Assuntos
Imunoglobulinas Intravenosas/uso terapêutico , Degeneração Paraneoplásica Cerebelar/tratamento farmacológico , Idoso , Antineoplásicos/efeitos adversos , Carboplatina/efeitos adversos , Feminino , Humanos , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/efeitos adversos , Polineuropatias/induzido quimicamenteRESUMO
Inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD, MIM 167320) is a recently identified autosomal dominant disorder due to mutations in the valosin-containing protein (VCP) that affects muscle, bone and brain. Brain involvement and neuropsychological findings of IBMPFD have not been described in detail. A patient carried a novel heterozygous base pair change, 47832C>T, in the VCP gene that resulted in substitution of an arginine residue by cysteine at position 93 (R93C). He presented first with myopathy while bone involvement remained subclinical. The patient developed behavioral abnormalities in his 60s and showed frank personality change with fluent empty speech at the age of 74 years. This syndrome was best classified as semantic dementia. Magnetic resonance imaging disclosed slight but progressive cerebral atrophy with prominent callosal and frontal white matter loss. Positron emission tomography demonstrated glucose hypometabolism of the frontal and temporal lobes disproportionate to their structural involvement. This first comprehensive clinical and neuroimaging study in IBMPFD may raise the awareness among clinicians as well as basic scientists for this exemplary genetic model of dementia.
Assuntos
Adenosina Trifosfatases/genética , Encéfalo/patologia , Proteínas de Ciclo Celular/genética , Demência/genética , Demência/patologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Idoso , Análise Mutacional de DNA , Demência/fisiopatologia , Predisposição Genética para Doença , Humanos , Imageamento por Ressonância Magnética , Masculino , Músculo Esquelético/patologia , Mutação , Miosite de Corpos de Inclusão/genética , Miosite de Corpos de Inclusão/patologia , Miosite de Corpos de Inclusão/fisiopatologia , Doenças Neurodegenerativas/fisiopatologia , Testes Neuropsicológicos , Osteíte Deformante/genética , Osteíte Deformante/patologia , Osteíte Deformante/fisiopatologia , Reação em Cadeia da Polimerase , Tomografia por Emissão de Pósitrons , Proteína com ValosinaRESUMO
In 1965, an adult-onset, autosomal dominant disorder with a peculiar scapuloperoneal distribution of weakness and atrophy was described in a large, multi-generation kindred and named 'scapuloperoneal syndrome type Kaeser' (OMIM #181400). By genetic analysis of the original kindred, we discovered a heterozygous missense mutation of the desmin gene (R350P) cosegregating with the disorder. Moreover, we detected DES R350P in four unrelated German families allowing for genotype-phenotype correlations in a total of 15 patients carrying the same mutation. Large clinical variability was recognized, even within the same family, ranging from scapuloperoneal (n = 2, 12%), limb girdle (n = 10, 60%) and distal phenotypes (n = 3, 18%) with variable cardiac (n = 7, 41%) or respiratory involvement (n = 7, 41%). Facial weakness, dysphagia and gynaecomastia were frequent additional symptoms. Overall and within each family, affected men seemingly bear a higher risk of sudden, cardiac death as compared to affected women. Moreover, histological and immunohistochemical examination of muscle biopsy specimens revealed a wide spectrum of findings ranging from near normal or unspecific pathology to typical, myofibrillar changes with accumulation of desmin. This study reveals that the clinical and pathological variability generally observed in desminopathies may not be attributed to the nature of the DES mutation alone, but may be influenced by additional genetic and epigenetic factors such as gender. In addition, mutations of the desmin gene should be considered early in the diagnostic work-up of any adult-onset, dominant myopathy, even if specific myofibrillar pathology is absent.
Assuntos
Desmina/genética , Miopatias Distais/genética , Mutação de Sentido Incorreto , Adulto , Idoso de 80 Anos ou mais , Biópsia , Análise Mutacional de DNA/métodos , Miopatias Distais/patologia , Feminino , Haplótipos , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fibras Musculares Esqueléticas/patologia , Músculo Esquelético/patologia , Distrofia Muscular do Cíngulo dos Membros/genética , Distrofia Muscular do Cíngulo dos Membros/patologia , Linhagem , Fenótipo , Fatores Sexuais , SíndromeRESUMO
We report on two unrelated patients clinically presenting with late-onset progressive limb girdle weakness; cardiomyopathy was seen in one patient. Muscle biopsy revealed a necrotic myopathy with numerous rimmed vacuoles, ultrastructurally typical paired-helical filaments, and reduced immunohistochemical staining for alpha-dystroglycan. Quadriceps sparing hereditary inclusion body myopathy due to mutations in GNE gene, and OPMD due to PABPN1 mutations were excluded, genetically. We detected a homozygous mutation of the FKRP gene (826C>A) in both patients. Mutations of FKRP have been reported in congenital muscular dystrophies, LGMD2I, cardiomyopathy and hyperCKemia, but not in myopathies with vacuoles and paired-helical filaments. Therefore, our findings further extend the morphological variability of muscular dystrophies due to FKRP mutations.
Assuntos
Distrofia Muscular do Cíngulo dos Membros/genética , Distrofia Muscular do Cíngulo dos Membros/patologia , Proteínas/genética , Adulto , Citoesqueleto/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Pentosiltransferases , Vacúolos/patologiaRESUMO
We describe an atypical case of nemaline myopathy with an unusual distribution of muscle weakness who presented at 14 years of age with kyphoscoliosis. In this patient, we demonstrate heterozygosity for a de novo CGT-CAT (Arg167His) mutation in a constitutively expressed exon (exon 5) of slow alpha-tropomyosin (TPM3). This is the first mutation identified in a constitutively expressed exon of TPM3 in a nemaline myopathy patient, but is similar to recently described mutations in beta-tropomyosin (TPM2) associated with nemaline myopathy and mutations in fast alpha-tropomyosin (TPM1) which cause hypertrophic cardiomyopathy.