Mutations and Deletions in PCDH19 Account for Various Familial or Isolated Epilepsies in Females

Mutations in PCDH19, encoding protocadherin 19 on chromosome X, cause familial epilepsy and mental retardation limited to females or Dravet-like syndrome. Heterozygous females are affected while hemizygous males are spared, this unusual mode of inheritance being probably due to a mechanism called cellular interference. To extend the mutational and clinical spectra associated with PCDH19, we screened 150 unrelated patients (113 females) with febrile and afebrile seizures for mutations or rearrangements in the gene. Fifteen novel point mutations were identified in 15 female patients (6 sporadic and 9 familial cases). In addition, qPCR revealed two whole gene deletions and one partial deletion in 3 sporadic female patients. Clinical features were highly variable but included almost constantly a high sensitivity to fever and clusters of brief seizures. Interestingly, cognitive functions were normal in several family members of 2 families: the familial condition in family 1 was suggestive of Generalized Epilepsy with Febrile Seizures Plus (GEFS+) whereas all three affected females had partial cryptogenic epilepsy. These results show that mutations in PCDH19 are a relatively frequent cause of epilepsy in females and should be considered even in absence of family history and/or mental retardation. © 2010 Wiley-Liss, Inc

Atteinte des voies aériennes distales et immunodépression

Introduction. - Innate or acquired immune deficiency may show respiratory manifestations,often characterized by small airway involvement. The purpose of this article is to provide anoverview of small airway disease across the major causes of immune deficiency.Background. - In patients with common variable immune deficiency, recurrent lower airwayinfections may lead to Bronchiolitis and Bronchiectasis. Follicular and/or granulomatous Bron-chiolitis of unknown origin may also occur. Bronchiolitis obliterans is the leading cause of deathafter the first year in patients with lung transplantation. Bronchiolitis obliterans also occurs inpatients with allogeneic haematopoietic stem cell transplantation, especially in the context ofsystemic graft-versus-host disease.Viewpoint and conclusion. - Small airway diseases have different clinical expression and patho-physiology across various causes of immune deficiency. A better understanding of small airwaysdisease pathogenesis in these settings may lead to the development of novel targeted therapies.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Factors associated with poor prognosis of hip arthritis in juvenile idiopathic arthritis: Data from the JIR cohort.

OBJECTIVES Hip involvement remains a predictor of severe juvenile idiopathic arthritis (JIA) course and carries a high risk of disability. This study aims to determine the factors of poor prognosis of hip involvement in patients with JIA and to assess the treatment response. METHODS This is a multicenter observational cohort study. Patients were selected from the JIR Cohort database. Hip involvement was defined as clinically suspected and confirmed by an imaging tool. Follow-up data were collected during 5 years. RESULTS Among the 2223 patients with JIA, 341(15%) patients had hip arthritis. Male gender, enthesitis-related arthritis, and North African origin were factors associated with hip arthritis. Hip inflammation was associated with disease activity parameters during the first year, particularly Physician Global Assessment, joint count, and inflammatory marks. Structural hip progression was associated with early onset of the disease, a longer time to diagnosis, geographic origin, and JIA subtypes. Anti-TNF therapy was found to be the only treatment able to effectively reduce structural damage progression. CONCLUSION The early onset diagnostic delay, origin, and systemic subtype of JIA predict a poor prognosis of hip arthritis in children with JIA. The use of anti-TNF was associated with a better structural prognosis

Movement disorders in patients with alternating hemiplegia: "Soft" and "stiff" at the same time

International audienceAIM: To assess non-paroxysmal movement disorders in ATP1A3 mutation-positive patients with alternating hemiplegia of childhood (AHC).METHODS: Twenty-eight patients underwent neurological examination with particular focus on movement phenomenology by a specialist in movement disorders. Video recordings were reviewed by another movement disorders specialist and data were correlated to patients’ characteristics.RESULTS: Ten patients were diagnosed with chorea, 16 with dystonia (nonparoxysmal), 4 with myoclonus, and 2 with ataxia. Nine patients had more than one movement disorder and 8 patients had none. The degree of movement disorder was moderate to severe in 12/28 patients. At inclusion, dystonic patients (n=16) were older (p=0.007) than nondystonic patients. Moreover, patients (n=18) with dystonia or chorea, or both, had earlier disease onset (p=0.042) and more severe neurological impairment (p=0.012), but this did not correlate with genotype. All patients presented with hypotonia, which was characterized as moderate or severe in 16/28. Patients with dystonia or chorea (n=18) had more pronounced hypotonia (p=0.011). Bradykinesia (n=16) was associated with an early age at assessment (p<0.01). Significant dysarthria was diagnosed in 11/25 cases. A history of acute neurological deterioration and further regression of motor function, typically after a stressful event, was reported in 7 patients.INTERPRETATION: Despite the relatively limited number of patients and the cross-sectional nature of the study, this detailed categorisation of movement disorders in patients with AHC offers valuable insight into their precise characterization. Further longitudinal studies on this topic are needed

Natural disease history and characterisation of SUMF1 molecular defects in ten unrelated patients with multiple sulfatase deficiency

International audienceBackground: Multiple sulfatase deficiency is a rare inherited metabolic disorder caused by mutations in the SUMF1 gene. The disease remains poorly known, often leading to a late diagnosis. This study aimed to provide improved knowledge of the disease, through complete clinical, biochemical, and molecular descriptions of a cohort of unrelated patients. The main objective was to identify prognostic markers, both phenotypic and genotypic, to accelerate the diagnosis and improve patient care.Methods: The phenotypes of ten unrelated patients were fully documented at the clinical and biochemical levels. The long-term follow-up of each patient allowed correlations of the phenotypes to the disease outcomes. Each patient’s molecular defects were also identified. Site-directed mutagenesis was used to individually express the mutants and assess their stability. Characterisation of the protein mutants was completed by in silico analyses based on sequence comparisons and structural models.Results: The most severe cases were characterised by the presence of non-neurological symptoms as well as the occurrence of psychomotor regression before 2 years of age. Nine novel SUMF1 mutations were identified. Clinically severe forms were often associated with SUMF1 mutations that strongly affected the protein stability and/or catalytic function as predicted from in silico and western blot analyses.Conclusions: This detailed clinical description and follow-up of a cohort of patients, together with the molecular characterisation of their underlying defects, contribute to improved knowledge of multiple sulfatase deficiency. Predictors of a bad prognosis were the presence of several non-neurological symptoms and the onset of psychomotor regression before 2 years of age. No strict correlation existed between in vitro residual sulfatase activity and disease severity. Genotype–phenotype correlations related to previously reported mutants were strengthened. These and previous observations allow not only improved prediction of the disease outcome but also provision of appropriate care for patients, in the expectation of specific treatment developme

Small airways diseases, excluding asthma and COPD: an overview.

This review is the summary of a workshop on small airways disease, which took place in Porquerolles, France in November 2011. The purpose of this workshop was to review the evidence on small airways (bronchiolar) involvement under various pathophysiological circumstances, excluding asthma and chronic obstructive pulmonary disease. Histopathological patterns associated with small airways disease were reviewed, including cellular and obliterative bronchiolitis. Many pathophysiological conditions have been associated with small airways disease including airway infections, connective tissue diseases and inflammatory bowel diseases, bone marrow and lung transplantation, common variable immunodeficiency disorders, diffuse panbronchiolitis, and diseases related to environmental exposures to pollutants, allergens and drugs. Pathogenesis, clinical presentation, a computed tomography scan and pulmonary function test findings are reviewed, and therapeutic options are described with the objective of providing an integrative approach to these disorders.CongressesSCOPUS: re.jinfo:eu-repo/semantics/publishe

Asthma outcomes: Exacerbations

BACKGROUND: The goals of asthma treatment include preventing recurrent exacerbations. Yet there is no consensus about the terminology for describing or defining “exacerbation,” or about how to characterize an episode’s severity. OBJECTIVE: National Institutes of Health (NIH) institutes and other federal agencies convened an expert group to propose how asthma exacerbation should be assessed as a standardized asthma outcome in future asthma clinical research studies. METHODS: We utilized comprehensive literature reviews and expert opinion to compile a list of asthma exacerbation outcomes, and classified them as either core (required in future studies), supplemental (used according to study aims and standardized), or emerging (requiring validation and standardization). This work was discussed at an NIH-organized workshop in March 2010 and finalized in September 2011. RESULTS: No dominant definition of “exacerbation” was found. The most widely used definitions included 3 components, all related to treatment, rather than symptoms: (1) systemic use of corticosteroids, (2) asthma-specific emergency department visits or hospitalization, and (3) use of short-acting β-agonists (SABAs) as quick-relief (sometimes referred to as “rescue” or “reliever”) medications. CONCLUSIONS: The working group participants propose that the definition of “asthma exacerbation” be “a worsening of asthma requiring the use of systemic corticosteroids to prevent a serious outcome.” As core outcomes, they propose inclusion and separate reporting of several essential variables of an exacerbation. Further, they propose the development of a standardized, component-based definition of “exacerbation” with clear thresholds of severity for each component