[Medium-chain acyl-CoA-dehydrogenase (MCAD) deficiency: French consensus for neonatal screening, diagnosis, and management]. / Déficit en acyl-CoA-déshydrogénase des acides gras à chaîne moyenne (MCAD): consensus français pour le dépistage, le diagnostic, et la prise en charge.

MCAD deficiency is the most common fatty acid oxidation disorder, with the prevalence varying from 1/10,000 to 1/27,000 in the countries adjacent to France. As the High Authority for Health has recently proposed including MCAD deficiency in the panel of diseases neonatally screened for in France, a consensus was written for the management of MCAD deficiency diagnosed either clinically or by neonatal screening. Patients may present acutely with hyperammonemia, hypoglycemia, encephalopathy, and hepatomegaly, mainly after a prolonged fast of intercurrent infection. Sudden death related to heartbeat disorders may also occur. The diagnosis of MCAD deficiency is suspected on the plasma acylcarnitine and/or the urinary organic acid profile. The diagnosis is confirmed by molecular biology and the enzymatic activity for patients who are not homozygous for the main mutation c.985A>G. However, some MCAD-deficient individuals may remain asymptomatic throughout life. The mainstay of treatment consists in avoiding prolonged fast and prescribing l-carnitine for patients who exhibit a deficiency in plasma carnitine. This management has radically modified the natural history of MCAD deficiency. This consensus will allow homogeneous management of these patients once the neonatal screening of MCAD deficiency has been introduced in France.

[Niemann-Pick type C disease: clinical presentations in pediatric patients]. / La maladie de Niemann-Pick type C: diagnostic clinique des formes pédiatriques.

Niemann-Pick type C disease (NPC) is a rare, neurovisceral, autosomic recessive, lysosomal lipid storage disorder associated with impaired intracellular lipid trafficking leading to accumulation of cholesterol and glycosphingolipids in the brain, the liver, the spleen and also the lung. NPC has a very heterogenous clinical presentation from perinatal period to adulthood. The perinatal presentation is visceral. In the early-infantile, late-infantile and juvenile period, a wide range of aspecific and progressive neurologic symptoms varies according to the age at onset, but four signs have a great diagnostic value : prolonged neonatal cholestasis, splenomegaly, cataplexy and vertical supranuclear gaze palsy. The diagnosis confirmation requires a fibroblast culture and molecular genetic testing of NPC1 and NPC2 genes. The recent approval of a specific treatment, reducing neurological disease progression, makes essential an early diagnosis of NPC.

[Failure to thrive and intestinal diseases in congenital disorders of glycosylation]. / Hypotrophie et manifestations digestives des désordres congénitaux de la glycosylation.

UNLABELLED: Congenital disorders of glycosylation type I (GDG-I) is a class of genetic multisystem disorders characterised by defective glycosylation of glycoproteins. The characteristics and mechanisms of failure to thrive and intestinal diseases present in CDG-I are anectodal. PATIENTS AND METHODS: The aim of this study was to analyse 7 CDG-I (4 CDG-Ia, 2 CDG-Ib and 1 CDG-Ix) with important digestive symptoms and failure to thrive in order to characterise the mechanisms implied. RESULTS: Four children had no skin abnormality or dysmorphia (1 CDG-Ia, 2 CDG-Ib, 1 CDG-Ix). An encephalopathy with cerebellar hypoplasia was present only in the 4 CDG-Ia. Failure to thrive and diarrhea were present during the first month of life in 6 and appeared at 5 years in one CDG-Ia associated to mild or severe hepatopathy in all patients. One CDG-Ia, 1 CDG-Ib, 1 CDG-Ix had an exsudative enteropathy. A positive steatorrhea was present in 3 patients. Five patients had an abnormal small bowel biopsy. Abnormalities were variable: moderate inflammation of the chorion without villous atrophy in 2, intra-enterocyte fat accumulation without villous atrophy in 2, and partial villous atrophy with lymphangectasia in 1. In 2 CDG-Ia the intestinal biopsy was normal. Enteral nutrition in 4 and parenteral nutrition in 2 were effective in 4 patients and 1 patient with an exsudative enteropathy respond to a free fat diet (CDG-Ix). CONCLUSION: The digestive symptoms with failure to thrive is a common feature of CDG-I and could be the first symptoms. The diagnostic should be suspected if no other cause is found. Mechanisms of the intestinal symptoms appear to be multiple such as inflammation, abnormal enterocyte lipid transport or intestinal permeability related to the abnormal glycosylation of intestinal mucosa glycoproteins.

Striatal and pontocerebellar hypoperfusion in Hallervorden-Spatz syndrome.

Hallervorden-Spatz syndrome is a group of rare and severe disorders marked by extrapyramidal symptoms and iron accumulation in the globi pallidi, usually visible by magnetic resonance imaging. To assist in determining the functional correlates of these structural abnormalities, positron emission tomography was used to measure regional cerebral blood flows and dopaminergic function in a patient with Hallervorden-Spatz syndrome that manifested as progressive generalized dystonia, optic atrophy, and bilateral pallidal "eye of the tiger" sign. Voxel-by-voxel analysis of positron emission tomography images revealed no pallidal abnormalities but demonstrated significant hypoperfusion of the head of the right caudate nucleus, pons, and cerebellar vermis. Dopaminergic function of the basal ganglia, which was assessed based on visual- analysis of fixation of 18F-labeled fluoro-levodopa, was normal. These data suggest that Hallervorden-Spatz syndrome pathogenesis is not confined to the globi pallidi, and these data also may help to generate new pathogenic hypothesis.

Long-term treatment with sodium phenylbutyrate in ornithine transcarbamylase-deficient patients.

Ornithine transcarbamylase deficiency is a very heterogeneous urea cycle disorder resulting in hyperammonemia with various presentations from the neonatal period through adulthood. We performed a retrospective study in nine patients (four male/five female, age at diagnosis ranging from 6 days to 14 years) to evaluate the safety and efficacy of sodium phenylbutyrate (Ammonaps) in long-term treatment. All patients were diagnosed by DNA mutational analysis and/or liver enzyme measurement. They had previously been treated with sodium benzoate (median dose 248 mg/kg/day; range 106-275) and low protein diet (median 0.84 g/kg/day) and were switched to sodium phenylbutyrate (median dose of 352 mg/kg/day) at 8.9 and 4.9 years of age (median) in males and females, respectively. We analyzed clinical and biochemical data and the median follow-up duration was 26 months. During that time, there were no hyperammonemic episodes requiring hospitalization. Median plasma ammonia and glutamine levels were 30 and 902 micromol/L, respectively. Total protein intake could be increased to 0.95 g/kg/day after 18 months. No side effects related to therapy were observed. Further prospective studies should be performed to define the optimal dosage of sodium phenylbutyrate and the requirements for protein diet at different ages.

Infantile spasms and Menkes disease.

Epileptic seizures are a common feature in Menkes disease, an X-linked genetic disorder of copper metabolism. Details of type of seizures are rarely reported. We report the evolution of infantile spasms in two patients with Menkes disease and the relation with subcutaneous administration of copper-histidine.

[Favorable outcome of treatment with NTBC of acute liver insufficiency disclosing hereditary tyrosinemia type I]. / Evolution favorable sous traitement par NTBC de l'insuffisance hépatique aiguë révélatrice de la tyrosinémie héréditaire de type I.

BACKGROUND: Hereditary tyrosinemia type I is a disease with a severe prognosis. Main causes of death are acute liver failure, neurologic crises and hepatocarcinoma. NTBC, which acts as an inhibitor of the 4-hydroxyphenylpyruvate dioxygenase, prevents the formation of toxic metabolites involved in hepatic, renal and neurologic lesions. CASE REPORTS: Results of NTBC therapy used in three infants with type I tyrosinemia who presented with acute liver failure are reported. The diagnosis relied on the finding of high plasmatic levels of tyrosine and methionine, and abnormal urinary excretion of succinyl acetone and delta aminolevulinic acid. Treatment with NTBC was initiated within 2 to 8 days from onset of symptoms. Signs of liver failure resolved after 3 weeks therapy. After 12 to 39 months of follow-up, outcome remains favorable. CONCLUSION: The results reported here highlight the efficiency of NTBC in type I tyrosinemia with early acute onset. However, the long term outcome needs to be determined with regards to prevention of hepatocarcinoma and toxicity of the drug.

Carbohydrate-deficient glycoprotein syndrome type I: a new cause of dysostosis multiplex.

We report on a 1-year-old boy, with carbohydrate-deficient glycoprotein (CDG) syndrome type I due to phosphomannomutase deficiency. Radiologic examination of the skeleton revealed previously unreported bone abnormalities that could be included in a dysostosis multiplex: wide ribs, squared iliac wings, horizontal acetabular roofs, widening and modeling abnormalities of ischial and pubic bones, dorsolumbar kyphosis, and slight hook-like dysplasia of the first lumbar vertebrae. Wormian bones were also present. We suggest that these features may be due to hypoglycosylation of bone proteins and that CDG syndrome type I should be included in the differential diagnosis of dysostosis multiplex.

Clinical outcome and long-term management of 17 patients with propionic acidaemia.

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.

Clinical outcome of long-term management of patients with vitamin B12-unresponsive methylmalonic acidemia.

We performed a retrospective study of all patients with methylmalonic acidemia diagnosed during the past 20 years. Only those patients who were nonresponsive to vitamin B12 in vivo and in vitro were included. The final study group consisted of 26 patients, of whom 16 had a neonatal (early) onset; in 10 patients the diagnosis was made after 2 months to 2.2 years (late onset). Of the early-onset patients, 14 (87%) died, with a mean survival time of 1.5 years (range, 10 days to 2.5 years), whereas four of the late-onset patients (40%) died (range, 1.2 to 15 years). At present, eight patients are alive; their mean age is 4.6 years (range, 1 to 10 years). In the early 1970s, treatment was based on the principles of treating patients with phenylketonuria: restricting natural protein intake and supplementing essential amino acids, vitamins, and trace elements. After about 1980, nasogastric tube feeding became a mainstay of the therapy, natural protein restriction became stricter, and the use of essential amino acid mixtures diminished. Carnitine was added to the therapy and, in later years, metronidazole. Since these changes were implemented, the number of episodes of metabolic decompensation and hospitalizations has decreased. Mean survival time of the patients, in particular those with early onset, has only slightly improved, partly because of psychosocial problems in many of these families. Almost all the patients, especially those with early onset, had some degree of neurologic impairment and mental retardation, and many patients were at less than 2 SD for weight or height or both. In contrast, the neurologic and mental status of the late-onset patients was frequently normal, and their weight and height were more often within normal limits. Our results show that the treatment of methylmalonic acidemia still poses considerable problems; despite intense medical efforts and familial stress, the prognosis for the early-onset patients is disappointing. The patients with late-onset disease, however, appear to have a fairly good prognosis with the present therapeutic approach. Liver transplantation or possibly genetic therapy might improve our results in the future.

[Mid-term outcome of 2 cases with maple syrup urine disease: role of liver transplantation in the treatment]. / Devenir à moyen terme de deux cas de leucinose: place de la transplantation hépatique dans le traitement.

BACKGROUND: Dietary treatment of maple syrup urine disease remains difficult; chronic nutritional support in the child does not always avoid acute crises so that liver transplantation may represent an alternate choice in some cases. CASE REPORTS: Two gypsy cousins were born by an interval of 4 days; both had maple syrup urine disease and were similarly treated from the first days of life. They were given exchange transfusions followed by diet restricted in the branched chain amino acids, maintaining normal growth and plasma leucine concentrations under 7 mg/100 ml. Laura, at 10 years, was retarded at school. Compliance to school attendance was limited by her diet problems. Helen suffered at 7 yr 3 mo from liver failure due to hepatitis A virus infection which required liver transplantation. Protein intake was normal 1 week later. At 10 years, she presented with the same degree of school retardation as her cousin, and was placed in the same class. CONCLUSION: Liver transplantation may be effective for treating metabolic problems in MSVD without significative difference between outcome post classic treatment or post liver transplantation.

Pre- and postnatal diagnosis of succinic semialdehyde dehydrogenase deficiency using enzyme and metabolite assays.

We report our cumulative experience for the prenatal diagnosis of succinic semialdehyde dehydrogenase (SSADH) deficiency in seven 'at-risk' pregnancies from four unrelated families. Prenatal diagnosis was performed by determination of 4-hydroxybutyric acid (4-HBA) concentration in amniotic fluid using isotope-dilution gas chromatography-mass spectrometry in conjunction with assay of SSADH activity in biopsied chorionic villus and/or cultured amniocytes. In three of four pregnancies predicted as affected, confirmation was obtained by demonstration of deficient SSADH activity in fetal tissues. Our results suggest that determination of 4-HBA concentration in amniotic fluid combined with enzyme determination in cultured or biopsied tissue represents a reliable method for the prenatal diagnosis of SSADH deficiency.,

[Neonatal hemolytic-uremic syndrome, methylmalonic aciduria and homocystinuria caused by intracellular vitamin B 12 deficiency. Value of etiological diagnosis]. / Syndrome hémolytique et urémique néonatal, acidurie méthylmalonique et homocystinurie par déficit intracellulaire de la vitamine B12. Intérêt du diagnostic étiologique.

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.

Clinical, metabolic, and genetic aspects of cytochrome C oxidase deficiency in Saguenay-Lac-Saint-Jean.

Thirty-four children with lactic acidosis and Leigh encephalopathy due to cytochrome C oxidase (COX) deficiency distributed in 28 families have recently been identified in northeastern Quebec, particularly in the Saguenay-Lac-Saint-Jean (SLSJ) region. The segregation analysis was consistent with an autosomal recessive mode of inheritance. The incidence was estimated at 1/2,063 live births between 1979 and 1990, and the carrier rate was estimated at 1/23 inhabitants in SLSJ. In SLSJ, the places of origin of the COX-deficient children and their parents did not show a clustered nonuniform distribution. The genealogical reconstruction of 54 obligate carriers identified 26 ancestors common to all of them. Twenty-two were 17th-century Europeans, suggesting that the COX-deficient gene was introduced in the French-Canadian population by early settlers. These results support the hypothesis of a founder effect for COX deficiency in northeastern Quebec. Clinical findings are reported for 15 of these COX-deficient patients, age 6 mo to 11 years. Moderate developmental delay, hypotonia, ataxia, strabismus, and mild facial dysmorphism were frequent. Eleven children died in episodes of fulminant metabolic acidosis. The patients had elevated blood and cerebrospinal fluid lactate levels, decreased blood bicarbonate levels, and normal blood pH. Leigh disease and microvesicular steatosis of the liver were present in all affected patients for whom postmortem examination was performed. This biochemically uniform group of patients showed a wide range of clinical severity.

Infantile familial cardiomyopathy due to mitochondrial complex I and IV associated deficiency.

Two brothers, aged 27 and 20 months, born from consanguineous healthy parents, presented with cardiomyopathy, lactic acidosis and carnitine abnormalities in serum and muscle, without clinical evidence of muscle involvement. The histochemical reaction for cytochrome c oxidase (COX) activity was negative in all muscle fibres, although the holoenzyme and subunits were present at a normal level, as shown by immunocytochemistry. The COX activity was, respectively, 5 and 25% of control values, in muscle biopsies. Partial deficiency of complex IV was confirmed in fresh isolated muscle mitochondria from patient 2 and was associated with a defect of complex I. Patient 1 died at age 3 yr 6 months. Partial improvement of cardiomyopathy in patient 2 was obtained under carnitine therapy, but seizures occurred and CT scan and magnetic resonance imaging (MRI) revealed thalamic hypodensity. Thus, the disorder appears to be progressive despite the clinical stabilization of the cardiomyopathy. This further demonstrates the complexity and clinical heterogeneity of combined respiratory chain complex deficiencies.