Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with Dopa-responsive dystonia

Dopa-responsive dystonia is a childhood-onset dystonic disorder, characterized by a dramatic response to low dose of l-Dopa. Dopa-responsive dystonia is mostly caused by autosomal dominant mutations in the GCH1 gene (GTP cyclohydrolase1) and more rarely by autosomal recessive mutations in the TH (tyrosine hydroxylase) or SPR (sepiapterin reductase) genes. In addition, mutations in the PARK2 gene (parkin) which causes autosomal recessive juvenile parkinsonism may present as Dopa-responsive dystonia. In order to evaluate the relative frequency of the mutations in these genes, but also in the genes involved in the biosynthesis and recycling of BH4, and to evaluate the associated clinical spectrum, we have studied a large series of index patients (n = 64) with Dopa-responsive dystonia, in whom dystonia improved by at least 50% after l-Dopa treatment. Fifty seven of these patients were classified as pure Dopa-responsive dystonia and seven as Dopa-responsive dystonia-plus syndromes. All patients were screened for point mutations and large rearrangements in the GCH1 gene, followed by sequencing of the TH and SPR genes, then PTS (pyruvoyl tetrahydropterin synthase), PCBD (pterin-4a-carbinolamine dehydratase), QDPR (dihydropteridin reductase) and PARK2 (parkin) genes. We identified 34 different heterozygous point mutations in 40 patients, and six different large deletions in seven patients in the GCH1 gene. Except for one patient with mental retardation and a large deletion of 2.3 Mb encompassing 10 genes, all patients had stereotyped clinical features, characterized by pure Dopa-responsive dystonia with onset in the lower limbs and an excellent response to low doses of l-Dopa. Dystonia started in the first decade of life in 40 patients (85%) and before the age of 1 year in one patient (2.2%). Three of the 17 negative GCH1 patients had mutations in the TH gene, two in the SPR gene and one in the PARK2 gene. No mutations in the three genes involved in the biosynthesis and recycling of BH4 were identified. The clinical presentations of patients with mutations in TH and SPR genes were strikingly more complex, characterized by mental retardation, oculogyric crises and parkinsonism and they were all classified as Dopa-responsive dystonia-plus syndromes. Patient with mutation in the PARK2 gene had Dopa-responsive dystonia with a good improvement with l-Dopa, similar to Dopa-responsive dystonia secondary to GCH1 mutations. Although the yield of mutations exceeds 80% in pure Dopa-responsive dystonia and Dopa-responsive dystonia-plus syndromes groups, the genes involved are clearly different: GCH1 in the former and TH and SPR in the late

Céphalées et calcifications des noyaux gris centraux (à propos de 4 observations)

PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Lésion malaciques de la substance blanche chez le nouveau-né à terme

Les lésions malaciques de la substance blanche constituent une entité bien connue chez le prématuré, sous le terme générique de leucomalacies périventriculaires, et dont l'étiopathogénie reste largement obscure. Chez le nouveau né à terme, en revanche, cette pathologie, certainement rare, n'a fait l'objet que de rapports ponctuels. L'objectif de ce travail rétrospectif, mené dans un centre unique sur une période de 11 années, était d'une part de recenser l'éventail des lésions malaciques de la substance blanche chez l 'enfant né à terme, d'autre part de confronter les leucomalacies périventriculaires d'aspect classique observées chez lui, aux connaissances générales sur cette pathologie. Les groupes ainsi distingués et les conclusions qu'ils suggèrent sont multiples. Le groupe des leucomalacies périventriculaires d'aspect classique (10 dossiers). Ces patients n'ont pour la plupart pas de pathologie périnatale patente, avec cependant chez quelques uns des évènements anténatals mineurs. L'ensemble évoque la survenue anténatale d'une pathologie conduisant aux leucomalacies mais permettant à la grossesse de suivre son cours. Chez une minorité, la présence de signes patents de souffrance fœtale antérieure. Le devenir de ces nouveaux nés, où les troubles résiduels excèdent fréquemment la simple diplégie spastique, suggère que des lésions corticales concomitantes occupent une place importante. Les lésions de la substance blanche dans un contexte d'encéphalopathie ischémique-anoxique patente : Ces lésions se distinguent des leucomalacies périventriculaires classiques, par leur volume, leur topographie débordant les zones juxtaventriculaires, et surtout leur association habituelle à des lésions cortico-sous-corticales ou de la substance grise centrale...PARIS7-Villemin (751102101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Dilatations primitives des espaces de Virchow Robin chez l'enfant (à propos de 10 observations)

Les espaces périvasculaires sont des espaces liquidiens qui entourent les vaisseaux perforants à leur entrée dans le parenchyme cérébral. L imagerie par résonance magnétique permet désormais la détection des EPV et de leurs caractères pathologiques, en fonction de leur distribution, de leur morphologie et de leur signal. Les EPV peuvent être dilatés soit dans le cadre de pathologies identifiables, séquellaires ou évolutives, soit de façon constitutionnelle. Nous rapportons dix dossiers d enfants âgés entre 18 mois et 16 ans porteurs de dilatation des EPV, où les données cliniques, biologiques et remnographiques permettent d exclure une pathologie secondaire. Le contexte clinique amenant à découvrir une dilatation constitutionnelle des EPV étant très variable, il semble difficile d établir une entité clinique univoque à partir de ce seul critère. Le pronostic à court et moyen terme semble plutôt favorable. Des cas familiaux sont possibles. Nous proposons une conduite à tenir devant la découverte d EPV élargis en pédiatrie. Lorsque le contexte clinique est clairement pathologique, il semble indispensable d éliminer les dilatations secondaires à des pathologies caractérisées, d assurer une surveillance clinique et remnographique à moyen et long terme, de dépister tout autre membre de la famille présentant un trouble du développement mental, même mineur.PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Acute transverse myelitis in children: clinical course and prognostic factors.

The objective of this study was to describe the clinical course of acute transverse myelitis in children, to identify prognostic factors, and to compare our findings with published data Twenty-four children, aged 2 to 14 years and admitted with a diagnosis of acute transverse myelitis, were studied. Clinical features and results of investigations were collected at admission and during the course of the disease. Motor, sphincter, and global outcomes were compared with those in the main adult and pediatric series. During the initial phase, the most common presenting symptoms were pain (88%) and fever (58%). Motor loss preceded sphincter dysfunction in two thirds of patients and became bilateral in half of the patients. When maximal deficit was achieved (plateau), the patients presented a combination of sensory, motor, and sphincter dysfunctions without radicular involvement The motor loss consistently involved the lower limbs but was inconsistent and moderate in the upper limbs. The mean duration of the plateau was 1 week. The recovery phase was characterized by a progressive improvement of all deficits. Sphincter dysfunction improved more slowly than did the other deficits. A full recovery was achieved by 31% of the patients; minimal sequelae were present in 25% and mild to severe sequelae in 44%. An unfavorable outcome was associated with complete paraplegia (P = .03) and/or a time to maximal deficit shorter than 24 hours (P = .005). A favorable outcome was associated with a plateau shorter than 8 days (P = .03), the presence of supraspinal symptoms (P = .01), and a time to independent walking shorter than 1 month (P = .01). The course of acute transverse myelitis in children proceeds through three stages, an initial phase, a plateau, and a recovery phase, each characterized by specific clinical features. The global outcome was favorable in 56% of patients. Several prognostic factors were identified

p13SUC1 and the WW domain of PIN1 bind to the same phosphothreonine-proline epitope

The WW domain of the human PIN1 and p13SUC1, a subunit of the cyclin-dependent kinase complex, were previously shown to be involved in the regulation of the cyclin-dependent kinase complex activity at the entry into mitosis, by an unresolved molecular mechanism. We report here experimental evidence for the direct interaction of p13(SUC1) With a model CDC25 peptide, dependent on the phosphorylation state of its threonine, Chemical shift perturbation of backbone H-1(N), N-15, and C-13 alpha, resonances during MMR titration experiments allows accurate identification of the binding site, primarily localized around the anion-binding site, occupied in the crystal structure of the homologous p9(CKSHs2) by a sulfate molecule. The epitope recognized by p13(SUC1) includes the proline at position +1 of the phosphothreonine, as was shown by the decrease in affinity for a mutated CDC25 phosphopeptide, containing an alanine/ proline substitution. No direct interaction between the PIN1 WW domain or its catalytic proline cis/transisomerase domain and p13(SUC1) was detected, but our study showed that in vitro the WW domain of the human PIN1 antagonizes the binding of the p13(SUC1) to the CDC25 phosphopeptide, by binding to the same phosphoepitope. We thus propose that the full cyclin-dependent kinase complex stimulates the phosphorylation of CDC25 through binding of its p13(SUC1) module to the phosphoepitope of the substrate and that the reported WW antagonism of p13(SUC1)-stimulated CDC25 phosphorylation is caused by competitive binding of both protein modules to the same phosphoepitope