RESUMO
PURPOSE: Israeli investigators have identified several relatively frequent disorders due to founder point mutations in Persian (Iranian) Jews, who, for nearly three centuries up to the Islamic Revolution of 1979, were completely isolated reproductively. METHODS: Using a community-based model previously employed with Tay-Sachs disease prevention, we developed a pilot program for the Persian Jewish community of greater Los Angeles. We screened for mutations responsible for four relatively frequent autosomal recessive conditions in Persian Jews in which effective interventions are available for each: Pseudocholinesterase deficiency (butyryl cholinesterase deficiency); Congenital hypoaldosteronism (corticosterone methyl oxidase II); Autoimmune polyendocrinopathy (autoimmune regulatory element); and Hereditary Inclusion Body myopathy. RESULTS: One thousand individuals volunteered. Mutations were assessed in saliva-derived DNA and were positive for 121/1000 butyryl cholinesterase deficiency; 92/1000 Hereditary Inclusion Body myopathy; 38/1000 corticosterone methyl oxidase II; and 37/1000 autoimmune regulatory element. Ten homozygous individuals (9 butyryl cholinesterase deficiency and 1 Hereditary Inclusion Body myopathy) and 10 "at-risk" couples (seven for butyryl cholinesterase deficiency and one each for the other three disorders) were identified. These frequencies are comparable with those in Israel and indicate an extraordinary level of inbreeding, as anticipated. CONCLUSIONS: A carefully planned effort can be delivered to an "increased risk" community if detailed attention is given to planning and organization. However, availability of an effective intervention for those found to be "at-risk" or possibly affected, is essential before embarking.
Assuntos
Predisposição Genética para Doença , Testes Genéticos , Hipoaldosteronismo/genética , Judeus/genética , Poliendocrinopatias Autoimunes/genética , Apneia , Butirilcolinesterase/deficiência , Colinesterases/deficiência , Colinesterases/genética , Consanguinidade , Hipersensibilidade a Drogas/diagnóstico , Hipersensibilidade a Drogas/genética , Hipersensibilidade a Drogas/prevenção & controle , Etnicidade/genética , Frequência do Gene , Triagem de Portadores Genéticos , Aconselhamento Genético , Humanos , Hipoaldosteronismo/diagnóstico , Hipoaldosteronismo/prevenção & controle , Irã (Geográfico)/etnologia , Judeus/etnologia , Los Angeles , Erros Inatos do Metabolismo , Mutação , Miosite de Corpos de Inclusão/congênito , Miosite de Corpos de Inclusão/diagnóstico , Miosite de Corpos de Inclusão/genética , Miosite de Corpos de Inclusão/prevenção & controle , Mutação Puntual , Poliendocrinopatias Autoimunes/diagnóstico , Poliendocrinopatias Autoimunes/prevenção & controle , Diagnóstico Pré-Natal , Medição de Risco , Estados UnidosRESUMO
Sporadic inclusion-body myositis (sIBM) is an age-related condition manifested after midlife. This review points out salient features of sIBM that are shared with normal aging in muscle and with inflammatory changes in vascular atheromas and senile plaques of Alzheimer disease (AD). The amyloid precursor protein (APP) and derived Abeta peptides are found in both AD and sIBM. Because transgenic expression of human APP induces sIBM like changes, it is of potential interest that an inducer of APP, IL-1, increases during aging in mouse muscle. Because various subsets of the usual aging changes in aging brain, muscle, and vessels can be attenuated in rodents by caloric intake and possibly in humans by drugs with anti-inflammatory and anticoagulant activities, this study suggests that diet and inflammation may be useful experimental variations in exploring the pathogenesis of sIBM.
Assuntos
Envelhecimento/patologia , Miosite de Corpos de Inclusão/etiologia , Idoso , Envelhecimento/genética , Envelhecimento/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/química , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Anti-Inflamatórios/uso terapêutico , DNA Mitocondrial/genética , Demência Vascular/metabolismo , Demência Vascular/patologia , Ingestão de Energia , Humanos , Interleucina-1/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Proteínas Musculares/metabolismo , Atrofia Muscular/patologia , Mutação , Miosite de Corpos de Inclusão/genética , Miosite de Corpos de Inclusão/metabolismo , Miosite de Corpos de Inclusão/patologia , Miosite de Corpos de Inclusão/prevenção & controle , Proteínas do Tecido Nervoso/metabolismo , Fosforilação , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Dobramento de Proteína , Processamento de Proteína Pós-Traducional , RatosRESUMO
The amyloid fibril represents a final common pathologic pathway for a variety of human proteins, all of which have a propensity to misfold. Each seems to require a predisposing event to realize its fibrillogenic potential. It may be mutation, inappropriate or incomplete cleavage, overproduction, or the availability of a template for misfolding. Therapies have been based on decreasing the stimulus (inflammation in the case of AA) reducing the number of producing cells (AL) and a variety of approaches to removing the extracellular aggregates. Sporadic inclusion-body myositis (sIBM), while physically resembling the extracellular amyloidoses, is an intracellular disease, hence imposes the additional requirement of developing a therapy that can access and function inside the affected or potentially affected, cell. Current approaches to the treatment of other forms of amyloidosis are discussed in the context of their applicability, or lack thereof, to sIBM.
Assuntos
Amiloide/metabolismo , Amiloidose/terapia , Miosite de Corpos de Inclusão/terapia , Amiloide/química , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Amiloidose/classificação , Amiloidose/etiologia , Amiloidose/prevenção & controle , Animais , Ensaios Clínicos como Assunto , Desenho de Fármacos , Encefalite/etiologia , Humanos , Imunização/efeitos adversos , Imunização Passiva , Camundongos , Camundongos Transgênicos , Modelos Biológicos , Miosite de Corpos de Inclusão/prevenção & controle , Pré-Albumina/metabolismo , Dobramento de ProteínaRESUMO
Inclusion body myositis is a disease of striated skeletal muscle of unclear etiopathogenesis. Its diagnosis is difficult. Corticosteroids and immunosuppressants are of limited efficacy. Positive responses to intravenous immune globulins have recently been reported in a few patients. We used a CYBEX 6000 isokinetic dynamometer to evaluate the efficacy of intravenous immune globulin therapy in a patient with inclusion body myositis. Measurements were done at the flexors and extensors of the knee, at baseline and four and eight months after treatment initiation. A course of intravenous immune globulins (2 g per course) was given every month for five months then every two months. Isokinetic muscle strength measured at an angular speed of 180 degrees/second increased by more than 41% at both knees. As compared with muscle imaging studies (computed tomography, X-ray absorptiometry, ultrasonography, magnetic resonance imaging), isokinetic strength testing has the advantage of providing data on functional improvements under treatment.
