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Neurology ; 92(8): e852-e865, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30659139


OBJECTIVE: To genotypically and phenotypically characterize a large pediatric myotonic dystrophy type 1 (DM1) cohort to provide a solid frame of data for future evidence-based health management. METHODS: Among the 2,697 patients with genetically confirmed DM1 included in the French DM-Scope registry, children were enrolled between January 2010 and February 2016 from 24 centers. Comprehensive cross-sectional analysis of most relevant qualitative and quantitative variables was performed. RESULTS: We studied 314 children (52% females, with 55% congenital, 31% infantile, 14% juvenile form). The age at inclusion was inversely correlated with the CTG repeat length. The paternal transmission rate was higher than expected, especially in the congenital form (13%). A continuum of highly prevalent neurodevelopmental alterations was observed, including cognitive slowing (83%), attention deficit (64%), written language (64%), and spoken language (63%) disorders. Five percent exhibited autism spectrum disorders. Overall, musculoskeletal impairment was mild. Despite low prevalence, cardiorespiratory impairment could be life-threatening, and frequently occurred early in the first decade (25.9%). Gastrointestinal symptoms (27%) and cataracts (7%) were more frequent than expected, while endocrine or metabolic disorders were scarce. CONCLUSIONS: The pedDM-Scope study details the main genotype and phenotype characteristics of the 3 DM1 pediatric subgroups. It highlights striking profiles that could be useful in health care management (including transition into adulthood) and health policy planning.

Nature ; 558(7711): 540-546, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29899452


CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic disorder that results from somatic, mosaic gain-of-function mutations of the PIK3CA gene, and belongs to the spectrum of PIK3CA-related overgrowth syndromes (PROS). This rare condition has no specific treatment and a poor survival rate. Here, we describe a postnatal mouse model of PROS/CLOVES that partially recapitulates the human disease, and demonstrate the efficacy of BYL719, an inhibitor of PIK3CA, in preventing and improving organ dysfunction. On the basis of these results, we used BYL719 to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated with any substantial side effects. In conclusion, this study provides the first direct evidence supporting PIK3CA inhibition as a promising therapeutic strategy in patients with PROS.

Eur J Med Genet ; 60(11): 583-588, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28811188


Unlike the 1p36 microdeletion syndrome, which has been extensively described, 1p36 microduplications have rarely been reported. We describe a three years old boy presenting with a severe global developmental delay and a few dysmorphic features. Cytogenetic analyses revealed a maternally inherited 3.35 Mb microduplication of chromosomal band 1p36.3. The maternal grandfather is also carrier of the same chromosomal rearrangement. Interestingly, the duplicated 1p36.3 segment was found to be localized at the telomeric end of the long arms of a chromosome 9, probably deriving from a 1p36.3-9qter non-reciprocal translocation. This particular type of chromosomal translocation has rarely been reported, and its mechanism is unclear. The phenotypical features associated with 1p36.3 microduplication vary due to the non-recurrent breakpoints of the rearrangements in this particular region. However when compiling the few described cases the phenotypical spectrum seems to include mainly developmental delay, mild facial dysmorphism, and neurological, cardiac and skeletal anomalies. The description of new patients carrying a 1p36.3 duplication like ours will lead to further delineation of the phenotypical spectrum and may help to find critical regions and causative genes implicated in the phenotype.

Transtornos Cromossômicos/genética , Duplicação Cromossômica , Cromossomos Humanos Par 1/genética , Translocação Genética , Adulto , Criança , Pontos de Quebra do Cromossomo , Transtornos Cromossômicos/diagnóstico , Feminino , Humanos , Lactente , Masculino , Linhagem , Fenótipo , Telômero/genética