Leuret O.,French Institute of Health and Medical Research |
Leuret O.,Reseau Maladies Metaboliques Hopitaux Universitaires du Grand Ouest |
Barth M.,Angers University Hospital Center |
Barth M.,Reseau Maladies Metaboliques Hopitaux Universitaires du Grand Ouest |
And 12 more authors.
Journal of Inherited Metabolic Disease | Year: 2012
Background: Sapropterin dihydrochloride, an EMEA-approved synthetic formulation of BH4, has been available in Europe since 2009 for PKU patients older than 4 years, but its use with younger children is allowed in France based on an expert recommendation. We report the cases of 15 patients treated under the age of 4 years and demonstrate the safety and efficacy of this treatment for patients in this age group. Patients and method: We report the use of BH4 in 15 PKU patients treated before the age of 4 years. Results: Fifteen patients were enrolled in this retrospective study. Mean phenylalaninemia at diagnosis was 542±164 μM and all patients had mild PKU (maximal phenylalaninemia: 600-1200 μM). BH4 responsiveness was assessed using a 24-hour BH4 loading test (20 mg/kg), performed during the neonatal period (n = 11) or before 18 months of age (n = 4). During the test, these patients exhibited an 80±12% decrease in phenylalaninemia. Long-term BH4 therapy was initiated during the neonatal period (n = 7) or at the age of 13±12 months (n = 8). The median duration of treatment was 23 months [min 7; max 80]. BH4 therapy drastically improved dietary phenylalanine tolerance (456±181 vs 1683±627 mg/day, p < 0.0001) and allowed a phenylalanine-free amino acid mixture to be discontinued or not introduced in 14 patients. Additionally, in the eight patients treated after a few months of diet therapy, BH4 treatment significantly decreased mean phenylalaninemia (352±85 vs 254±64μM, p < 0.05), raised the percentage of phenylalaninemia tests within therapeutic targets [120-300 μM] (35±25 vs 64±16%, p < 0.05), and reduced phenylalaninemia variance (130±21 vs 93±27μM, p < 0.05). No side effects were reported. Conclusion: BH4-therapy is efficient and safe before the age of 4 years in mild PKU, BH4-responsive patients. © 2012 SSIEM and Springer.
Raymond L.,Laboratoire Of Biochimie Et Genetique Moleculaire |
Diebold B.,Laboratoire Of Biochimie Et Genetique Moleculaire |
Leroux C.,Laboratoire Of Biochimie Et Genetique Moleculaire |
Maurey H.,Neurologie pediatrie |
And 13 more authors.
Gene | Year: 2013
Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) have been predominantly described in epileptic encephalopathies of female, including infantile spasms with Rett-like features. Up to now, detection of mutations in this gene was made by laborious, expensive and/or time consuming methods. Here, we decided to validate high-resolution melting analysis (HRMA) for mutation scanning of the CDKL5 gene. Firstly, using a large DNA bank consisting to 34 samples carrying different mutations and polymorphisms, we validated our analytical conditions to analyse the different exons and flanking intronic sequences of the CDKL5 gene by HRMA. Secondly, we screened CDKL5 by both HRMA and denaturing high performance liquid chromatography (dHPLC) in a cohort of 135 patients with early-onset seizures. Our results showed that point mutations and small insertions and deletions can be reliably detected by HRMA. Compared to dHPLC, HRMA profiles are more discriminated, thereby decreasing unnecessary sequencing. In this study, we identified eleven novel sequence variations including four pathogenic mutations (2.96% prevalence). HRMA appears cost-effective, easy to set up, highly sensitive, non-toxic and rapid for mutation screening, ideally suited for large genes with heterogeneous mutations located along the whole coding sequence, such as the CDKL5 gene. © 2012 Elsevier B.V.
Mortaud S.,University of Orleans |
Nicolas L.,Hoffmann-La Roche |
Pinoteau W.,Genetique |
Tordjman S.,CNRS Laboratory of Physiology of Perception |
And 3 more authors.
Behavior Genetics | Year: 2010
STS is the single enzyme that converts all steroid sulfates into their free steroid forms. Initiation of attack behavior against conspecific male mice appeared to be linked to Sts. Here we have confirmed the role of Sts through an association study with attack behavior. Previous studies indicated a positive correlation between the initiation of attack behavior and liver STS concentration levels in male mice, but this finding was not compatible with established knowledge of STS mechanisms. High STS concentrations induce low concentrations of sulfated steroids. Sulfated and un-sulfated steroids are GABAA receptor agonists and NMDA receptor positive allosteric modulators. This synaptic pattern of functioning can generate attack behavior and we have confirmed here that an injection of the sulfated steroid dehydroepiandrosterone sulfate (DHEA-S) increases attack behavior. To solve the paradox, we measured the transcription activity of the genes underlying the pathways involved in the hydrolysis of sulfated steroids and leading to the formation of un-conjugated steroids in the mouse brain. We observed that the genes monitoring the steroid biosynthesis pathways exhibited a transcription pattern resulting in an increased sulfotransferase activity in the attacking males that could counterbalance the de-sulfating activity of Sts in the attacking mice. © 2010 Springer Science+Business Media, LLC.
Endo T.,Tokyo Metropolitan University |
Manya H.,Tokyo Metropolitan University |
Seta N.,Laboratoire Of Biochimie Metabolique Et Cellulaire |
Methods in Enzymology | Year: 2010
α-Dystroglycanopathies are a group of rare inherited neuromuscular disorders characterized by reduced glycosylation of α-dystroglycan (α-DG). Mutations in six genes (POMT1, POMT2, POMGNT1, FKTN, FKRP, and LARGE) have been identified in patients with α-dystroglycanopathies. Due to an extremely broad clinical spectrum and relatively poor phenotype-genotype correlation, diagnosis of α-dystroglycanopathies is difficult and requires searching for mutations gene by gene. At present, of the six proteins involved on α-dystroglycanopathies, the function of the gene products is only known for POMT1, POMT2, and POMGnT1, all responsible for the O-mannosylglycan biosynthesis. This chapter describes the assay protocols to diagnose patients with α-dystroglycanopathy by measuring glycosyltransferase activity. © 2010 Elsevier Inc.
Curie A.,French National Center for Scientific Research |
Curie A.,University of Lyon |
Curie A.,Massachusetts General Hospital |
Nazir T.,French National Center for Scientific Research |
And 40 more authors.
Orphanet Journal of Rare Diseases | Year: 2014
Background: The c.429-452dup24 of the ARX gene is a rare genetic anomaly, leading to X-Linked Intellectual Disability without brain malformation. While in certain cases c.429-452dup24 has been associated with specific clinical patterns such as Partington syndrome, the consequence of this mutation has been also often classified as "non-specific Intellectual Disability". The present work aims at a more precise description of the clinical features linked to the c.429-452dup24 mutation. Methods. We clinically reviewed all affected patients identified in France over a five-year period, i.e. 27 patients from 12 different families. Detailed cognitive, behavioural, and motor evaluation, as well as standardized videotaped assessments of oro-lingual and gestural praxis, were performed. In a sub-group of 13 ARX patients, kinematic and MRI studies were further accomplished to better characterize the motor impairment prevalent in the ARX patients group. To ensure that data were specific to the ARX gene mutation and did not result from low-cognitive functioning per se, a group of 27 age- and IQ-matched Down syndrome patients served as control. Results: Neuropsychological and motor assessment indicated that the c.429-452dup24 mutation constitutes a recognizable clinical syndrome: ARX patients exhibiting Intellectual Disability, without primary motor impairment, but with a very specific upper limb distal motor apraxia associated with a pathognomonic hand-grip. Patients affected with the so-called Partington syndrome, which involves major hand dystonia and orolingual apraxia, exhibit the most severe symptoms of the disorder. The particular "reach and grip" impairment which was observed in all ARX patients, but not in Down syndrome patients, was further characterized by the kinematic data: (i) loss of preference for the index finger when gripping an object, (ii) major impairment of fourth finger deftness, and (iii) a lack of pronation movements. This lack of distal movement coordination exhibited by ARX patients is associated with the loss of independent digital dexterity and is similar to the distortion of individual finger movements and posture observed in Limb Kinetic Apraxia. Conclusion: These findings suggest that the ARX c.429-452dup24 mutation may be a developmental model for Limb Kinetic Apraxia. © 2014 Curie et al.; licensee BioMed Central Ltd.