RESUMEN
MECP2 duplication syndrome (MDS) is an X-linked neurodevelopmental disorder characterized by a severe to profound intellectual disability, early onset hypotonia and diverse psycho-motor and behavioural features. To date, fewer than 200 cases have been published. We report the clinical and molecular characterization of a Spanish MDS cohort that included 19 boys and 2 girls. Clinical suspicions were confirmed by array comparative genomic hybridization and multiplex ligation-dependent probe amplification (MLPA). Using, a custom in-house MLPA assay, we performed a thorough study of the minimal duplicated region, from which we concluded a complete duplication of both MECP2 and IRAK1 was necessary for a correct MDS diagnosis, as patients with partial MECP2 duplications lacked some typical clinical traits present in other MDS patients. In addition, the duplication location may be related to phenotypic severity. This observation may provide a new approach for genotype-phenotype correlations, and thus more personalized genetic counselling.
Asunto(s)
Discapacidades del Desarrollo/genética , Discapacidad Intelectual/genética , Quinasas Asociadas a Receptores de Interleucina-1/genética , Discapacidad Intelectual Ligada al Cromosoma X/genética , Proteína 2 de Unión a Metil-CpG/genética , Adolescente , Adulto , Niño , Preescolar , Cromosomas Humanos X/genética , Hibridación Genómica Comparativa , Discapacidades del Desarrollo/patología , Femenino , Estudios de Asociación Genética , Humanos , Lactante , Discapacidad Intelectual/patología , Masculino , Discapacidad Intelectual Ligada al Cromosoma X/patología , Hipotonía Muscular/genética , Hipotonía Muscular/patología , Linaje , Medicina de Precisión , Adulto JovenAsunto(s)
Paraplejía Espástica Hereditaria , Adolescente , Toxinas Botulínicas Tipo A/uso terapéutico , Muletas , Progresión de la Enfermedad , Disnea/etiología , Subunidades gamma de la Proteína de Unión al GTP/genética , Heterogeneidad Genética , Heterocigoto , Humanos , Imagen por Resonancia Magnética , Masculino , Examen Neurológico , Penetrancia , Reflejo Anormal , Paraplejía Espástica Hereditaria/diagnóstico , Paraplejía Espástica Hereditaria/genética , Siringomielia/etiología , Disfunción de los Pliegues Vocales/etiologíaAsunto(s)
Síndrome de Cockayne/genética , Codón sin Sentido , Enzimas Reparadoras del ADN/genética , Factores de Transcripción/genética , Encéfalo/patología , Parálisis Cerebral/diagnóstico , Síndrome de Cockayne/diagnóstico , Síndrome de Cockayne/epidemiología , Síndrome de Cockayne/patología , Codón/genética , Errores Diagnósticos , Progresión de la Enfermedad , República Dominicana/etnología , Estudios de Seguimiento , Homocigoto , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Fenotipo , Análisis de Secuencia de ADNAsunto(s)
Cefalea/etiología , Linfocitosis/líquido cefalorraquídeo , Linfocitosis/etiología , Enfermedades del Sistema Nervioso/líquido cefalorraquídeo , Enfermedades del Sistema Nervioso/etiología , Papiledema/líquido cefalorraquídeo , Papiledema/complicaciones , Adolescente , Femenino , Cefalea/líquido cefalorraquídeo , Humanos , Enfermedades del Sistema Nervioso/complicaciones , SíndromeRESUMEN
OBJECTIVE: Eosinophilic myositis (EM) constitutes a rare pathological entity characterized by eosinophilic infiltration of skeletal muscles, usually associated with parasite infections, systemic disorders, or the intake of drugs or L-tryptophan. The exclusion of such causes defines the spectrum of idiopathic EM. Based on a protein analysis performed in one affected patient, we identified the gene encoding calpain-3, CAPN3, as a candidate for a subset of idiopathic EM. METHODS: We screened CAPN3 for mutations using DHPLC and direct sequencing in six unrelated patients, recruited for EM diagnosed after histological examination of muscle biopsy samples, without any identified causative factor. RESULTS: We identified CAPN3 mutations in the six unrelated patients originally diagnosed with idiopathic EM. INTERPRETATION: Mutations in CAPN3 can cause EM. Thus, a subset of idiopathic EM is genetically determined, with an autosomal recessive mode of inheritance. Patients presented with a triad that appears to be indicative of CAPN3 mutations: (1) EM in the first decade, (2) elevated serum creatine phosphokinase levels (isolated or with little corresponding weakness), and (3) inconstant peripheral hypereosinophilia. However, that EM represents a distinct phenotype associated to CAPN3 mutations or, rather, an early histopathological picture of LGMD2A must be further evaluated. Our findings should be of interest toward further investigating the role of calpain-3 in skeletal muscle. Furthermore, patients with idiopathic EM should undergo calpain-3 protein analysis and be considered for subsequent molecular analysis of the CAPN3 gene.