GENETIC METABOLIC MYOPATHIES--PHOSPHOFRUCTOKINASE/ACID MALTASE DEFICIENCY

在研究炎症性肌肉疾病(多发性肌炎， 皮肌炎和相关疾病)，我们遇到过 其他肌肉疾病。我们研究了患有两种基因的患者 详细的代谢性肌病：磷酸果糖激酶(PFK)缺乏，以及 酸性麦芽糖酶(酸性α-葡萄糖苷酶，或GAA)缺乏症。 对PFK缺乏症的研究旨在揭示其遗传特征。 几组患者的缺陷及其相关的临床表现 病人。因为PFK缺乏症是一种轻微的和罕见的 情况，我们已经停止了对它的工作，除了临床咨询或 对偶尔会诊的患者进行基因测试。 酸性麦芽糖酶缺乏症更常见，也更严重。它可以 在婴儿期(庞培病)或以后的生活中是致命的，当肌病 临床上类似肌炎的肺部疾病在中年是致命的。 目前正在进行以下研究：1)认真分析大多数 常见的成人突变。对体外模型系统的研究表明 多嘧啶末端的一个单碱基突变 内含子1的突变会降低转录速率，显然是通过改变 剪接因子的结合，并改变剪接变异体与 有利于非生产性基因的剪接。此外，消音器具有 已在该内含子的其他位置被鉴定，并可能是 药物干预以上调该基因。毒剂研究 在过去的一年里进行了上调转录的工作 到目前为止还没有很好的临床试验候选者。2)我们已经确定了 四名非洲人和一些非裔美国人患者的突变 确定患者共享所有已确定的基因内 多态(但具有相同突变的法国患者不会)。我们 正在构建扩展的单倍型，目的是了解更多 关于基因的历史，由此推断，这些基因的迁移 他们把它从非洲带到了新世界。3)我们成功地 利用逆转录病毒载体进行体外基因转移，以及合作者 约翰斯·霍普金斯大学正在研究一种AAV病毒载体。4)三种不同的GAA 基因敲除小鼠模型(一次尝试3个不同的中断位置 以模拟人类疾病的严重程度)在 发展。计划在受影响的小鼠体内进行基因转移研究。

In the course of studying inflammatory muscle diseases (polymyositis, dermatomyositis, and related diseases), we have encountered patients with other muscle diseases. We have studied patients with two genetic metabolic myopathies in detail: phosphofructokinase (PFK) deficiency, and acid maltase (acid alpha-glucosidase, or GAA) deficiency. The studies of PFK deficiency were aimed at characterizing the genetic defects and the associated clinical picture in several groups of patients. Because PFK deficiency is a mild as well as an infrequent condition, we have ceased work on it except to consult clinically or perform genetic tests on occasional patients in consultation. Acid maltase deficiency is both more frequent and more serious. It can be fatal in infancy (Pompe disease) or later in life, when a myopathy with lung disease clinically similar to myositis is fatal in middle age. The following studies are underway: 1) Careful analysis of the most common adult mutation. Studies with an in vitro model system have shown that a single base mutation in the polypyrimidine tract towards the end of intron 1 reduces the transcription rate, apparently by altering the binding of a splicing factor, and alters the ratio of splice variants to favor the splicing of non-productive mRNA. Furthermore, a silencer has been identified elsewhere in this intron, and may be a candidate for pharmacological intervention to up-regulate this gene. Studies of agents to up-regulate transcription have been carried out in the past year with as yet no good candidate for clinical trial. 2) We have identified a mutation in four African and a number of African-American patients and established that the patients share all identified intragenic polymorphisms (but a French patient with the same mutation does not). We are constructing an extended haplotype with the aim of learning more about the history of the gene and, by inference, the migration of those who bore it from Africa to the new world.3) We have successfully carried out gene transfer in vitro with a retroviral vector, and collaborators at Johns Hopkins are working with an AAV vector. 4) Three different GAA knockout mouse models (3 different sites of interruption in an attempt to mimic the range of severity of the human disease) are under development. Gene transfer studies in vivo in affected mice are planned.