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Unlabelled: We report the French experience regarding pregnancies in maternal phenylketonuria (PKU). In 2001, a questionnaire was sent to each referring PKU specialist in the 20 centres of each region of France, collecting reports on 135 pregnancies in 79 women born between 1958 and 1980. The majority of the 135 pregnancies occurred after 1990. A total of 42 women were informed of the risks of untreated pregnancy, while 26 were not informed (no data for 11). A strict diet was achieved in 83% of informed and in 16% of uninformed mothers prior to conception. Healthy offspring were observed in 43% of the 135 pregnancies, spontaneous abortions in 10.4%, elective abortions in 4.4%, therapeutic abortions in 12.6%, and embryopathies (EP) in 21.5%. In 8.1% of cases, the outcomes (in earliest pregnancies) are unknown. The proportion of healthy children increased over time and reached 80% of the pregnancies of informed females. There were seven heart defects, all in cases of EP, but although microcephaly and intrauterine growth retardation (IUGR) were almost constant in EP, we also found nine healthy children with IUGR. A continuum between EP and healthy children is suggested. The anthropometric data of the mothers showed that their body mass index (BMI) distribution was shifted to the left compared to women of the general population. This lower BMI and poor weight gain during pregnancy could contribute to the IUGR observed in normal babies whose mothers received a phenylalanine-restricted diet during pregnancy., Conclusion: the information and the preconception diet are effective for avoiding embryopathies in maternal phenylketonuria. Nutritional parameters can influence fetal growth and the nutritional state must be closely monitored throughout pregnancies of women with phenylketonuria.

Unlabelled: Primary persistent hyperinsulinaemic hypoglycaemia of infancy is rare. Diazoxide treatment remains the mainstay of medical therapy in long-term management. We reviewed 77 cases of primary persistent hyperinsulinism in neonates and infants who were treated with diazoxide and studied criteria predictive of therapeutic efficacy. The only criterion identified was age at manifestation. All but 1 of the 31 neonatal cases were unresponsive to diazoxide. Responsiveness increased with age: 12 of 39 early-infantile cases, and all seven late-infantile cases were diazoxide-responsive. In responders, a diazoxide dose of 10-15 mg/kg per day was always effective, suggesting an "all or none" response. Diazoxide-resistant hyperinsulinism is characterized by its severity with higher plasma insulin levels. The analysis of 46 surgically treated patients showed that the efficacy of diazoxide is not related to the aetiology of the pancreatic lesions. In six cases, after many years of management, diazoxide treatment was stopped without recurrence of hypoglycaemia., Conclusion: Diazoxide is an efficient treatment in the long-term management of most persistent hyperinsulinaemic hypoglycaemia of infancy revealed in infants and children but is usually ineffective in neonatal forms. Drug efficacy does not correlate with anatomical lesions. Medical treatment can sometimes be stopped after many years of management without recurrence of disease manifestations.

The main remethylation defects include disorders which all have defective methionine synthesis in common. Methylenetetrahydrofolate reductase deficiency impairs methyltetrahydrofolate synthesis, defects in cytosolic reduction of hydroxocobalamin (CblC/D) impair the synthesis of both methyl- and adenosyl cobalamin and deficiencies of methionine synthase (CblE/G) are associated with defective methyl cobalamin synthesis. The clinical presentation is characterized by acute neurological distress in early infancy. In childhood, patients present with progressive encephalopathy with an end-stage which has many signs in common with the adult onset form. In fact, both have more or less severe signs of subacute degeneration of the cord. Cobalamin defective patients must be treated with parenteral supplementation of hydroxocobalamin (1-2 mg per dose). Some methylenetetrahydrofolate patients could be folate responsive and must have a high-dosage folate trial. In addition, oral betaine supplementation (2-9 g per day depending on age) appears an effective means to prevent further neurological deterioration.

Unlabelled: A retrospective study was performed on the clinical outcome and long-term treatment of 17 patients with propionic acidaemia diagnosed during the last 20 years in our hospital. The study group consisted of 12 patients with early onset type of disease and 5 patients with late onset. Seven (41%) patients died, five with early onset and two with late onset. The deceased early onset patients had a median survival of 0.4 years while the deceased late onset patients died at the age of 2.8 and 4 years respectively. Median age of the living early onset patients was 5.2 (1-9.25) years, the late onset patients were 4, 7 and 23 years old. Patients were all treated with natural protein restriction and in most cases carnitine and metronidazole were added. The early onset patients were almost all treated with daily home tube feeding. The mean natural protein intake of early onset patients (6.3 +/- 1.5 g/day) was significantly lower than the natural protein intake of late onset patients (17.6 +/- 5.3 g/day). Supplemental protein intake was higher in early onset patients. The general neurological outcome of our study group was satisfactory with a better outcome for early onset patients. As to growth, many patients showed a failure to thrive, this was particularly for height. The strong protein restriction during the first years of life probably contributed to this., Conclusion: The prognosis for patients with propionic acidaemia appeared to be satisfactory in terms of survival and outcome characteristics such as neurological and mental development. Despite these results the authors feel that the prognosis and quality of life of these patients might be improved with liver transplantation or possibly somatic gene therapy in the future.

We describe two asymptomatic newborns with nutritional vitamin B12 deficiency in whom increased urinary methylmalonic acid was detected by routine neonatal screening at 3 weeks of age. Both infants were exclusively breast-fed. One mother suffered from pernicious anaemia, and the other was a strict vegetarian. Both mothers had no clinical or haematological abnormality, aside from a borderline mean corpuscular volume for the vegetarian mother. This report illustrates the early appearance of functional vitamin B12 deficiency in breast-fed infants of vitamin B12-depleted mothers. It also demonstrates that urinary methylmalonic acid measurement is a sensitive indicator of tissue vitamin B12 deficiency.

A 24-h fasting test was performed in 48 control children, in 9 hypoketotic patients with inherited defects of fatty acid oxidation and in 2 hyperketotic patients with inherited defects of ketolysis. The control group was then divided into three age groups on the basis of different adaptation to fasting. Concentrations of blood glucose, lactate, free fatty acids (FFA), 3-hydroxybutyrate, acetoacetate and carnitine were measured after 15 h, 20 h and 24 h of fasting. Significant negative correlations were found in the control group between plasma total ketone bodies (KB) and plasma glucose (P less than 0.001), plasma carnitine (P less than 0.005) and the amplitude of glycaemic response to glucagon at the end of the fast (P less than 0.01). FFA/KB ratio and the product of final fasting values of glucose and ketones were useful to differentiate between hypoketotic or hyperketotic patients and normal subjects. In children with a suspected or definite hyperketotic or hypoketotic disorder, a fasting test must only be performed in healthy patients, in good nutritional condition with non-diagnostic basal biochemical investigations. Carefully supervised fasting should be continued sufficiently to allow ketogenesis and ketolysis to become activated.

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.