RESUMO
Linkage analysis of the dominant distal myopathy we previously identified in a large Australian family demonstrated one significant linkage region located on chromosome 7 and encompassing 18.6 Mbp and 151 genes. The strongest candidate gene was FLNC because filamin C, the encoded protein, is muscle-specific and associated with myofibrillar myopathy. Sequencing of FLNC cDNA identified a c.752T>C (p.Met251Thr) mutation in the N-terminal actin-binding domain (ABD); this mutation segregated with the disease and was absent in 200 controls. We identified an Italian family with the same phenotype and found a c.577G>A (p.Ala193Thr) filamin C ABD mutation that segregated with the disease. Filamin C ABD mutations have not been described, although filamin A and filamin B ABD mutations cause multiple musculoskeletal disorders. The distal myopathy phenotype and muscle pathology in the two families differ from myofibrillar myopathies caused by filamin C rod and dimerization domain mutations because of the distinct involvement of hand muscles and lack of pathological protein aggregation. Thus, like the position of FLNA and B mutations, the position of the FLNC mutation determines disease phenotype. The two filamin C ABD mutations increase actin-binding affinity in a manner similar to filamin A and filamin B ABD mutations. Cell-culture expression of the c.752T>C (p.Met251)Thr mutant filamin C ABD demonstrated reduced nuclear localization as did mutant filamin A and filamin B ABDs. Expression of both filamin C ABD mutants as full-length proteins induced increased aggregation of filamin. We conclude filamin C ABD mutations cause a recognizable distal myopathy, most likely through increased actin affinity, similar to the pathological mechanism of filamin A and filamin B ABD mutations.
Assuntos
Proteínas Contráteis/genética , Miopatias Distais/genética , Proteínas dos Microfilamentos/genética , Actinas/metabolismo , Adulto , Idoso , Austrália , Cromossomos Humanos Par 7/genética , Proteínas Contráteis/metabolismo , Miopatias Distais/metabolismo , Miopatias Distais/patologia , Feminino , Filaminas , Humanos , Itália , Masculino , Proteínas dos Microfilamentos/metabolismo , Pessoa de Meia-Idade , Mutação , Linhagem , Estrutura Terciária de Proteína/genéticaAssuntos
Blefaroptose/etiologia , Debilidade Muscular/etiologia , Transtornos Parkinsonianos/diagnóstico , Degenerações Espinocerebelares/etiologia , Ubiquitina-Proteína Ligases/genética , Adulto , Radioisótopos de Carbono , Cerebelo/fisiopatologia , Pré-Escolar , Corpo Estriado/diagnóstico por imagem , Heterozigoto , Humanos , Hipocinesia/etiologia , Radioisótopos do Iodo , Masculino , Mitocôndrias Musculares/metabolismo , Mitocôndrias Musculares/ultraestrutura , Mutação de Sentido Incorreto , Transtornos Parkinsonianos/complicações , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/genética , Cintilografia , Deleção de Sequência , Tropanos , Ubiquitina-Proteína Ligases/deficiênciaRESUMO
BACKGROUND: Persistent high creatine kinase (CK) levels may reflect underlying subclinical myopathies. In most cases, pathogenesis is unknown and clinical management is unclear. Though clinically asymptomatic, these subjects are potentially susceptible to malignant hyperthermia. METHODS: The authors analyzed 37 subjects with persistent elevation of CK without significant weakness or other neurologic symptoms. Neurologic examination was performed according to manual muscle testing. Muscle biopsy and the in vitro contracture test were performed in all subjects. RESULTS: Twenty-three subjects (51.1%) were completely asymptomatic. The others had minor symptoms such as occasional cramps (11 subjects, 24.4%), fatigue (5 subjects, 11.1%), a combination of cramps and fatigue (5 subjects, 11.1%), and muscle pain (1 case, 2.2%). Muscle biopsy enabled precise diagnosis in 3 cases and was normal in 3 cases. The more frequent changes were variation in fiber size (31.1%), a combination of nuclear internalization and variation in fiber size (26.6%), nuclear internalization (6.6%), minor mitochondrial changes (4.4%), and neurogenic atrophy (4.4%). Immunocytochemical analysis was normal in all patients. In vitro contracture testing detected one malignant hyperthermia-susceptible and one malignant hyperthermia-equivocal subject. CONCLUSIONS: The evidence of malignant hyperthermia susceptibility by in vitro contracture test seems to be relatively infrequent among subjects with idiopathic hyperCKemia, but the incidence of true malignant hyperthermia in idiopathic hyperCKemia is unknown. Muscle biopsy should be considered a useful, though not very sensitive, diagnostic tool in idiopathic hyperCKemia, because it enables potentially treatable disorders, such as inflammatory myopathies, to be discovered. No uniform morphologic finding typical of idiopathic hyperCKemia or malignant hyperthermia susceptibility was identified by muscle biopsy.
Assuntos
Creatina Quinase/sangue , Contração Muscular , Músculo Esquelético/patologia , Adolescente , Adulto , Idoso , Biópsia , Criança , Feminino , Humanos , Masculino , Hipertermia Maligna/etiologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Canal de Liberação de Cálcio do Receptor de Rianodina/genéticaRESUMO
We report a 36-year-old patient with 46XY pure gonadal dysgenesis (GD), who manifested a syndrome of progressive motor-sensory neuropathy. Sural nerve biopsy showed severe axonal neuropathy. Since reported cases of chronic motor-sensory neuropathy and pure gonadal dysgenesis have been characterized by nerve biopsy evidence of minifascicle formation, we suggest that this clinical association may be a new type of hereditary motor-sensory neuropathy, not necessarily associated with minifascicle formation.
Assuntos
Axônios/patologia , Disgenesia Gonadal 46 XY/complicações , Neuropatia Hereditária Motora e Sensorial/complicações , Neuropatia Hereditária Motora e Sensorial/patologia , Adulto , Biópsia , Feminino , Disgenesia Gonadal 46 XY/genética , Proteínas Hedgehog/genética , Neuropatia Hereditária Motora e Sensorial/genética , Humanos , Nervo Sural/patologiaRESUMO
We sequenced all mitochondrial tRNA genes from a patient with sporadic external ophthalmoplegia (PEO) and 5% COX-negative fibers in muscle biopsy, who had no detectable large mtDNA deletions. Direct sequencing showed a heteroplasmic mutation at nucleotide 7506 in the dihydrouridine stem of the tRNA(Ser(UCN)) gene. RFLP analysis confirmed that 30% of muscle and 20% of urinary epithelium mtDNA harbored the mutation, which was absent in other tissues of the proband as well as in mtDNA of his mother and 100 patients with various encephalomyopathies. Several point mutations on mitochondrial tRNA genes have been reported in PEO patients without large-scale rearrangements of mtDNA but no point mutations have hitherto been found in the gene coding for tRNA(Ser(UCN)).
Assuntos
DNA Mitocondrial/genética , Perda Auditiva/genética , Oftalmoplegia Externa Progressiva Crônica/genética , Mutação Puntual/genética , RNA de Transferência de Serina/genética , Uridina/análogos & derivados , Adulto , Análise Mutacional de DNA/métodos , Feminino , Perda Auditiva/complicações , Humanos , Masculino , Oftalmoplegia Externa Progressiva Crônica/complicações , Polimorfismo de Fragmento de Restrição , Uridina/químicaRESUMO
Mutations of the Cav-3 gene are associated with distinct, sometimes overlapping muscle disease phenotypes. We report a new Italian family with autosomal dominant rippling muscle disease. Immunocytochemical analysis of muscle showed a deficit of caveolin-3 protein and molecular genetic analysis showed a novel mutation of the Cav-3 gene.
Assuntos
Caveolina 3/genética , Predisposição Genética para Doença/genética , Músculo Esquelético/metabolismo , Doenças Musculares/genética , Mutação de Sentido Incorreto/genética , Adulto , Idoso , Cavéolas/metabolismo , Cavéolas/patologia , Cavéolas/ultraestrutura , Caveolina 3/deficiência , Transtornos Cromossômicos/genética , Análise Mutacional de DNA , Feminino , Genes Dominantes/genética , Testes Genéticos , Humanos , Masculino , Microscopia Eletrônica de Transmissão , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Fibras Musculares Esqueléticas/ultraestrutura , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Doenças Musculares/metabolismo , Doenças Musculares/fisiopatologiaRESUMO
We report the case of a 51-year-old woman with anosmia and chronic sensory ataxic neuropathy. Olfactory tests suggested neurosensory anosmia. Immunocytochemical analysis showed serum antibodies against dorsal root ganglion (DRG) cells and olfactory neurons, in the absence of other known causes of anosmia and sensory neuropathy. Clinical and laboratory data suggested a slow autoimmune process affecting dorsal root ganglion and olfactory cells.