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La galactosa es uno de los componentes del disacarido lactosa, que es el carbohidrato mas abundante en la leche de los mamiferos. Existen tres enfermedades hereditarias del metabolismo de la galactosa. El deficit de galactocinasa provoca un cuadro de catarata aislada. La galactosemia es la enfermedad debida al deficit de galactosa-1-fosfato-uridil-transferasa; se revela a traves de la aparicion de manifestaciones hepaticas, renales u oculares y presenta una evolucion favorable con una dieta exenta de galactosa; su pronostico a largo plazo depende de la afectacion neurologica. El deficit de uridina-difosfato-galactosa-4-epimerasa es excepcional y es responsable de formas benignas o graves de galactosemia. La fructosa es un azucar muy abundante en la alimentacion humana. Existen tres enfermedades hereditarias que afectan a su metabolismo. El deficit de fructocinasa es asintomatico. La intolerabilidad a la fructosa, debida al deficit de fructosa aldolasa, ocasiona sintomas digestivos agudos, con o sin hipoglucemias, o manifestaciones hepaticas o renales que pueden comprometer el pronostico vital si no se instaura rapidamente una dieta exenta de fructosa. El deficit de fructosa-1,6-difosfatasa es una anomalia de la gluconeogenesis que se manifiesta a traves de hipoglucemias con hiperlactacidemia.

UNLABELLED: Sjogren-Larsson syndrome (SLS) is a neurocutaneous autosomal recessive disease caused by fatty aldehyde dehydrogenase (FADH) deficiency. This enzyme is involved in the biosynthesis pathways of some fatty acids, phytanic acid, and leukotrienes. The main features of the disease are its association with congenital ichthyosis, mental retardation, and spastic tetraplegia. METHODS: We report on the diagnostic and therapeutic management of 2 cases of SLS. RESULTS: The diagnosis of SLS was suspected in the first patient at 2 years of age before the clinical triad appeared and confirmed at 4 years of age by the culture of fibroblasts and the peak of lipids on 1.3 ppm spectroscopy. After 3 months of treatment with zileuton, an inhibitor of leukotriene synthesis, moderate clinical efficacy for pruritus and ichthyosis was observed. The second patient was diagnosed at 1 year of age with the association of psychomotor retardation and congenital ichthyosis, in accordance with acute Guillain-Barre syndrome. Diagnosis was confirmed with enzymology, and cerebral spectro-MRI featured an abnormal lipidic peak. Zileuton therapy was initiated at the time of diagnosis and was effective for pruritus after 6 months of treatment. CONCLUSION: We report 2 cases of SLS with delayed diagnosis, due to non neonatal symptoms. Treatment with zileuton shows partial efficacy especially in pruritus. The uncommon association of this rare dysmyelinating disease with Guillain-Barre syndrome in the second patient is discussed.

Background Pyruvate dehydrogenase complex (PDHc) deficiencies are an important cause of primary lactic acidosis. Most cases result from mutations in the X-linked gene for the pyruvate dehydrogenase E1α subunit ( PDHA1 ) while a few cases result from mutations in genes for E1β ( PDHB ), E2 ( DLAT ), E3 ( DLD ) and E3BP ( PDHX ) subunits or PDH-phosphatase ( PDP1 ). Aim To report molecular characterization of 82 PDHc-deficient patients and analyze structural effects of novel missense mutations in PDHA1. Methods PDHA1 variations were investigated first, by exon sequencing using a long range PCR product, gene dosage assay and cDNA analysis. Mutation scanning in PDHX , PDHB, DLAT and DLD cDNAs was further performed in unsolved cases. Novel missense mutations in PDHA1 were located on the tridimensional model of human E1 protein to predict their possible functional consequences. Results PDHA1 mutations were found in 30 girls and 35 boys. Three large rearrangements, including two contiguous gene deletion syndrome were identified. Novel missense, frameshift and splicing mutations were also delineated and a nonsense mutation in a mosaic male. Mutations p.Glu75Ala, p.Arg88Ser, p.Arg119Trp, p.Gly144Asp, p.Pro217Arg, p.Arg235Gly, p.Tyr243Cys, p.Tyr243Ser, p.Arg245Gly, p.Pro250Leu, p.Gly278Arg, p.Met282Val, p.Gly298Glu in PDHA1 were predicted to impair active site channel conformation or subunit interactions. Six out of the seven patients with PDHB mutations displayed the recurrent p.Met101Val mutation; 9 patients harbored PDHX mutations and one patient DLD mutations. Conclusion We provide an efficient stepwise strategy for mutation screening in PDHc genes and expand the growing list of PDHA1 mutations analyzed at the structural level.

Background Deficiency of mitochondrial trifunctional protein (MTP) is caused by mutations in the HADHA and HADHB genes, which have been mostly delineated at the genomic DNA level and have not been always elucidated. Aim To identify mutations in a French cohort of 52 MTP deficient patients and the susceptibility of mutations generating premature termination codons (PTCs) to the nonsense mRNA mediated decay (NMD). Methods Mutation screening in fibroblasts was performed at the cDNA level and real-time RT-PCR was used to compare the levels of the different PTC-bearing mRNAs before and after a treatment of fibroblasts by emetine, a translation inhibitor. Results A mutation detection rate of 100% was achieved. A total of 22 novel mutations were identified, including a large-sized genomic deletion in HADHB gene. A high proportion of all identified mutations were non-sense, frameshift and splicing mutations, generating (PTCs), distributed essentially on HADHA coding regions. We could demonstrate that the majority of mutations resulting in PTCs conform to the established rules governing the susceptibility to NMD. Conclusion Our results emphasize the value of cDNA analysis in the characterization of HADHA and HADHB mutations and further strengthen the model of haploinsufficiency as a major pathomechanism in MTP defects.

A 22 year-old woman with tyrosinemia type I (HT1) married her first cousin who is heterozygous for the same FAH mutation for which the patient is homozygous. During her pregnancy she was treated with diet (prescribed tyrosine intake 300 mg/day), and nitisinone (60 mg/day). Median plasma tyrosine levels were 560 μmol/L (range: 375-838, n = 21) and nitisinone 51 μmol/L (range: 41-57, n = 3) during pregnancy. She gave birth to a clinically healthy girl affected with tyrosinemia type 1. Birth was normal (birth weight 2615 g) and the baby had normal liver function, normal plasma alpha-fetoprotein concentrations, low urinary excretion of phenolic acids and no detectable succinylacetone. At birth, the baby had hypertyrosinemia (860 μmol/L in blood cord) and nitisinone levels of 14 μmol/L. Following molecular confirmation of the diagnosis of HT1 specific treatment began on day 15 by which time she had detectable urinary succinylacetone.

Resume La maladie de Niemann-Pick type C (NPC) est une maladie de surcharge lysosomale neuroviscerale, rare, autosomique recessive, liee a une anomalie du trafic intracellulaire de lipides conduisant a leur accumulation dans le cerveau, le foie, la rate et aussi le poumon. La presentation clinique de la maladie est heterogene et varie selon l’âge de debut. Chez l’enfant, on distingue les formes perinatales viscerales et les formes neurologiques infantiles precoces, infantiles tardives et juveniles. L’atteinte neurologique est progressive et souvent aspecifique mais quatre signes ont une grande valeur d’orientation diagnostique : une cholestase neonatale prolongee, une splenomegalie, des acces cataplectiques et surtout une paralysie supranucleaire verticale du regard. La confirmation du diagnostic necessite une culture de fibroblastes et l’etude moleculaire des genes NPC1 et NPC2. L’approbation recente d’un traitement specifique, qui reduit la progression de l’atteinte neurologique, rend essentiel un diagnostic precoce de NPC.

This paper describes MRI aspects of a leukodystrophy due to the Mitochondrial Neurogastrointestinal Encephalomyopathy syndrome in an adolescent girl investigated for nocturnal recurrent emesis leading to major cachexia.

In a series of 137 patients with methylmalonic acidaemia (MMA) and propionic acidaemia (PA) diagnosed since the early 1970s, we report in more detail 81 patients (51 MMA and 30 PA) diagnosed between 1988 and 2005. In this series, 14% of patients died at initial access revealing the disease before or despite treatment, 18% died later, and the remainder (68%) are still alive. All patients were treated with the same protocol of enteral feeds with a low-protein diet adjusted to individual tolerance, carnitine, antibiotics, and only occasional use of an amino acid (AA) mixture. There was intensive follow-up and monitoring using measurements of urinary urea. Thirty-nine patients with severe forms, followed for more than 3 years, are analysed in particular detail. Of the 17 PA patients, 6 had moderate disability (all neonatal-onset forms), whereas 11 were normal or slightly delayed in their mental development. Four presented with cardiomyopathy, of whom 2 died. Of the 22 MMA patients, 13 presented in the neonatal period, of whom 3 died later, 2 are in renal failure and only 5 are still alive and have a normal or slightly delayed mental development. In the 9 patients with late-onset forms, there were no deaths and all patients but one have normal mental development. Among the 39 patients, only 40% were given an AA supplement at 3 years, and 50% between 6 and 11 years. The actual intake of natural protein was 0.92, 0.78 and 0.77 g/kg per day at 3, 6 and 11 years, respectively, in patients without AA supplementation, whereas it was 0.75, 0.74 and 0.54 g/kg per day in the group who received small quantities of AA (0.4-0.6 g/kg per day). In both groups, feeding disorders were frequent: 55% at 3 years, 35% at 6 years and 12% at 11 years. Many patients were given a food supplement by tube overnight or were even exclusively tube fed: 60% at 3 years, 48% at 6 years and still 27% at 11 years. Growth velocity was near the normal values. Plasma valine and isoleucine were low to very low, as were leucine and phenylalanine but to a lesser extent. Albumin, vitamins, trace elements and markers of bone metabolism were within the normal values. IGF1, 24-hour urine calcium and body mass density were low. Body composition showed a normal to low lean mass and a normal to high fat mass.

Resume Le galactose est un des constituants du disaccharide lactose, lequel est le carbohydrate le plus abondant dans le lait des mammiferes. Il existe trois maladies hereditaires du metabolisme du galactose. Le deficit en galactokinase est une cause de cataracte isolee. La galactosemie est la maladie due au deficit en galactose-1-phosphate uridyltransferase. Cette maladie se revele par des manifestations hepatiques, renales ou oculaires, dont lʼevolution est favorable sous regime sans galactose. Le pronostic a long terme est lie aux atteintes neurologiques. Le deficit en uridine diphosphate-galactose-4-epimerase est exceptionnel et responsable, soit de formes benignes, soit de formes severes de galactosemies. Le fructose est un sucre tres repandu dans lʼalimentation humaine. Trois maladies hereditaires affectent son metabolisme. Le deficit en fructokinase est asymptomatique. Lʼintolerance au fructose, liee au deficit en fructose aldolase, entraine, soit des symptomes digestifs aigus, avec ou sans hypoglycemies, soit des manifestations hepatiques ou renales qui peuvent mettre en jeu le pronostic vital si un regime dʼexclusion du fructose nʼest pas rapidement debute. Le deficit en fructose-1,6-diphosphatase est une anomalie de la neoglucogenese se manifestant par des hypoglycemies avec hyperlactacidemie.

Organic acidurias comprise many various disorders. Methylmalonic aciduria (MMA) and propionic aciduria (PA) are the most frequent diseases and the two organic acidurias for which we have better knowledge of the long-term outcome. Comparing the outcome of patients born before and after 1990, it appears that better neonatal and long-term management have improved the survival rate. Less than 20% of the patients died in either the neonatal period or before the age of 10 years. However, most surviving patients showed poor nutritional status with growth retardation and about 40% present some kind of visceral or neurological impairment. The developmental outcome may have improved in MMA patients, with IQ higher than 75 in about 40% patients aged more than 4 years. Conversely, poor intellectual development is the rule in PA patterns, with 60% having an IQ less than 75 and requiring special education. Successful liver and/or renal transplantations, in a few patients, have resulted in better quality of life but have not necessarily prevented neurological and various visceral complications. These results emphasize the need for permanent metabolic follow-up whatever the therapeutic strategy.

Phenylketonuria (PKU) is an inherited metabolic disease affecting about one birth out of 15 000. From 1978, a national systematic neonatal screening was set up in France with a regional organisation. French rational and guidelines have been established by the national PKU group with the collaboration of all the physicians responsible for the regional centres. These guidelines specify the minimal diagnosis procedures leading to an optimal treatment of all patients. A low-phenylalanine diet must be started as soon as possible in the neonatal period for all newborns whose phenylalanine levels are above 10 mg/dl. The dietary control must keep the phenylalanine plasma levels between 2 and 5 mg/dl until 10 years of age. After this age, several data argue for a progressive and controlled relaxation of the diet, keeping the phenylalanine level below 15 mg/dl until the end of the adolescence and below 20 to 25 mg/dl in adulthood. All PKU patients must be followed up for life, in order to screen those who may not bear the diet relaxation and in order to strictly prevent maternal PKU deleterious consequences.

El disacarido lactosa es el carbohidrato mas abundante en la leche de los mamiferos. Uno de sus componentes es la galactosa. Existen tres enfermedades hereditarias del metabolismo de la galactosa. El deficit de galactocinasa provoca un cuadro de catarata aislada. La galactosemia, enfermedad debida al deficit de galactosa-1-fosfato uridiltransferasa, se revela por la aparicion de manifestaciones hepaticas, renales u oculares, que evolucionan de manera favorable con un regimen sin galactosa. El pronostico a largo plazo depende de las lesiones neurologicas. El deficit de uridina difosfato-galactosa-4-epimerasa se revela excepcional, y produce galactosemias benignas o graves. La fructosa es un azucar muy abundante en la alimentacion humana. Existen tres enfermedades hereditarias que afectan a su metabolismo. El deficit de fructocinasa es asintomatico. La intolerancia a la fructosa, debida al deficit de fructosa aldolasa, ocasiona sintomas digestivos agudos con o sin hipoglucemias, o bien manifestaciones hepaticas o renales que pueden causar la muerte si no se instaura de inmediato un regimen sin fructosa. El deficit de fructosa-1,6-difosfatasa es una anomalia de la gluconeogenesis, que se manifiesta mediante hipoglucemias con hiperlactacidemia.

Haematological symptoms can be helpful for the diagnosis of metabolic diseases. A megaloblastic anemia orientates to folate and cobalamine anomalies when associated with homocystinemia and decreased plasma methionine levels, or to congenital oroticuria (hypochromia), Pearson syndrome (sideroblasts and vacuolisation of precursors) and thiamine transporter abnormality (sideroblasts) in the absence of homocystinuria. An hemolytic anemia orientates to anomalies of anaerobic glycolysis, heme synthesis, or iron metabolism, and Wilson disease. A pancytopenia orientates to organic aciduria, lysinuric protein intolerance, mevalonic aciduria and lysosomal storage diseases (Gaucher, Niemann Pick, Wolman) when hepatosplenomegaly is present. Uremic hemolytic syndrome and hemophagocytic lymphohistiocytosis respectively orientate to B12 anomalies, lysinuric protein intolerance, lysosomal storage diseases and organic aciduria.

Branched chain organic acidurias are a group of disorders that result from an abnormality of specific enzymes involving the catabolism of branched chain amino acids (leucine, isoleucine, valine). Maple syrup urine disease (MSUD), isovaleric acidaemia (IVA), propionic aciduria (PA) and methylmalonic aciduria (MMA) represent the most commonly encountered abnormal organic acidurias. All these four disorders present in neonates as a neurologic distress of the intoxication type with either ketosis or ketoacidosis and hyperammonaemia. There is a free interval between birth and clinical symptoms. MMA, PA and IVA present with a severe dehydration, leuconeutropenia and thrombopenia which can mimic sepsis. All these disorders can be diagnosed by identifying acylcarnitine and other organic acid compounds in plasma and urine by gas chromatography mass spectrometry or tandem MS-MS. These disorders are amenable to treatment by removing toxic compounds and by using special diets and carnitine.

The cobalamin type C deficiency is a rare condition that results from impaired biosynthesis of both methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl). Hemizygous mutations of the HCFC1 gene explain the majority of clinically and biologically compatible cblC patients without MMACHC mutations (OMIM 309541). We report a family with two maternal half-brothers with multiple congenital anomalies and HCFC1 gene mutation in the second Kelch domain. Both presented with dysmorphic features (flat profile, cleft lip for one), increased nuchal translucency, prenatal onset microcephaly and hypospadias. Additionally to early onset intractable epilepsy and profound neurocognitive impairment, this familial observation suggests that HCFC1 gene should be considered in boys with midline malformations, even without proven cobalamin C deficiency.

Resume La tyrosinemie hereditaire de type I est une maladie de pronostic severe. Les causes principales de deces sont l'insuffisance hepatique, les crises neurologiques et l'hepatocarcinome. Le NTBC, en inhibant la 4-hydroxyphenylpyruvate dioxygenase, previent la formation des metabolites toxiques impliques dans les lesions hepatiques, renales et neurologiques. Observations Nous rapportons les resultats du NTBC chez trois nourrissons atteints de tyrosinemie de type I revelee par une insuffisance hepatique aigue severe. Le diagnostic a ete confirme par la mise en evidence d'une concentration plasmatique elevee de tyrosine et de methionine et d'une excretion urinaire anormale de succinyl acetone et d'acide δ-aminolevulinique. Le traitement par NTBC a ete debute 2 a 8 jours apres le debut des symptomes. La correction des fonctions de synthese hepatique a ete notee des la 3 e semaine de traitement. Apres 12 a 39 mois de recul, l'evolution reste favorable. Conclusion Ces resultats illustrent l'efficacite du NTBC dans les formes aigues de la maladie. Toutefois, les resultats a long terme restent a determiner, notamment en termes de prevention de l'hepatocarcinome et de toxicite propre au medicament.

A case of holocarboxylase synthetase (HCS) deficiency of late-infantile onset is presented and compared with the common manifestations in previously reported patients. Our patient had her first episode at 20 months followed by recurrent episodes of metabolic acidosis with ketolactic acidosis responding dramatically to a short trial of biotin and thiamin. The main clinical findings were metabolic acidosis with alteration in consciousness and respiration, which are in accordance with findings in earlier reported patients with both neonatal-onset and infantile-onset forms of HCS deficiency. The diagnosis of HCS deficiency was made only at the age of 5.5 years during a metabolic work-up when organic acid analysis was performed. This revealed elevated urinary excretion of the characteristics metabolites, 3-hydroxypropionate, 3-hydroxyisovalerate and methylcitrate, suggesting multiple carboxylase deficiency (MCD). MCD was demonstrated in fibroblasts of our patient, but only when the cells were grown in a medium with a very low biotin concentration of 10(-10) mol/L. Kinetics studies of reactivation of deficient propionyl-CoA carboxylase activity with biotin in intact fibroblasts revealed a midly decreased reactivation rate and only a 3-5 times higher biotin requirement as compared with controls. These findings are in accordance with a mild form of HCS deficiency. This child responded to 10 mg/day of biotin with normal lymphocyte carboxylase activities and adequate school performance at 10 years of age.

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.

Resume Les myelogrammes des enfants presentant une intolerance aux proteines dibasiques avec lysinurie sont habituellement normaux, meme si des aspects d'autoerythrophagocytose ont ete decrits chez certains d'entre eux. Observation. — Un diagnostic d'intolerance aux proteines dibasiques avec lysinurie a ete porte chez deux freres âges de 12 et 15 ans a la suite d'une investigation immunohematologique. La symptomatologie avait debute en periode neonatale par une association de signes compatibles avec un diagnostic de syndrome d'activation macrophagique. Il existait une hepatosplenomegalie, une pancytopenie, une hypofibrinogenemie, une hypertriglyceridemie. Ulterieurement, l'hypothese d'une lymphohistiocytose familiale avait ete recusee devant l'evolution inhabituellement favorable et le caractere intermittent du syndrome d'activation macrophagique. Durant les annees qui ont suivi, outre les anomalies hematologiques, l'evolution s'etait caracterisee par l'installation d'une anorexie elective pour les proteines, avec retard de croissance, osteoporose et retard psychomoteur. Ce n'est qu'a 12 et 15 ans que l'investigation clinique et biologique de ces patients a permis de mettre en evidence une hyperammoniemie chronique. La supplementation en L-citrulline, en faisant apparaitre une hyperaminoacidurie specifique (arginine, ornithine, lysine), a permis le diagnostic. L'analyse des medullogrammes, pratiques en periode neonatale et lors du diagnostic, a revele une phagocytose particuliere des erythroblastes et des polynucleaires neutrophiles simultanement par des macrophages et des progeniteurs granuleux. Conclusions. — Cet aspect du myelogramme pourrait etre un des signes specifiques de la maladie. Ces donnees suggerent l'importance des investigations metaboliques devant tout syndrome d'activation macrophagique inexplique.

Resume L'hyperphenlalaninemie maternelle expose les femmes enceintes a un risque eleve d'avortement spontane et les enfants a naitre a un risque de microcephalie, d'arrieration mentale et de malformations congenitales, en particulier cardiaques. Quatre-vingt-quinze pour cent des meres dont la phenylalaninemie excede 20 mg/100 mL (1 200 μmol/L) ont au moins un enfaut mentalement retarde. La remise a un regime strict avant la conception et le controle de la phenylalaninemie tout au long de la grossesse reduisent ces risques. Les parametres de croissance de l'enfant, notamment son perimetre crânien, sont mieux conserves chez les femmes dont la phenylalaninemie a ete maintenue en dessous de 6 mg/100 mL (360 μmol/L) que chez celles dont la phenylalaninemie a ete plus souvent comprise entre 6 et 10 mg/100 mL (360–600 μmol/L). Il est par consequent hautement souhaitable que la grossesse soit programmee et qu'une contraception systematique soit mise en œuvre chez les jeunes femmes en âge de procreer, jusqu'a ce que la decision de mise en route d'une grossesse ait ete prise. Dans ce but, une information de ces jeunes filles et de leurs parents devrait etre realisee sans tarder et tous les efforts devraient etre entrepris afin de recenser les jeunes femmes hyperphenylalaninemiques depistees a la naissance et en âge de procreer, qu'elles aient ete traitees ou non par un regime de restriction. Enfin les medecins generalistes, les pediatres, les gynecologues-obstetriciens et les sages-femmes devraient etre sensibilises au risque de recurrence chez les femmes qui ont donne naissance a un enfant microcephale et/ou malforme, situation qui justifie pleinement un depistage « cible a. Une information dans la presse specialisee serait sans doute aussi d'une grande utilite.

We report 8 cases of severe cytochrome c oxidase deficiency with onset in the neonatal period. Clinical symptoms were heterogeneous: antenatal cerebral malformations, neurological distress with ketoacidosis, severe myopathy, or isolated respiratory control failure. Lactic acid was elevated in blood and/or CSF in 7 cases. Muscle biopsy (7 patients), liver biopsy (4 patients), and cultured skin fibroblasts (7 patients) were used to assess the cytochrome c oxidase deficiency. Among the patients, the enzymatic defect differed in the level of residual activity, expression in different tissues and subunit composition in muscle (as analysed by immunohistochemistry). Southern blot analysis of the mitochondrial DNA was normal in 7 patients. The heterogeneity of cytochrome c oxidase deficiency was therefore demonstrated by these clinical presentations and by the biochemical assessment of the enzyme defect. This reflects, most probably, the diverse nature of the causal mutations.

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.

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.985AG. 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.

Sjögren-Larsson syndrome (SLS) is a neurocutaneous autosomal recessive disease caused by fatty aldehyde dehydrogenase (FADH) deficiency. This enzyme is involved in the biosynthesis pathways of some fatty acids, phytanic acid, and leukotrienes. The main features of the disease are its association with congenital ichthyosis, mental retardation, and spastic tetraplegia.We report on the diagnostic and therapeutic management of 2 cases of SLS.The diagnosis of SLS was suspected in the first patient at 2 years of age before the clinical triad appeared and confirmed at 4 years of age by the culture of fibroblasts and the peak of lipids on 1.3 ppm spectroscopy. After 3 months of treatment with zileuton, an inhibitor of leukotriene synthesis, moderate clinical efficacy for pruritus and ichthyosis was observed. The second patient was diagnosed at 1 year of age with the association of psychomotor retardation and congenital ichthyosis, in accordance with acute Guillain-Barré syndrome. Diagnosis was confirmed with enzymology, and cerebral spectro-MRI featured an abnormal lipidic peak. Zileuton therapy was initiated at the time of diagnosis and was effective for pruritus after 6 months of treatment.We report 2 cases of SLS with delayed diagnosis, due to non neonatal symptoms. Treatment with zileuton shows partial efficacy especially in pruritus. The uncommon association of this rare dysmyelinating disease with Guillain-Barré syndrome in the second patient is discussed.

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.

The clinical and morphologic findings of three patients with metabolic acidosis, methylmalonic aciduria, and homocystinuria are presented. The clinical evolution of the patients was similar and was characterized in the first weeks of life by failure to thrive, hypotonia, and lethargy associated with pancytopenia and hepatic dysfunction, eventually progressing to severe respiratory insufficiency and renal failure consistent with a hemolytic-uremic syndrome. The patients died at 40, 45, and 75 days of age. Biochemical analyses and complementation studies revealed a congenital anomaly of vitamin B12 metabolism (cobalamin C disease). Postmortem morphologic findings in all three cases were dominated by a thrombotic microangiopathy of the kidneys and lungs, diffuse hepatic steatosis, and megaloblastic changes in the bone marrow. A severe gastritis with striking cystic dysplastic mucosal changes and total absence of parietal and chief cells was a consistent finding in all three cases, the rest of the gastrointestinal tract appearing essentially normal. Cobalamin C disease is an intracellular defect of cobalamin metabolism with possible recessive inheritance that can result in multiorgan failure early in life, with a thrombotic microangiopathy and unusual changes in the gastric mucosa.

Diabetes mellitus is occasionally observed in patients with skeletal muscle respiratory chain deficiency, suggesting that skeletal muscle mitochondrial dysfunction might play a pathogenic role in type 2 diabetes (T2D). In support of this hypothesis, decreased muscle mitochondrial activity has been reported in T2D patients and in mouse models of diabetes. However, recent work by several groups suggests that decreased muscle mitochondrial function may be a consequence rather than a cause of diabetes, since decreased mitochondrial function in mice affords protection from diabetes and obesity. We review the data on this controversial but important issue of potential links between mitochondrial dysfunction and diabetes.

Hyperargininaemia is a rare inborn error of metabolism due to a defect in the final step of the urea cycle. Infantile onset is the most common presentation with recurrent vomiting and psychomotor delay associated with spastic paraparesis; chronic hyperammonaemia is often overlooked. Neonatal and early-onset presentations are very uncommon and their clinical course not well-described. We report on a 3-week-old hyperargininaemic girl who presented with neurological deterioration associated with liver failure and 47-day ammonia intoxication before diagnosis could be made and treatment started. Despite appropriate but delayed treatment, our patient exhibited severe psychomotor delay at age 1 year. Conclusion Early identification and management of this rare but potentially treatable affection is crucial as delayed management may result in poor neurological outcome.

Resume L'âge de decouverte et la symptomatologie revelatrice de l'intolerance aux proteines du lait de vache (IPLV) sont varies; l'acidose lactique y est exceptionnelle. Observation Un nourrisson de 32 jours avait ete affecte d'un malaise grave avec acidose metabolique et hyperlactacidemie. Cette enfant, sans antecedent neonatal et familial particulier, sevree a j25, avait eu a j29 un pic de fievre, puis une degradation neurologique progressive avec deux episodes de pâleur, puis perte de connaissance breve imposant l'hospitalisation. A l'admission, l'enfant etait lethargique et hypotonique. Le bilan infectieux etait negatif ainsi que les explorations neuroradiographiques. Il existait une acidose metabolique compensee avec une hyperlactacidemie (5,96 mmol/L). La recherche d'un reflux gastro-œsophagien, d'une hypertonie vagale et, compte tenu de l'atteinte neurologique avec acidose, d'une cytopathie mitochondriale etait negative. Apres 24 heures d'arret alimentaire, l'etat clinique s'est ameliore progressivement pour se normaliser a h48. L'enfant est sortie du service sous hydrolysat de proteines. La mere a tente une reintroduction « sauvagedes proteines de lait de vache (PLV) a j64, entrainant immediatement des manifestations allergiques de type reaginique. Malgre l'absence de tests biologiques specifiques, l'evolution clinique est en faveur d'une intolerance aux proteines du lait de vache. Conclusion Ce mode de revelation (tableau neurologique et hyperlactacidemie) est rare. L'origine de cette hyperlactacidemie reste meconnue, probablement liee a la souffrance tissulaire de la muqueuse intestinale, organe glycolytique exclusif.

International audience; BACKGROUND: Cobalamin C disease is the most common inborn error of cobalamin metabolism with an autosomal recessive mode of inheritance and mutations within the MMACHC gene. Clinical features, including systemic, haematological and neurological abnormalities, usually occur in the first year of life. Adolescent and adult onset presentations are rare. METHODS: We report on the clinical, molecular and imaging features in three patients aged 40, 42 and 42 years at the last follow-up. We examine these cases together with eight previously described cases to determine the clinical and molecular features of the disease in adults. RESULTS: Mean age at onset of clinical symptoms was 26 years; clinical features included predominant neurological disturbances and thromboembolic complications. White matter abnormalities on brain MRI were sometimes observed. Most patients (eight of nine patients investigated) were compound heterozygotes for the 271dupA mutation and a missense mutation. Intramuscular or intravenous hydroxycobalamin therapy stopped the progression of the disease and resulted in a better clinical outcome and favourable biological status in 7/9 treated cases, while the two untreated patients died quickly. CONCLUSIONS: As cobalamin C disease and related disorders of homocysteine metabolism are treatable conditions, homocysteinaemia should be included in the investigations of patients with progressive neurological deterioration, unexplained psychiatric disturbances or recurrent thromboembolic events.