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Background: We analysed 5-year treatment with agalsidase alfa enzyme replacement therapy in patients with Fabry's disease who were enrolled in the Fabry Outcome Survey observational database (FOS). Methods: Baseline and 5-year data were available for up to 181 adults (126 men) in FOS. Serial data for cardiac mass and function, renal function, pain, and quality of life were assessed. Safety and sensitivity analyses were done in patients with baseline and at least one relevant follow-up measurement during the 5 years (n=555 and n=475, respectively). Findings: In patients with baseline cardiac hypertrophy, treatment resulted in a sustained reduction in left ventricular mass (LVM) index after 5 years (from 71.4 [SD 22.5] g/m(2.7) to 64.1 [18.7] g/m(2.7), p=0.0111) and a significant increase in midwall fractional shortening (MFS) from 14.3% (2.3) to 16.0% (3.8) after 3 years (p=0.02). In patients without baseline hypertrophy, LVM index and MFS remained stable. Mean yearly fall in estimated glomerular filtration rate versus baseline after 5 years of enzyme replacement therapy was -3.17 mL/min per 1.73 m(2) for men and -0.89 mL/min per 1.73 m(2) for women. Average pain, measured by Brief Pain Inventory score, improved significantly, from 3.7 (2.3) at baseline to 2.5 (2.4) after 5 years (p=0.0023). Quality of life, measured by deviation scores from normal EuroQol values, improved significantly, from -0.24 (0.3) at baseline to -0.17 (0.3) after 5 years (p=0.0483). Findings were confirmed by sensitivity analysis. No unexpected safety concerns were identified. Interpretation: By comparison with historical natural history data for patients with Fabry's disease who were not treated with enzyme replacement therapy, long-term treatment with agalsidase alfa leads to substantial and sustained clinical benefits. Funding: Shire Human Genetic Therapies AB.

The term 'early intervention' designates educational and neuroprotection strategies aimed at enhancing brain development. Early educational strategies seek to take advantage of cerebral plasticity. Neuroprotection, a term initially used to characterize substances capable of preventing cell death, now encompasses all interventions that promote normal development and prevent disabilities, including organisational, therapeutic and environment-modifying measures, such as early stimulation programs. Early stimulation programs were first devised in the United States for vulnerable children in low-income families; positive effects were recorded regarding school failure rates and social problems. Programs have also been implemented in several countries for premature infants and low-birth-weight infants, who are at high risk for neurodevelopmental abnormalities. The programs target the child, the parents or both. The best evaluated programs are the NIDCAP (Newborn Individualized Developmental Care and Assessment Program) in Sweden for babies<1500 g in neonatal intensive care units and the longitudinal multisite program IHDP (Infant Health and Development Program) created in the United States for infants<37 weeks or <2500 g. CONCLUSION: Although the NIDCAP and the IHDP targeted different populations, they produced similar effects in several regards: efficacy was greatest with programs involving both the parents and the child; long-term stimulation improved cognitive outcomes and child-parent interactions; cognition showed greater improvements than motor skills and larger benefits were obtained in families that combined several risk factors including low education attainment by the mothers.

On entend souvent dire que "l'enfant n'est pas un adulte en miniature", soulignant ainsi la réalité existentielle d'un être en développement, condition qui le distingue fondamentalement de l'adulte. La maturation des activités sensori-motrices et cognitives représente un processus dynamique étroitement dépendant de facteurs génétiques et d'influences exercées par l'environnement. L'inachèvement anatomofonctionnel du cerveau de l'enfant et la plasticité neuronale qui en découle font en sorte qu'à pathologie identique, les manifestations cliniques observées chez lui diffèrent de celles de l'adulte. Malgré les avancées médico-techniques spectaculaires des dernières décennies et l’émergence de nouveaux moyens d’exploration morphologique et fonctionnelle du système nerveux, la clinique demeure souveraine dans la démarche diagnostique en neurologie pédiatrique. L'aide apportée par les bases de données informatiques pourtant très étoffées s'avère tout compte fait assez limitée. Malgré leur indéniable intérêt, ces outils sont incapables de se substituer à l’esprit humain dans le traitement des renseignements recueillis par l'anamnèse et par l'examen clinique. Cette réflexion s'applique également aux explorations médico-techniques qui ne peuvent être considérées comme des raccourcis supplétifs à la clinique; dans ce domaine, la demande actuelle succombe trop souvent à une offre dont l’ampleur impose des restrictions drastiques et des choix rationnels fondés sur des hypothèses diagnostiques mûrement balancées. Au delà de leur valeur générale, ces considérations méthodologiques s’avèrent particulièrement pertinentes dans l’approche des troubles du développement psychomoteur de l’enfant.

La tomographie d'émission positronique (TEP) ou "positron emission tomography" (PET) a été et demeure une technique de recherche fructueuse en neurosciences cognitives. Durant les dernières décades, son application au diagnostic des maladies nerveuses s'est avérée également très utile et a suscité un intérêt croissant. L'essentiel de notre exposé y est consacré. Le glucose compose avec l'oxygène le substrat énergétique principal du tissu nerveux. Le décompte de sa consommation à un endroit particulier de l'encéphale peut constituer un précieux indicateur du fonctionnement neuronal à ce niveau. Par ailleurs, la perfusion tissulaire régionale est dans la plupart des cas couplée au métabolisme glucosé. Dès lors, les informations acquises tant par la mesure des dépenses énergétiques que par celle du débit sanguin locorégional sont susceptibles de reconnaître les cibles anatomiques de maladies du système nerveux et de corréler leurs modifications aux symptômes présentés. L'utilisation de l'une ou de l'autre méthode (TEP ou TEMP) dépend des indications cliniques et du contexte environnemental.

L'enfant (hyper)agité présente ce qu'on appelle actuellement des troubles externalisés du comportement (impulsivité, agressivité, manque d'obéissance). Ces troubles font l'objet de nombreuses plaintes et consultations en médecine générale et dans les services de neuropédiatrie et de pédopsychiatrie. Cet article propose une approche multifactorielle de ces troubles. Il pose également la question du diagnostic en insistant sur la notion de diagnostic différentiel. Il souligne l'importance d'une évaluation multidisciplinaire et propose finalement une revue des traitements vers lesquels les enfants, les adolescents et leur famille peuvent être orientés.

Traumatic brain injury is a major cause of mortality and morbidity in children younger than 15 years of age. To evaluate the role of subcortical lesions on neurodevelopmental outcomes, long-term outcomes of 50 children with severe traumatic brain injury before 4 years of age (accidental injury, n = 21, nonaccidental injury, n = 29) were reviewed retrospectively and compared with late magnetic resonance imaging (MRI) findings: no visible lesions, cortical lesions, or subcortical lesions. Subcortical lesions occurred in both accidental and nonaccidental traumatic brain injuries. Traumatic brain injury severity (initial Glasgow Coma Scale or coma duration) was significantly associated with subcortical lesions. Long-term motor or visual deficiencies occurred in one third of patients and cognitive deficiencies in 52.1%. Although deficiencies occurred without visible MRI lesions, global outcome scores, motor delay, visual impairment, head growth slowing, global intellectual quotients, and planning performances were significantly worse in patients with subcortical lesions. An alarming deterioration in intellectual quotient over time was noted. It was concluded that neurodevelopmental outcomes are worrisome after severe traumatic brain injury in young children, and subcortical lesions affect the prognosis.

Background: Dystroglycanopathies are a group of congenital muscular dystrophies (CMDs) with autosomal recessive inheritance, often associated with CNS and ocular involvement. They are characterized by the abnormal glycosylation of alpha-dystroglycan, and caused by mutations in at least six genes encoding enzymes: FKTN, POMGNT1, POMT1, POMT2, FKRP, and LARGE. POMT2 mutations have recently been identified in Walker-Warburg syndrome and in a milder muscle-eye-brain disease-like form. Methods: We studied mentally retarded patients with CMD, analyzed POMT2 by sequencing the coding regions, and also performed a haplotype analysis in all patients and their family members carrying the new POMT2 mutation. Results: We report three novel POMT2 mutations. One of these, p.Tyr666Cys, was homozygous in two unrelated patients and in a compound heterozygous state in others. All patients showed severe diffuse muscle weakness, microcephaly, severe mental retardation, and marked lordoscoliosis with hyperextencled head. Elevated CK levels, cerebral cortical atrophy, and cerebellar vermis hypoplasia were constant findings. Mild cardiac abnormalities, focal white matter abnormalities, or partial corpus callosum hypoplasia were detected in single cases. Eye involvement was absent or mild. By genotype analysis, we defined a distinct 170kb haplotype encompassing POMT2 and shared by all the subjects harboring the mutation p.Tyr666Cys. Conclusions: Our results broaden the clinical spectrum associated with POMT2 mutations, which should be considered in patients with CMD associated with microcephaly, and severe mental retardation with or without ocular involvement.

Recent studies have shown that same-race (SR) faces are processed more holistically than other-race (OR) faces, a difference that may underlie the greater difficulty at recognizing OR than SR faces (the "other-race effect"). This article provides original evidence suggesting that the holistic processing of faces may be sensitive to the observers' racial categorization of the face. In Experiment 1, Caucasian participants performed a face-composite task with Caucasian faces, Asian faces, and racially ambiguous morphed face stimuli. Identical morphed face stimuli were processed more holistically when categorized as SR than as OR faces. Experiment 2 further suggests that this finding was not underlain by strategic or training effects. Overall, these results support the view that one's categorization of a face as belonging to the same or another race plays a critical role in the holistic processing of this face.

Early intervention include educational and neuroprotection strategies. Early educational strategies are based on the cerebral plasticity concept. Neuroprotection, initially reserved for molecules preventing cell death phenomena, can be extended now to all actions promoting harmonious development and preventing handicaps, and include organisational, therapeutic and environmental aspects. Early stimulation programs have been first devised in United States for vulnerable children who belong to an unfavorable socio-economic category; positive effects were recorded in school failure rates and social problems; programs have also beeen launched in several countries for premature infants and infants with a low birth weight, population exposed to a high risk of deficiencies. The programs are targetted either to the child, or to the parents, or combined to provide assistance for both the child and the parents. The programs given the best evaluation are NIDCAP Program in Sweden (Newborn Individualized Developmental Care and Assessment Program), intended for babies < 1500g in neonatal intensive care units, then a longitudinal, multisite program, known as IHDP (Infant Health and Development Program). It was launched in United States for infants < 37 weeks or < 2500 g. Results show that combined parent-child programs are the most useful. Effects on parent-child relationships and on child's cognitive development are especially effective if stimulation is maintained and when mothers have a low level of education. (C) 2007 Elsevier-Masson SAS. Tons droits reserves.

[Children displaying externalizing behaviour. Epigenetic and developmental framework]. Externalizing behaviour is related to hard to manage behaviour in children and adolescents displaying agitation, impulsivity, aggressiveness or non compliance. Numerous pediatric and psychiatric counseling situations for children and adolescents are motivated by such behaviour patterns. The current paper presents an etiological multi factorial framework for these patterns focusing on epigenetic and developmental background. It provides neurological, psychodynamic and developmental theoretical purposes. The developmental theory designs the child development through a sequence of stages and suggests the importance of its interactions with life environments: attachment figures — its parents —, siblings and peers. The diagnostic process is examined by mean of differential diagnostic and by highlighting importance of multidisciplinary assessment procedure. The paper finally proposes a brief review of available treatments for children, adolescents and their family., Les troubles de comportement dits externalisés se rapportent à de l'agitation, de l'impulsivité, de l'agressivité ou encore un manque d'obéissance. Ils font l'objet de nombreuses consultations chez les enfants et les adolescents dans les services de neuropédiatrie et de pédopsychiatrie. Cet article propose une approche étiologique multifactorielle de ces troubles, axée plus particulièrement sur leur dimension épigénétique et développementale. Pour ce faire, il s'appuie sur des éléments relevant des champs neurologique et psychodynamique, ainsi que sur une approche typiquement développementale. Celle-ci conçoit le développement d'un enfant inséré dans ses milieux de vie, en interaction avec ses figures d'attachement — ses parents en particulier —, sa fratrie et ses pairs. Cet article pose également la question du diagnostic en insistant sur la notion de diagnostic différentiel. Il souligne l'importance d'une évaluation multidisciplinaire et propose finalement une revue des traitements vers lesquels les enfants, les adolescents et leur famille peuvent être orientés.

OBJECTIVE: We investigated a large consanguineous Moroccan family with progressive myoclonic epilepsy (PME) consistent with autosomal recessive inheritance, to describe the phenotype and identify the causal gene. METHODS: We recorded the clinical course of the disease and the response to drug therapy, whereas carefully excluding known causes of progressive myoclonic epilepsy. We then linked the disease by homozygosity mapping using microsatellite markers and single nucleotide polymorphism microarrays (11K GeneChip), and studied candidate genes in the critical linkage region. RESULTS: Epilepsy started between 16 and 24 months of age after normal initial development. Seizures were multifocal myoclonus aggravated by movements, and generalized tonic-clonic seizures were experienced by two patients. Electroencephalogram showed slow dysrhythmia, multifocal and occasionally generalized epileptiform discharges, and photosensitivity. Brain magnetic resonance images were normal. All patients were demented. Two had refractory epilepsy and a severe course. Seizures were controlled in the third patient, whose disease course was less severe. Linkage analyses identified a new locus on 7q11.2, with a maximum multipoint logarithm of odds of 4.0 at D7S663. In the critical linkage region, we found a C to T mutation in exon 2 of the potassium channel tetramerization domain containing 7 gene (KCTD7). The mutation affected a highly conserved segment of the predicted protein, changing an arginine codon into a stop codon (R99X). INTERPRETATION: Neurodegeneration in progressive myoclonic epilepsy presented by our patients paralleled the refractoriness of epilepsy. The disease was transmitted as an autosomal recessive trait linked to a novel locus at 7q11.2, where we identified a mutation in KCTD7.

Reduced folate transport to the CNS was identified in two autism spectrum disorders, i.e., Rett syndrome and infantile low-functioning autism with neurological abnormalities. Twenty-five patients with early-onset low-functioning autism with or without neurological deficits, were evaluated for serum folate, cerebrospinal fluid (CSF) 5-methyltetrahydrofolate (5MTHF), and serum FR autoantibodies of the blocking type to determine the significance of folate receptor (FR) autoantibodies with respect to folate transport across the blood-CSF barrier. In spite of normal serum folate, CSF 5MTHF was low in 23 of 25 patients. The reduced CSF folate in 19 of these 23 patients could be explained by serum FR autoantibodies blocking the folate binding site of the membrane-attached FR on the choroid epithelial cells. Oral folinic acid supplements led to normal CSF 5MTHF and partial or complete clinical recovery after 12 months. Serum FR autoimmunity appears to represent an important factor in the pathogenesis of reduced folate transport to the nervous system among children with early-onset low-functioning autism associated with or without neurological deficits. Early detection of FR autoantibodies may be a key factor in the prevention and therapeutic intervention among this subgroup of patients with autism.

We have previously shown that some visual motion areas can be specifically recruited by auditory motion processing in blindfolded sighted subjects [Poirier, C., Collignon, O., De Volder, A.G., Renier, L., Vanlierde, A., Tranduy, D., Scheiber, C., 2005. Specific activation of V5 brain area by auditory motion processing: an fMRI study. Brain Res. Cogn. Brain Res. 25, 650-658]. The present fMRI study investigated whether auditory motion processing may recruit the same brain areas in early blind subjects. The task consisted of simultaneously determining both the nature of a sound stimulus (pure tone or complex sound) and the presence or absence of its movement. When a movement was present, blind subjects had to identify its direction. Auditory motion processing, as compared to static sound processing, activated the brain network of auditory and visual motion processing classically observed in sighted subjects. Accordingly, brain areas previously considered as specific to visual motion processing could be specifically recruited in blind people by motion stimuli presented through the auditory modality. This indicates that the occipital cortex of blind people could be organized in a modular way, as in sighted people. The similarity of these results with those we previously observed in sighted subjects suggests that occipital recruitment in blind people could be mediated by the same anatomical connections as in sighted subjects.

Recent advances in diffusion tensor imaging (DTI) have made it possible to reveal white matter anatomy and to detect neurological abnormalities in children. However, the clinical use of this technique is hampered by the lack of a normal standard of reference. The goal of this study was to initiate the establishment of a database of DTI images in children, which can be used as a normal standard of reference for diagnosis of pediatric neurological abnormalities. Seven pediatric volunteers and 23 pediatric patients (age range: 0-54 months) referred for clinical MR examinations, but whose brains were shown to be normal, underwent anatomical and DTI acquisitions on a 1.5 T MR scanner. The white matter maturation, as observed on DTI color maps, was described and illustrated. Changes in diffusion fractional anisotropy (FA), average apparent diffusion constant (ADC(ave)), and T2-weighted (T2W) signal intensity were quantified in 12 locations to characterize the anatomical variability of the maturation process. Almost all prominent white matter tracts could be identified from birth, although their anisotropy was often low. The evolution of FA, shape, and size of the white matter tracts comprised generally three phases: rapid changes during the first 12 months; slow modifications during the second year; and relative stability after 24 months. The time courses of FA, ADC(ave), and T2W signal intensity confirmed our visual observations that maturation of the white matter and the normality of its architecture can be assessed with DTI in young children. The database is available online and is expected to foster the use of this promising technique in the diagnosis of pediatric pathologies.

BACKGROUND & AIMS: Donor cell engraftment with expression of enzyme activity is the goal of liver cell transplantation for inborn errors of liver metabolism with a view to achieving sustained metabolic control. METHODS: Sequential hepatic cell transplantations using male and female cells were performed in a 3.5-year-old girl with argininosuccinate lyase deficiency over a period of 5 months. Beside clinical, psychomotor, and metabolic follow-up, engraftment was analyzed in repeated liver biopsies (2.5, 5, 8, and 12 months after first infusion) by fluorescence in situ hybridization for the Y-chromosome and by measurement of tissue enzyme activity. RESULTS: Metabolic control was achieved together with psychomotor catch-up, changing the clinical phenotype from a severe neonatal one to a moderate late-onset type. The child was no longer hospitalized and was able to attend normal school. Sustained engraftment of male donor liver cells was shown in repeated biopsies, reaching 19% at 8 months and 12.5% at the 12-month follow-up. XXYY tetraploid donor cells were mainly detected during the infusion period (2.5- and 5-month biopsies), whereas in the follow-up 8-month and 1-year biopsies, diploid donor cell subpopulations had become dominant. Moreover, argininosuccinate lyase activity, originally absent, became measurable in 2 different biopsy samples at 8 months, reaching 3% of control activity, indicating in situ metabolic effect and supporting the clinical evolution to a moderate form of the disease. CONCLUSIONS: Liver cell transplantation can achieve donor cell engraftment in humans in a significant proportion, leading to sustained metabolic and clinical control with psychomotor catch-up.

We report a case of Gitelman syndrome (GS) in a dizygotic twin who presented at 12 years of age with growth delay, metabolic alkalosis, hypomagnesemia and hypokalemia with inappropriate kaliuresis, and idiopathic intracranial hypertension with bilateral papilledema (pseudotumor cerebri). The patient, her twin sister, and her mother also presented with cerebral cavernous malformations. Based on the early onset and normocalciuria, Bartter syndrome was diagnosed first. However, mutation analysis showed that the proband is a compound heterozygote for 2 mutations in SLC12A3: a substitution of serine by leucine at amino acid position 555 (p.Ser555Leu) and a novel guanine to cytosine transition at the 5' splice site of intron 22 (c.2633+1G>C), providing the molecular diagnosis of GS. These mutations were not detected in 200 normal chromosomes and cosegregated within the family. Analysis of complementary DNA showed that the heterozygous nucleotide change c.2633+1G>C caused the appearance of 2 RNA molecules, 1 normal transcript and 1 skipping the entire exon 22 (r.2521_2634del). Supplementation with potassium and magnesium improved clinical symptoms and resulted in catch-up growth, but vision remained impaired. Three similar associations of Bartter syndrome/GS with pseudotumor cerebri were found in the literature, suggesting that electrolyte abnormalities and secondary aldosteronism may have a role in idiopathic intracranial hypertension. This study provides further evidence for the phenotypical heterogeneity of GS and its association with severe manifestations in children. It also shows the independent segregation of familial cavernomatosis and GS.

L-2-Hydroxyglutaric (L-2-HG) aciduria is a rare inherited metabolic disease usually observed in children. Patients present a very slowly progressive deterioration with cerebellar ataxia, mild or severe mental retardation, and various other clinical signs including extrapyramidal and pyramidal symptoms, and seizures. The disease is characterized by increased levels of L-2-HG in body fluids such as urine and cerebrospinal fluid. We report on two sisters from consanguineous parents, in whom L-2-HG aciduria was diagnosed at an adult age. Although magnetic resonance imaging and spectroscopic findings were severely abnormal in both, they experienced a different clinical course. The older sister presented with severe mental retardation, recurrent epileptic seizures, and progressive deterioration in her ability to walk and to talk; she is now confined to a wheelchair with severe speech deficit. In contrast, the younger sister only had a few epileptic seizures in childhood and moderate mental retardation, is still able to walk, and performs manual work, and has a social life in a specialized institution for moderately mentally handicapped persons. For the two patients, a complete deletion of exon 9 was demonstrated in a gene located on chromosome 14q22.1, which most probably encodes for L-2-hydroxyglutarate dehydrogenase. The pathological findings observed in this metabolic disorder could therefore be related to a toxic effect of L-2-hydroxyglutarate on the central nervous system, although the presence of other toxic metabolites cannot be excluded.

Aims: Trauma during pregnancy is commonly viewed as benign for the foetus when the delivery occurs normally. This study revisits that point of view. Method: We included eighteen patients having a neurological handicap with an anamnesis of an accident during pregnancy and a follow-up sufficient to determine a definite outcome. Results: Pregnancy outcome and observed management. Foetal abnormalities were detected in six cases between the first and the thirteenth day after the trauma. Emergency delivery or rapid birth after signs of foetal distress occurred in five cases. One baby died soon after birth. One-third of cases were not submitted to any investigation. Various neurological handicaps were recorded: Congenital microcephaly (three patients), congenital hydrocephalus (three), Infantile cerebral hemiplegy (six), quadriplegy with severe encephalopathy (four), diplegy (one), clumsiness with cerebellar atrophy (one), Moebius syndrome (one), mental retardation with autistic features (two), learning disability (one) auditory agnosia (one).Cerebral imaging showed macroscopic abnormalities in fourteen patients, evoking various pathogenetic hypotheses. Conclusion: The association between maternal trauma and foetal brain lesions lacks sufficient investigation in many cases. Prospective studies are needed to clarify both medical and legal issues. Guidelines are proposed for obstetrical and paediatric management after significant maternal trauma.

This report illustrates the usefulness and safety of very early hemispherotomy in an infant with Ohtahara syndrome (OS) secondary to left parieto-occipital megalencephaly. It provides evidence that surgical intervention might provide promising results in selected cases, and that young age is not a contraindication for this type of surgery.

This paper reviews the clinical presentation of 217 patients with urea cycle defects, including 121 patients with neonatal-onset forms and 96 patients with late-onset forms. Long-term outcome of these patients is also reported with the severity of the neonatal forms of these disorders, mostly for ornithine carbamoyltransferase-deficient males. Patients with late-onset forms may present at any age and carry a 28% mortality rate and a subsequent risk of subsequent disabilities.

Maternal drug use during pregnancy is associated with fetal passive addiction and neonatal withdrawal syndrome. Cigarette smoking-highly prevalent during pregnancy-is associated with addiction and withdrawal syndrome in adults. We conducted a prospective, two-group parallel study on 17 consecutive newborns of heavy-smoking mothers and 16 newborns of nonsmoking, unexposed mothers (controls). Neurologic examinations were repeated at days 1, 2, and 5. Finnegan withdrawal score was assessed every 3 h during their first 4 d. Newborns of smoking mothers had significant levels of cotinine in the cord blood (85.8 +/- 3.4 ng/mL), whereas none of the controls had detectable levels. Similar findings were observed with urinary cotinine concentrations in the newborns (483.1 +/- 2.5 microg/g creatinine versus 43.6 +/- 1.5 microg/g creatinine; p = 0.0001). Neurologic scores were significantly lower in newborns of smokers than in control infants at days 1 (22.3 +/- 2.3 versus 26.5 +/- 1.1; p = 0.0001), 2 (22.4 +/- 3.3 versus 26.3 +/- 1.6; p = 0.0002), and 5 (24.3 +/- 2.1 versus 26.5 +/- 1.5; p = 0.002). Neurologic scores improved significantly from day 1 to 5 in newborns of smokers (p = 0.05), reaching values closer to control infants. Withdrawal scores were higher in newborns of smokers than in control infants at days 1 (4.5 +/- 1.1 versus 3.2 +/- 1.4; p = 0.05), 2 (4.7 +/- 1.7 versus 3.1 +/- 1.1; p = 0.002), and 4 (4.7 +/- 2.1 versus 2.9 +/- 1.4; p = 0.007). Significant correlations were observed between markers of nicotine exposure and neurologic-and withdrawal scores. We conclude that withdrawal symptoms occur in newborns exposed to heavy maternal smoking during pregnancy.

The purpose of this study was to identify the biochemical and genetic defect in L-2-hydroxyglutaric aciduria, a neurometabolic disorder characterized by the presence of elevated concentrations of L-2-hydroxyglutaric acid in urine, plasma, and cerebrospinal fluid. Evidence is provided for the existence in rat tissues of a FAD-dependent enzyme catalyzing specifically the oxidation of L-2-hydroxyglutarate to alpha-ketoglutarate. This enzyme is mainly expressed in liver and kidney but also at lower levels in heart, brain, and other tissues. Subcellular fractionation indicates that the liver enzyme is present in mitochondria, where it is bound to membranes. Based on this information, a database search led to the identification of a gene encoding a human hypothetical protein homologous to bacterial FAD-dependent malate dehydrogenases and targeted to mitochondria. The gene encoding this protein, present on chromosome 14q22.1, was found to be in a region homozygous in patients with L-2-hydroxyglutaric aciduria from two consanguineous families. Three mutations that replaced a highly conserved residue (Lys-71-Glu and Glu-176-Asp) or removed exon 9 were identified in homozygous state in patients from three distinct families and were found to cosegregate with the disease. It is concluded that L-2-hydroxyglutarate is normally metabolized to alpha-ketoglutarate in mammalian tissues and that L-2-hydroxyglutaric aciduria is caused by mutations in the gene that most likely encodes L-2-hydroxyglutarate dehydrogenase. The pathological findings observed in this metabolic disorder must therefore be due to a toxic effect of L-2-hydroxyglutarate on the central nervous system.

This paper reports that cocaine may induce a lysosomal storage disorder. Indeed, culture of Rat-1 fibroblasts with 250-500 microM cocaine induced after 2-3 days a major accumulation in lysosomes of electron-dense lamellar structures. By subcellular fractionation, this was reflected by a selective decrease of the buoyant density of several lysosomal enzymes, indicating lysosomal lipid overload. Biochemical analysis confirmed an increased cellular content of major phospholipids and sphingomyelin, but not of cholesterol. Cocaine, a membrane-permeant weak base, is concentrated by acidotropic sequestration, because its accumulation was abrogated by the proton ionophore, monensin and the vacuolar ATPase inhibitor, bafilomycin A1. At its estimated lysosomal concentration, cocaine almost completely inhibited phospholipase A1 activity on liposomes. Cell incubation with cocaine, but not with its inactive metabolite, benzoylecgonine, rapidly inactivated acid sphingomyelinase, as reflected by a 10-fold decrease in Vmax with identical Km. Acid sphingomyelinase inactivation was fully prevented by the thiol proteinases inhibitors, leupeptin and E64, indicating that cocaine induces selective sphingomyelinase proteolysis. Upon cocaine removal, acid sphingomyelinase activity was rapidly restored, pointing to its fast turnover. In contrast, the cellular content of several other lysosomal hydrolases was increased up to 2-fold. Together, these data show that acidotropic accumulation of cocaine in lysosomes rapidly inhibits acid phospholipase A1 and inactivates acid sphingomyelinase, which can explain induction of a mixed lysosomal lipidosis.

To better understand outcomes after early brain injuries, studies must address multiple variables including age at injury, the mechanisms and severity of injury, environmental factors (before and after injury) and developmental factors. Animal models are helpful for elucidating these different aspects. First, this paper describes a new model of shaken baby syndrome (SBS) in mice, without impact or hypoxia. Mortality was 27%; 75% of survivors had focal brain lesions consisting of haemorrhagic or cystic lesions of the white matter, corpus callosum and cerebellum. All shaken animals, with and without focal lesions, showed delayed white matter atrophy. White matter damage and atrophy were reduced by pre-treatment with an NMDA receptor antagonist, indicating that excess glutamate release contributed to the pathophysiology of the lesions. Secondly, it discusses data on neuroprotection after early brain injuries; drugs targeting the NMDA receptors cannot be used in clinical practice but indirect neuroprotection strategies including anti-NO, anti-free radicals and trophic factors hold promise for limiting the excitotoxic white matter damage induced by early injury, in particular caused by shaking, during brain development. Thirdly, it describes two experimental models in which SBS outcomes are determined when the trauma is combined with environmental influences, namely medications during the acute phase, most notably anti-epileptic drugs and rearing conditions.

Congenital hyperinsulinism (CHI) is related to two main histological pancreas anomalies: focal adenomatous hyperplasia and diffuse beta-cell hypersecretion. Pharmacological tests to measure acute insulin responses (AIR) to peripheral i.v. injections of glucose, calcium, and tolbutamide have been reported as potential means to distinguish between these histological forms. In patients with defects in ATP-sensitive potassium channels, tolbutamide will fail to induce insulin release in affected portions of the pancreas, whereas calcium gluconate will enhance insulin release through spontaneously active voltage-gated Ca(2+) channels. Consequently, in focal CHI patients, calcium should promote AIRs from the lesion, whereas tolbutamide should act to promote insulin secretion from the healthy region of the pancreas (outside the focal hyperplasia). We therefore studied AIRs to calcium and tolbutamide stimulation tests in 16 children with focal (n = 9) or diffuse (n = 7) CHI before pancreatic surgery. We found hypervariable AIRs to glucose and calcium stimulation in both focal and diffuse CHI patients. AIRs to tolbutamide stimulation were found modest in focal CHI patients, which might account for beta-cell quiescence in the healthy portion of the pancreas of these patients. We conclude that AIRs to calcium and tolbutamide stimulation tests are not sufficient to differentiate the focal from the diffuse CHI patients.

NADH-ubiquinone oxidoreductase or complex 1 deficiency is a frequently diagnosed enzyme defect of the oxidative phosphorylation (OXPHOS) system in humans. However, in many patients, with complex 1 deficiency and clinical symptoms suggestive of mitochondrial disease, often no genetic defect can be found after investigation of the most common mitochondrial DNA (mtDNA) mutations. In this study, 20 patients were selected with a biochemically documented complex 1 defect and no common mtDNA mutation. We used the Denaturing Gradient Get Electrophoresis (DGGE) method with primers encompassing all mitochondrial encoded fragments, to search in a systematic manner for mutations in the mitochondrial genome of complex 1. In our group of patients, we we re able to detect a total of 96 nucleotide changes. We were not able to find any disease causing mutation in the mitochondrial encoded subunits of complex 1. These results suggested that the complex 1 deficiency in this group of patients is most probably caused by a defect in one of the nuclear encoded structural genes of complex 1, or in one of the genes involved in proper assembly of the enzyme. (C) 2004 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.

Conditions associated with arterial ischaemic stroke in children include a great variety of diseases and triggers such as congenital heart malformations, sickle cell disease, infections and vasculopathies, although up to 50% are cryptogenic. An abnormal vascular status can be demonstrated by vascular imaging in up to 80% of children with ischaemic stroke, and case control studies demonstrate an association between ischaemic stroke in children and hereditary prothrombotic risk factors and infections such as Varicella. Conventional risk factors such as hypertension and dyslipidaemia may also play a role, and most children have several potential triggers rather than one single cause. This review focuses on clinical presentations, imaging methods, stroke subtypes, underlying conditions including prothrombotic risk factors, outcome and recurrence. Although data from randomised controlled trials, on which clinical practice might be based, are sparse, therapeutic approaches and future research directions are discussed.

OBJECTIVE: Studies of long-term outcome on nonaccidental head injury (NAHI) in young children have shown severe neurodevelopmental sequelae in most cases. For improving the knowledge of outcome and for identifying prognostic factors, additional clinical and cerebral imaging data are needed. The aim of this study was to describe clinical and imaging features over time and to consider their value for predicting neurodevelopmental outcome. METHODS: A retrospective medical record review was conducted of 23 children with confirmed NAHI, for whom an extended follow-up of 2.5 to 13 years (mean: 6 years) was contemplated. Glasgow Coma Scale scores, severity of retinal hemorrhages, presence of skull fractures, cranial growth deceleration, and sequential neuroimaging data (computed tomography and/or magnetic resonance imaging) were compared with patterns of clinical evolution assessed by the Glasgow Outcome Scale. RESULTS: Clinical outcome showed that 14 (61%) children had severe disabilities, 8 (35%) had moderate disabilities, and 1 (4%) was normal. A low initial Glasgow Coma Scale score, severe retinal hemorrhages, presence of skull fracture, and cranial growth deceleration were significantly associated with poor developmental outcome. Eighteen of the 23 patients had abnormal magnetic resonance imaging scans. This examination disclosed atrophy when performed beyond 15 days of injury. Atrophy seemingly resulted from various brain lesions, namely, contusions, infarcts, and other lesions within the white matter. Presence of intraparenchymal brain lesions within the first 3 months was significantly associated with neurodevelopmental impairment. Severity of motor and cognitive dysfunctions was related to the extent of intraparenchymal lesions. CONCLUSIONS: Early clinical and radiologic findings in NAHI are of prognostic value for neurodevelopmental outcome.

A father and his daughter displayed strictly similar focal brain dysplasia at MR examination, characterized by regional medial posterior laminar sub-cortical grey matter heterotopia. To our knowledge, no family presenting such anomalies has yet been described. LIS1 and DCX gene defects were excluded. Collecting patients with such inherited dysplasia should improve our knowledge of the genetic basis of cortical malformations.

Cerebellar mutism (anarthria) is a well-described complication of posterior fossa tumor resection. It is accompanied by a characteristic behavior including irritability and autistic features. This syndrome is typically reversible within days to months. Underlying pathophysiology is unknown. We describe two children who presented with a similar clinical finding after nonsurgical cerebellar involvement, hemolytic-uremic syndrome in one and cerebellitis in the other. Postmortem pathologic findings in the first patient indicated cerebellar ischemic necrosis. Single-photon emission computed tomography in the second patient revealed diffuse cerebellar hypoperfusion with no supratentorial abnormalities, refuting a phenomenon of diaschisis between cerebellar and frontal connections. These findings confirm that this clinical syndrome may occur in a nonsurgical, nontraumatic context. They are consistent with recent integrative hypotheses explaining cerebellar anarthria. (C) 2003 by Elsevier Science Inc. All rights reserved.

Before the completion of visual development, visual deprivation impairs synaptic elimination in the visual cortex. The purpose of this study was to determine whether the distribution of central benzodiazepine receptor (BZR) is also altered in the visual cortex in subjects with early-onset blindness. Positron emission tomography was carried out with [(15)O]water and [(11)C]flumazenil on six blind subjects and seven sighted controls at rest. We found that the CBF was significantly higher in the visual cortex for the early-onset blind subjects than for the sighted control subjects. However, there was no significant difference in the BZR distribution in the visual cortex for the subject with early-onset blindness than for the sighted control subjects. These results demonstrated that early visual deprivation does not affect the distribution of GABA(A) receptors in the visual cortex with the sensitivity of our measurements. Synaptic elimination may be independent of visual experience in the GABAergic system of the human visual cortex during visual development.

Central nervous system (CNS) dysfunction is a cardinal feature in 22q11 deletion. The underlying CNS abnormalities remain, however, unknown. We report unilateral hemispheric polymicrogyria in a child with 22q11 deletion presenting with hemiplegia and cognitive and behavioural disorders. This observation widens the spectrum of brain malformations associated with this genetic defect. It further suggests a relationship between the 22q11 deletion and disorders of cerebral gyration. It would therefore be interesting to look for neuronal migration disorders in patients with 22q11 deletion presenting neurological signs, and on the other hand to screen for 22q11 deletion in patients with isolated neuronal migration disorders.

This study was undertaken to determine the effect of antiepileptic treatment on a child with attention-deficit-hyperactivity disorder and subclinical electroencephalographic discharges without seizures. We performed a longitudinal follow-up study correlating clinical, neuropsychologic, and electroencephalographic features with antiepileptic drug therapy. The results revealed a temporal relation between subclinical epileptiform discharges and cognitive dysfunction and a significant effectiveness of antiepileptic drugs on attention-deficit-hyperactivity disorder and electroencephalographic discharges. The practice of monitoring antiepileptic treatment limited to seizure control should be revised; cognitive impairments also need to be taken into account even without occurrence of seizure. The classical principle of treating only seizures needs to be reconsidered.

Brain plasticity was investigated in a child with a hemiplegia due to unilateral schizencephaly involving the sensorimotor cortex. This focal lesion led to a dramatic functional reorganization of the undamaged hemisphere, as evidenced by the unusual pattern of fMRI activation during paretic finger movements. The functional relevance of the activation in the undamaged motor cortex was supported by the finding that TMS of this area yielded a response in the paretic hand, indicating that it controls both hands. However, this reorganization was not restricted to the primary motor cortex, but also concerned other structures involved in the control of movements, as shown by the activation of contralesional SMA and thalamus. In contrast, the fMRI activation in the damaged sensorimotor cortex during paretic hand movements appears functionally irrelevant.

Adenylosuccinate lyase (ADSL; also called "adenylosuccinase") catalyzes two steps in the synthesis of purine nucleotides: (1) the conversion of succinylaminoimidazolecarboxamide ribotide into aminoimidazolecarboxamide ribotide and (2) the conversion of adenylosuccinate into adenosine monophosphate. ADSL deficiency, a recessively inherited disorder, causes variable-but most often severe-mental retardation, frequently accompanied by epilepsy and/or autism. It is characterized by the accumulation, in body fluids, of succinylaminoimidazolecarboxamide riboside and succinyladenosine, the dephosphorylated derivatives of the two substrates of the enzyme. Analysis of the ADSL gene of three unrelated patients with ADSL deficiency, in whom one of the ADSL alleles displayed a normal coding sequence, revealed a -49T-->C mutation in the 5' untranslated region of this allele. Measurements of the amount of mRNA transcribed from the latter allele showed that it was reduced to approximately 33% of that transcribed from the alleles mutated in their coding sequence. Further investigations showed that the -49T-->C mutation provokes a reduction to 25% of wild-type control of promoter function, as evaluated by luciferase activity and mRNA level in transfection experiments. The mutation also affects the binding of nuclear respiratory factor 2 (NRF-2), a known activator of transcription, as assessed by gel-shift studies. Our findings indicate that a mutation of a regulatory region of the ADSL gene might be an unusually frequent cause of ADSL deficiency, and they suggest a role for NRF-2 in the gene regulation of the purine biosynthetic pathway.

BACKGROUND/PURPOSE: Permanent hyperinsulinemic hypoglycaemia in infancy (PHHI)I is a severe disease that leads to brain damage. Since 1989, pathologists have identified 2 different forms of the disease: a diffuse form (DiPHHI) and a focal form (FoPHHI). The purpose of this study was to adapt surgical techniques in case of FoPHHI to cure these infants without risk of diabetes. METHODS: All patients with PHHI underwent pancreatic venous sampling (PVS) and elective partial pancreatectomy (EPP). Molecular biology and immunohistochemistry were used to ascertain that FoPHHI was a different disease from DiPHHI. RESULTS: 45 EPPs were performed, guided by PVS and peroperative pathology. The lesions were 17 in the head, 4 in the isthmus, 6 in the body, 15 in the tail of the pancreas. Age at surgery ranged from 25 days to 4 years. Two patients already had been operated on elsewhere, and the focal lesion could be found at second operation. All 45 patients except one, were cured with euglycemia at both fasting and hyperglycaemic tests. Molecular biology has shown a specific anomaly in FoPHHI, which never has been encountered in DiPHHI. CONCLUSIONS: PHHI is not a homogeneous disease. In one third of cases, only a small amount of endocrine pancreas is abnormal, and conservative surgery is mandatory. The pre- and perioperative conditions to point out the focal pancreatic lesion are described.