RESUMEN
In 2005 the commonality of sarcotubular myopathy (STM) and limb girdle muscular dystrophy type 2H (LGMD2H) was demonstrated, as both are caused by the p D487N missense mutation in TRIM32 originally found in the Manitoba Hutterite population. Recently, three novel homozygous TRIM32 mutations have been described in LGMD patients. Here we describe a three generation Swedish family clinically presenting with limb girdle muscular weakness and histological features of a microvacuolar myopathy. The two index patients were compound heterozygotes for a frameshift mutation in TRIM32 (c.1560delC ) and a 30 kb intragenic deletion, encompassing parts of intron 1 and the entire exon 2 of TRIM32. In these patients, no full-length or truncated TRIM32 could be detected. Interestingly, heterozygous family members carrying only one mutation showed mild clinical symptoms and vacuolar changes in muscle. In our family, the phenotype encompasses additionally a mild demyelinating polyneuropathic syndrome. Thus STM and LGMD2H are the result of loss of function mutations that can be either deletions or missense mutations.
Asunto(s)
Eliminación de Gen , Heterocigoto , Enfermedades Musculares/genética , Distrofia Muscular de Cinturas/genética , Factores de Transcripción/genética , Adolescente , Adulto , Secuencia de Bases , Análisis Mutacional de ADN , Familia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Mutación Missense , Fenotipo , Suecia , Proteínas de Motivos Tripartitos , Ubiquitina-Proteína LigasasRESUMEN
Here we describe a patient with limb girdle muscular dystrophy 1A (LGMD1A) due to a novel myotilin gene (MYOT) mutation with late onset, rapid progression, loss of ambulation and respiratory failure. The onset of weakness in proximal muscles and muscle MRI findings are clearly different from the pattern identified in myofibrillar myopathies (MFM) related to MYOT mutations. Moreover, there was very limited evidence of myofibrillar pathology in several muscle biopsies obtained during the disease course. We conclude, that MYOT mutations need to be considered as a rare cause of adult-onset, dominant LGMD without clear-cut MFM pathology.
Asunto(s)
Proteínas del Citoesqueleto/genética , Proteínas Musculares/genética , Músculo Esquelético/patología , Distrofia Muscular de Cinturas/genética , Distrofia Muscular de Cinturas/patología , Mutación Missense , Adulto , Conectina , Femenino , Humanos , Imagen por Resonancia Magnética , Proteínas de Microfilamentos , Persona de Mediana Edad , Distrofia Muscular de Cinturas/fisiopatología , Fenotipo , Reacción en Cadena de la PolimerasaRESUMEN
Sarcotubular myopathy (OMIM 268950) is a rare autosomal recessive myopathy first described in two Hutterite brothers from South Dakota and in two non-Hutterite brothers from Germany. We report that sarcotubular myopathy (STM) is caused by mutation in TRIM32, the gene encoding the tripartite motif-containing protein 32. TRIM32 was found to be the gene mutated in limb girdle muscular dystrophy type 2H (LGMD2H [OMIM 254110]), a disorder that has been confined to the Hutterite population. The TRIM32 mutation found in the STM patients is identical to the causative mutation for LGMD2H (D487N), Haplotype analysis shows that the disease chromosomes share common ancestry.