylglycine excretion) and enzyme deficiency (MCAD), they did not respond similarly to glucose infusion.