RESUMO
Inclusion body myopathy associated with Paget's disease of the bone and frontotemporal dementia is a rare but highly penetrant autosomal dominant progressive disorder linked to mutations in valosin containing protein (VCP). Here, we characterize a novel mutation in the linker 1 domain of VCP leading to inclusion body myopathy and/or frontotemporal dementia in 3 generations of a Swiss family. A detailed history of several years of clinical follow-up and electrophysiological, radiological and pathological findings are presented. Five out of 6 individuals suffered from progressive myopathy and 2 out of 6 from frontotemporal dementia, respectively. A radiologically suspected Paget's disease of the bone could not been confirmed at autopsy. This case study illustrates that only a subset of individuals shows the full triad of the disease complex and that clinicopathological findings are - when interpreted apart from familial history - hard to distinguish from sporadic inclusion body myositis.
Assuntos
Adenosina Trifosfatases/genética , Proteínas de Ciclo Celular/genética , Demência Frontotemporal/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Mutação/genética , Miosite de Corpos de Inclusão/genética , Osteíte Deformante/genética , Biópsia , Feminino , Demência Frontotemporal/etnologia , Demência Frontotemporal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Distrofia Muscular do Cíngulo dos Membros/etnologia , Distrofia Muscular do Cíngulo dos Membros/patologia , Miosite de Corpos de Inclusão/etnologia , Miosite de Corpos de Inclusão/patologia , Osteíte Deformante/etnologia , Osteíte Deformante/patologia , Linhagem , Suíça , Proteína com ValosinaRESUMO
OBJECTIVE: To identify the genetic and epigenetic defects in patients presenting with a facioscapulohumeral (FSHD) clinical phenotype without D4Z4 contractions on chromosome 4q35 tested by linear gel electrophoresis and Southern blot analysis. DESIGN AND PATIENTS: The authors studied 16 patients displaying an FSHD-like phenotype, with normal cardiovascular and respiratory function, a myopathic pattern on electromyography, and a muscle biopsy being normal or displaying only mild and aspecific dystrophic changes. They sequenced the genes calpain 3 (CAPN3), valosin containing protein (VCP) and four-and-a-half LIM domains protein 1 (FHL1), and they analysed the D4Z4 repeat arrays by extensive genotyping and DNA methylation analysis. RESULTS: The authors identified one patient carrying a complex rearrangement in the FSHD locus that masked the D4Z4 contraction associated with FSHD1 in standard genetic testing, one patient with somatic mosaicism for the D4Z4 4q35 contraction, six patients that were diagnosed as having FSHD2, four patients with CAPN3 mutations and two patients with a VCP mutation, No mutations were detected in FHL1, and in two patients, the authors could not identify the genetic defect. CONCLUSIONS: In patients presenting with an FSHD-like clinical phenotype with a negative molecular testing for FSHD, consider (1) detailed genetic testing including D4Z4 contraction of permissive hybrid D4Z4 repeat arrays, p13E-11 probe deletions, and D4Z4 hypomethylation in the absence of repeat contraction as observed in FSHD2; (2) mutations in CAPN3 even in the absence of protein deficiency on western blot analysis; and (3) VCP mutations even in the absence of cognitive impairment, Paget disease and typical inclusion in muscle biopsy.
Assuntos
Adenosina Trifosfatases/genética , Calpaína/genética , Proteínas de Ciclo Celular/genética , Epigênese Genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas com Domínio LIM/genética , Proteínas Musculares/genética , Distrofia Muscular Facioescapuloumeral/genética , Adulto , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Mosaicismo , Distrofia Muscular Facioescapuloumeral/diagnóstico , Fenótipo , Proteína com ValosinaRESUMO
We report the clinical, histological and genetic findings in 10 families (19 patients) presenting mutations in the valosin-containing protein (VCP). The mean age at onset was 42 years. The clinical pattern was characterized by an early involvement of the proximal upper limbs with scapular winging. Axial and lower limb muscles were often affected, whereas facial, oculobulbar muscles were spared. Ten patients were wheelchair bound after a mean disease course of 9 years and six patients required canes for walking. Two patients required mechanically assisted ventilation and seven patients had reduced vital capacity. There was no cardiac involvement. Paget's disease of bone was observed in eight patients and cognitive impairment in nine patients. Seven patients died as a consequence of weakness and respiratory distress. Muscle biopsy showed rimmed vacuolar myopathy. Genetic analysis revealed missense heterozygous mutations mostly located in exon 5 of the VCP gene, four of which were not previously reported. We observed intrafamilial and interfamilial variability in terms of severity, distribution of weakness and presence or not of Paget's disease or cognitive impairment.