RESUMEN
Fukuyama congenital muscular dystrophy (FCMD) is frequent in Japan, due to a founder mutation of the fukutin gene (FKTN). Outside Japan, FKTN mutations have only been reported in a few patients with a wide spectrum of phenotypes from Walker-Warburg syndrome to limb-girdle muscular dystrophy (LGMD2M). We studied four new Caucasian patients from three unrelated families. All showed raised serum CK initially isolated in one case and muscular dystrophy. Immunohistochemical studies and haplotype analysis led us to search for mutations in FKTN. Two patients (two sisters) presented with congenital muscular dystrophy, mental retardation, and posterior fossa malformation including cysts, and brain atrophy at Brain MRI. The other two patients had normal intelligence and brain MRI. Sequencing of the FKTN gene identified three previously described mutations and two novel missense mutations. Outside Japan, fukutinopathies are associated with a large spectrum of phenotypes from isolated hyperCKaemia to severe CMD, showing a clear overlap with that of FKRP.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Discapacidad Intelectual/genética , Proteínas de la Membrana/genética , Distrofias Musculares/genética , Mutación/genética , Malformaciones del Sistema Nervioso/genética , Adulto , Atrofia/genética , Atrofia/patología , Atrofia/fisiopatología , Encéfalo/anomalías , Encéfalo/patología , Encéfalo/fisiopatología , Niño , Creatina Quinasa/análisis , Creatina Quinasa/sangre , Análisis Mutacional de ADN , Resultado Fatal , Femenino , Marcadores Genéticos/genética , Predisposición Genética a la Enfermedad/etnología , Genotipo , Humanos , Discapacidad Intelectual/patología , Discapacidad Intelectual/fisiopatología , Masculino , Distrofias Musculares/patología , Distrofias Musculares/fisiopatología , Malformaciones del Sistema Nervioso/patología , Malformaciones del Sistema Nervioso/fisiopatología , Fenotipo , Síndrome , Población Blanca , Adulto JovenRESUMEN
OBJECTIVE: To characterize the muscle involvement of patients with central core disease (CCD) caused by mutations in the ryanodine receptor 1 gene (RYR1) and to compare these findings with those from patients with core myopathies unlinked to the RYR1 gene. METHODS: We performed a systematic muscular imaging assessment in 11 patients with an RYR1 gene mutation and compared these findings with those of 5 patients from two unrelated families with autosomal dominant core myopathies not linked to RYR1, ACTA1, or MYH7 gene loci. RESULTS: All patients with RYR1 CCD had a characteristic pattern with predominant involvement of the gluteus maximus, adductor magnus, sartorius, vastus intermediolateralis, soleus, and lateral gastrocnemius muscles. In contrast, muscle CT in the first family not linked to RYR1 showed predominant affection of the gluteus minimus and hamstring muscles, whereas the second family presented with predominant involvement of the gluteus minimus, vastus intermediolateralis, tibialis anterior, and medial gastrocnemius muscles. In addition to muscle imaging data, we present detailed information on the clinical and pathologic findings of these novel phenotypes of core myopathies not linked to RYR1. CONCLUSIONS: Our data suggest genetic heterogeneity in autosomal dominant core myopathies and the existence of additional unidentified genes.
Asunto(s)
Trastornos de los Cromosomas/genética , Trastornos de los Cromosomas/patología , Músculo Esquelético/patología , Miopatía del Núcleo Central/genética , Miopatía del Núcleo Central/patología , Canal Liberador de Calcio Receptor de Rianodina/genética , Predisposición Genética a la Enfermedad/genética , Humanos , Estadística como AsuntoRESUMEN
Dropped head syndrome is characterized by severe weakness of neck extensor muscles with sparing of the flexors. It is a prominent sign in several neuromuscular conditions, but it may also be an isolated feature with uncertain aetiology. We report two children in whom prominent weakness of neck extensor muscles is associated with mutations in lamin A/C (LMNA) and selenoprotein N1 (SEPN1) genes, respectively. This report expands the underlying causes of the dropped head syndrome which may be the presenting feature of a congenital muscular dystrophy.
Asunto(s)
Laminas/genética , Proteínas Musculares/genética , Distrofias Musculares/genética , Distrofias Musculares/fisiopatología , Mutación , Arginina/genética , Niño , Análisis Mutacional de ADN/métodos , Femenino , Glicina/genética , Humanos , Lactante , Lamina Tipo A , Masculino , Debilidad Muscular/genética , Debilidad Muscular/fisiopatología , Músculos del Cuello/patología , Músculos del Cuello/fisiopatología , Selenoproteínas , SíndromeRESUMEN
The region of chromosome 21 between genes CBR and ERG (CBR-ERG region), which spans 2.5 Mb on 21q22.2, has been defined by analysis of patients with partial trisomy 21. It contributes significantly to the pathogenesis of many characteristics of Down syndrome, including morphological features, hypotonia, and mental retardation. Cosmid contigs covering 80% of the region were constructed and EcoRI maps produced. These cosmids were used for exon trapping and cDNA selection from three cDNA libraries (fetal brain, fetal liver, and adult skeletal muscle). Isolated exons and cDNAs were mapped on the EcoRI map, organized into contigs, sequenced, and used as probes for Northern blot analysis of RNA from fetal and adult tissues. We identified 27 genuine or highly probable transcriptional units evenly distributed along the CBR-ERG region. Eight of the transcriptional units are known genes.
