RESUMEN
Emery-Dreifuss muscular dystrophy (EDMD) is a heterogeneous genetic disorder characterized by peripheral muscular weakness often associated with dilated cardiomyopathy. We characterize clinically a large family with a mutation in FHL1 gene (p.Cys255Ser). Penetrance was 44%, 100% for males and 18% for females. The heart was the main organ involved. Affected adult males had mild hypertrophy, systolic dysfunction and restriction with non-dilated ventricles. Carriers had significant QTc prolongation. The proband presented with resuscitated cardiac arrest. There were two transplants. Pathological study of explanted heart showed fibrofatty replacement and scarring consistent with arrhythmogenic cardiomyopathy and prominent left ventricular trabeculations. Myopathic involvement was evident in all males. Females had no significant neuromuscular disease. Mutations in FHL1 cause unclassifiable cardiomyopathy with coexisting EDMD. Prognosis is poor and systolic impairment and arrhythmias are frequent. Thrombopenia and raised creatine phosphokinase should raise suspicion of an FHL-1 disorder in X-linked cardiomyopathy.
Asunto(s)
Arritmias Cardíacas/genética , Cardiomiopatía Dilatada/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas con Dominio LIM/genética , Proteínas Musculares/genética , Distrofia Muscular de Emery-Dreifuss/genética , Mutación , Adolescente , Adulto , Anciano , Arritmias Cardíacas/complicaciones , Arritmias Cardíacas/patología , Arritmias Cardíacas/cirugía , Biomarcadores/sangre , Cardiomiopatía Dilatada/complicaciones , Cardiomiopatía Dilatada/patología , Cardiomiopatía Dilatada/cirugía , Niño , Preescolar , Creatina Quinasa/sangre , Análisis Mutacional de ADN , Femenino , Expresión Génica , Trasplante de Corazón , Humanos , Masculino , Persona de Mediana Edad , Distrofia Muscular de Emery-Dreifuss/complicaciones , Distrofia Muscular de Emery-Dreifuss/patología , Distrofia Muscular de Emery-Dreifuss/cirugía , Miocardio/metabolismo , Miocardio/patología , Linaje , Factores Sexuales , Trombocitopenia/fisiopatología , Remodelación VentricularRESUMEN
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an important cause of malignant arrhythmia and sudden death particularly in young people. Although it is considered a desmosomal disease, mutations in non-desmosomal genes have also been identified. We report on a family where a mutation in LDB3 is associated with this condition. The index case and first and second degree relatives underwent a complete clinical evaluation: physical examination, electrocardiography (ECG), signal-averaged ECG, 2D echocardiogram, cardiac magnetic resonance and 24-h monitoring. After ruling out mutations in the five desmosomal genes, genetic testing by means of Next Generation Sequencing was carried out on the proband. A heterozygous missense mutation in LDB3 c.1051A>G was identified. This result was confirmed by subsequent Sanger DNA sequencing. Another six carriers were identified amongst her relatives. Three subjects fulfilled the criteria for a definitive diagnosis of ARVC and one reached a borderline diagnosis. In conclusion, this is the first family with ARVC where a mutation in LDB3 is associated with ARVC. Next generation sequencing arises as a particular useful tool to point to new causative genes in ARVC.