RESUMEN
BACKGROUND: Haploinsufficiency of the gene encoding for transcription factor 4 (TCF4) was recently identified as the underlying cause of Pitt-Hopkins syndrome (PTHS), an underdiagnosed mental-retardation syndrome characterised by a distinct facial gestalt, breathing anomalies and severe mental retardation. METHODS: TCF4 mutational analysis was performed in 117 patients with PTHS-like features. RESULTS: In total, 16 novel mutations were identified. All of these proven patients were severely mentally retarded and showed a distinct facial gestalt. In addition, 56% had breathing anomalies, 56% had microcephaly, 38% had seizures and 44% had MRI anomalies. CONCLUSION: This study provides further evidence of the mutational and clinical spectrum of PTHS and confirms its important role in the differential diagnosis of severe mental retardation.
Asunto(s)
Apnea , Análisis Mutacional de ADN , Proteínas de Unión al ADN/genética , Cara/anomalías , Hiperventilación , Discapacidad Intelectual/genética , Factores de Transcripción/genética , Adolescente , Apnea/diagnóstico , Apnea/genética , Apnea/patología , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice , Niño , Preescolar , Cara/patología , Femenino , Genotipo , Humanos , Hiperventilación/diagnóstico , Hiperventilación/genética , Hiperventilación/patología , Lactante , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/patología , Masculino , Microcefalia , Fenotipo , Síndrome , Factor de Transcripción 4 , Adulto JovenRESUMEN
The field of translational research in Duchenne muscular dystrophy (DMD) has been transformed in the last decade by a number of therapeutic targets, mostly studied in ambulant patients. A paucity of studies focus on measures that capture the non-ambulant stage of the disease, and the transition between the ambulant and non-ambulant phase. In this prospective natural history study, we report the results of a comprehensive assessment of respiratory, upper limb function and upper limb muscle strength in a group of 89 DMD boys followed in 3 European countries, 81 receiving corticosteroids, spanning a wide age range (5-18 years) and functional abilities, from ambulant (nâ¯=â¯60) to non-ambulant (nâ¯=â¯29). Respiratory decline could be detected in the early ambulatory phase using Peak Expiratory Flow percentage predicted (PEF%), despite glucocorticoid use (mean annual decline: 4.08, 95% CI [-7.44,-0.72], pâ¯=â¯0.02 in ambulant; 4.81, 95% CI [-6.79,-2.82], p < 0.001 in non-ambulant). FVC% captured disease progression in non-ambulant DMD subjects, with an annual loss of 5.47% (95% CI [-6.48,-4.45], p < 0.001). Upper limb function measured with the Performance of Upper Limb (PUL 1.2) showed an annual loss of 4.13 points (95% CI [-4.79,3.47], p < 0.001) in the non-ambulant cohort. Measures of upper limb strength (MyoGrip and MyoPinch) showed a continuous decline independent of the ambulatory status, when reported as percentage predicted (grip force -5.51%, 95% CI [-6.54,-4.48], p < 0.001 in ambulant and a slower decline -2.86%; 95% CI -3.29,-2.43, p < 0.001, in non-ambulant; pinch force: -2.66%, 95% CI [-3.82,-1.51], p < 0.001 in ambulant and -2.23%, 95% CI [-2.92,-1.53], p < 0.001 in non-ambulant). Furthermore, we also explored the novel concept of a composite endpoint by combining respiratory, upper limb function and force domains: we were able to identify clear clinical progression in patients in whom an isolated measurement of only one of these domains failed to appreciate the yearly change. Our study contributes to the field of natural history of DMD, linking the ambulant and non-ambulant phases of the disease, and suggests that composite scores should be explored further.
Asunto(s)
Limitación de la Movilidad , Actividad Motora/fisiología , Fuerza Muscular/fisiología , Músculo Esquelético/fisiopatología , Distrofia Muscular de Duchenne/fisiopatología , Evaluación de Resultado en la Atención de Salud , Trastornos Respiratorios/fisiopatología , Extremidad Superior/fisiopatología , Adolescente , Niño , Preescolar , Europa (Continente) , Humanos , Masculino , Distrofia Muscular de Duchenne/complicaciones , Estudios Prospectivos , Respiración , Trastornos Respiratorios/etiología , Pruebas de Función RespiratoriaRESUMEN
Cognitive and behavioral difficulties occur in approximately a third of patients with Duchenne muscular dystrophy. The aim of our study was to assess the prevalence of epilepsy in a cohort of 222 DMD patients. Epileptic seizures were found in 14 of the 222 DMD patients (6.3%). The age of onset ranged from 3 months to 16 years (mean 7.8). Seizures were more often focal epilepsy (n=6), generalized tonic-clonic seizures (n=4) or absences (n=4). They were present in 12 of the 149 boys with normal IQ (8.1%) and in two of the 73 with mental retardation (2.7%). In two cases the parents did not report any past or present history of seizures but only 'staring episodes' interpreted as a sign of 'poor attention'. In both patients EEG showed the typical pattern observed in childhood absence epilepsy. Our results suggest that the prevalence of epilepsy in our study (6.3%) is higher than in the general pediatric population (0.5-1%). The risk of epilepsy does not appear to increase in patients with mental retardation.