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A case of combined deficiency of sulphite-oxidase and xanthine-oxidase with a defect of the molybdenum cofactor, which is vital to the activity of sulphite-, xanthine- and aldehyde-oxidase, is reported here. Seven cases of combined deficiencies have been described with regard to both clinical and laboratory findings. The clinical, laboratory and anatomo-pathological features and, in particular, the central nervous system lesions of the present case correspond exactly to those in the case described Rosenblum in which an isolated deficiency in sulphite-oxidase was present. As the cerebral alterations in the present case are comparable to those described in Rosenblum's case, they probably result from the defect in sulphite-oxidase activity.

We describe a patient with severe muscle cytochrome c oxidase deficiency who had de Toni-Fanconi-Debre syndrome and acute neurologic deterioration resembling Leigh syndrome, without clear evidence of muscle abnormality. Metabolic investigations revealed elevated cerebrospinal fluid lactate values contrasting with normal blood lactate, and high 3-hydroxybutyrate/acetoacetate ratio with normal lactate/pyruvate ratio. This case emphasizes the importance of performing metabolic and biochemical investigations in every patient with Leight syndrome, even in the absence of hyperlactatemia or myopathy.

Peroxisomes were visualized by cytochemical staining for catalase or/and electron microscopy in liver biopsies of two boys with childhood adrenoleukodystrophy (ALD), and of two girls with autopsy confirmed neonatal adrenoleukodystrophy (NALD). In a third patient previously described as NALD, unusual organelles were seen which may be large abnormal microbodies. Enlarged peroxisomes (determined by morphometry) were also present in the livers of the other two NALD patients. In the ALD patient whose clinical disease was more severe, peroxisomes were larger than in the older ALD case. Catalase staining was diminished and markedly heterogeneous. Additional unusual features such as a separate population of tubular forms, contact with fat droplets, of tubular forms, contact with fat droplets, marginal plate and invaginations containing glycogen were seen in the neonatal cases. These data are compared to the enlarged or elongated peroxisomes and heterogeneous staining in the thiolase-deficient "pseudo-Zellweger" patient (Goldfischer et al. 1986) and in 2 siblings with acylCoA oxidase deficiency (Poll-Thé et al. 1986, 1988). Enlarged peroxisomes are a common feature in this group of patients with peroxisomal deficiency disorders, suggesting that increased size and lowered metabolic capacity are associated. Nevertheless a marked morphopathological heterogeneity of peroxisomes thus exists in syndromes described as NALD including previously published cases. Most likely this heterogeneity reflects different enzymatic deficiencies, as confirmed by the biochemical data available. Clinically similar syndromes cover divergent microscopical and enzymatic peroxisomal patterns, and naming of the disease should be adapted to reflect such data. Cytochemical studies are urged in every suspected patient.

Summary Of 61 newborns with disorders in amino acid metabolism, 20 had seizures; 15 of them have been recorded. Clinically, seizures are mostly partial clonic jerks. There seems to be some homogeneity of EEG features in relation to causal amino acidopathy. In every case where seizures, either electroclinical or only infraclinical, occurred the evolution was very poor, even in those diseases that would have had a good prognosis. Therefore the EEG in the newborns is especially interesting, both as an aid to diagnosis by interictal recording and as a prognostic tool by registration of seizures.

Infantile Refsum's disease was diagnosed in three male patients, presenting with facial dysmorphia, retinitis pigmentosa, neurosensory hearing loss, hepatomegaly, osteopenia and delayed growth and psychomotor development. An elevated plasma phytanic acid concentration and a deficient phytanic acid oxidase activity in fibroblasts were found with an accumulation of very long chain fatty acids in plasma and fibroblasts. There were elevated pipecolic acid levels in plasma, urine and CSF, and abnormal bile acid metabolites in plasma. Deficient activity of acylCoA: dihydroxyacetone phosphate acyl transferase was found in thrombocytes and fibroblasts of these patients as well as an impaired de novo plasmalogen biosynthesis in fibroblasts. These biochemical abnormalities, previously described in the Zellweger syndrome, suggest multiple peroxisomal dysfunction in our patients.

Hyperammonia has been reported in several disorders of branched chain amino acid metabolism including propionic, isovaleric, methylmalonic acidemia, and β-ketothiolase deficiency.1 Nevertheless the true incidence of hyperammonemia and its variation during the course of these diseases are not yet well known. The purpose of this study was to compare the blood ammonia concentrations and the concomitant serum organic acid accumulation in patients with propionic and isovaleric acidemia. MATERIALS AND METHODS Seven patients with propionic acidemia have been studied. The diagnosis was usually made during the first episode of the disease by gas chromatography. It was always confirmed by the direct measurement of propionyl coenzyme A (CoA) carboxylase activity in fibroblasts.2

Therapeutic guidelines have been obtained from a retrospective review of 41 patients affected with organic acidaemias, 16 patients with neonatal maple syrup urine disease (MSUD), 11 methylmalonic acidaemia, (MMA) seven propionic acidaemias (PA) and seven isovaleric acidaemias (IVA), and by comparing this personal series with similar reported cases. The emergency treatment of these organic acidurias in the neonate has to main goals: toxin removal and anabolism. Anabolism is always promoted by early diet therapy. The best method of toxin removal depends on the nature of the defect; peritoneal dialysis with exchange transfusions or multiple or prolonged exchange transfusions in MSUD and in PA, diuresis and exchange transfusions in MMA and glycine supplementation in IVA. Vitamin supplementation (thiamine 20 mg, biotin 10 mg, B12 2 mg and riboflavin 100 mg) should be tried in all cases although the neonatal forms of these defects are very rarely vitamin responsive. Additional treatments such as carnitine or insulin may prove to be useful.

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.

We did not observe any loss of mean IQ scores measured at 11 when PKU diet was stopped as early as 5 years of age compared to 8 years. Nevertheless, 44% of these children presented learning disabilities and repeated one or more school years. These difficulties appear before or at early elementary school level and are independent of the age of diet discontinuation between 5 and 8 years. They seem to be related to perceptual motor dysfunction, suggesting the possibility of a specific deficit that could seriously interfere with academic progress but which is not accompanied by obvious impairment of overall intellectual functioning [1, 4–7, 9]. Among the children who repeated at least 1 year, there was a much higher percentage of pupils who repeated 2 or more school years than in the scholar national average population. The most important factor related to these difficulties seems to be the parents' socioeconomic status, which is also correlated with the children's IQ scores. This influence is not due to the quality of the diet, which is roughly similar for all the patients whatever their school performance. PKU seems to amplify learning difficulties already present in unaffected siblings. Whether the difficulties would be avoided by continuing the diet throughout elementary school remains undemonstrated.

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.

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 authors report the cases of two unrelated children 16 and 5 years of age respectively, affected with hypertyrosinaemia type II. This condition is characterized by palmo-plantar hyperkeratosis associated with a herpetiform keratitis. The diagnosis is based on the finding of hypertyrosinaemia and hypertyrosyluria, and may be confirmed by their biopsy findings of a cytoplasmic tyrosine amino-transferase deficiency. It is a hereditary autosomal recessive disease. A low phenylalanine and tyrosine diet produced a spectacular improvement but the ocular complications could have been avoided by an earlier diagnosis.

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.

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.

A familial case of acrogeria, occurring in a mother and her daughter, is reported. A 12-year old mentally retarded girl was seen with a history of repeated ecchymoses despite normal hemostasis. On clinical examination, the skin was diffusely atrophic with atrophy and wrinkling most pronounced on the extremities. The venous pattern was noticeable on the upper aspect of the anterior trunk and the extremities. The feet were small and the nose was pinched. "Cigarette paper" scars and molluscoid pseudotumors were seen over the elbows and the knees. Some skin hyperextensibility was noted and loose-jointedness of the fingers was demonstrated. The fingernails, hair, dentition, and bone roentgenograms were normal. The mother, a 34-year old woman, presented with the same abnormalities and reported the same condition in her mother. A younger brother was normal and there was no history of consanguinity. In both cases, the skin biopsy specimens showed dermal atrophy with irregular increase of the elastic staining material in the mid dermis. Ultrastructural studies showed a widened endoplasmic reticulum within the fibroblasts. Biochemical studies, performed in the daughter, showed complete lack of collagen III in the dermis. This, together with the visceral complications occurring in the mother and in previously reported patients, suggests that acrogeria represents a clinical variant of Ehlers-Danlos type IV. Its association with phenylketonuria in the daughter is considered to be coincidental.

A six-month-old girl with chronic lactic acidosis and neurological deterioration is described, who underwent a sudden severe decompensation during her initial neurological investigations. She responded dramatically to biotin therapy. The diagnosis of late onset multiple carboxylase deficiency due to biotinidase deficiency was confirmed. This entity should be considered in the differential diagnosis of hyperlactacidemic encephalopathies.

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.

Of 61 newborns with disorders in amino acid metabolism, 20 had seizures; 15 of them have been recorded. Clinically, seizures are mostly partial clonic jerks. There seems to be some homogeneity of EEG features in relation to causal amino acidopathy. In every case where seizures, either electroclinical or only infraclinical, occurred the evolution was very poor, even in those diseases that would have had a good prognosis. Therefore the EEG in the newborns is especially interesting, both as an aid to diagnosis by interictal recording and as a prognostic tool by registration of seizures.

Hyperammonia has been reported in several disorders of branched chain amino acids metabolism including propionic, isovaleric, methylmalonic acidemia and B ketothiolase deficiency 1. Nevertheless the true incidence of hyperammonemia and its variation during the course of these diseases are not yet well known. The purpose of this study was to compare the blood ammonia concentrations and the concomitant serum organic acid accumulation in patients with propionic, isovaleric and methylmalonic acidemia.

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.

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.

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.

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.