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），我们遇到的患者 其他肌肉疾病 我们研究了患有两种遗传病的患者， 代谢性肌病详细：磷酸果糖激酶（PFK）缺乏症， 酸性麦芽糖酶（酸性α-葡糖苷酶或GAA）缺乏。 PFK缺乏症的研究旨在表征遗传性 缺陷和相关的临床表现在几组患者。 奋进后一项研究发现了一个奇怪的发现， 一个来自小村庄的瑞典近亲家庭的疾病是由于 通过两个不同的世代传播 疾病相关的突变。 再加上最大的 病人的水库，德系犹太人，也来自同一个 波罗的海沿着的地理区域（尽管突变不同）， 这就提出了一个有趣的可能性， 国家在这一地区是有利的。 因为这是一种温和的， 这是一种罕见的情况，我们已经停止了对它的研究。 酸性麦芽糖酶缺乏症更常见，也更严重。 可以 在婴儿期（庞贝氏症）或以后的生活中致命，当肌病伴 在临床上类似于肌炎的肺病在中年是致命的。 的 以下研究正在进行中：1）仔细分析最常见的 成人突变 体外模型系统的研究表明， 内含子末端多聚嘧啶序列中的单碱基突变 1降低了转录速率，显然是通过改变一个 剪接因子，并改变剪接变异体的比例，以有利于 非生产性mRNA的剪接。 此外，一个消音器已经被 在这个内含子的其他地方发现，可能是一个候选人， 药物干预来上调该基因。 2)分析 临床变异中的突变。 对非典型青少年形式的研究 发现了一种失活的酶 西方患者研究 非洲（在华盛顿儿童医院发表）已经表明， 共享相同的突变，并且它是在 只有非裔美国人参与了研究。 因此，这种突变似乎 是来自西非某个部落的标志 这项工作正在 与其他学科的学者合作进行。 3)基因 用逆转录病毒载体转移。 由于酸性麦芽糖酶缺乏是一种 溶酶体贮积病，它是一个有吸引力的候选基因 更换. 逆转录病毒载体已被证明不仅在 成肌细胞和成纤维细胞，以去除溶酶体糖原，但也 在其他受影响的肌肉细胞中提供类似的表型改善 通过分泌-甘露糖-6-磷酸再摄取途径和通过 细胞融合 这表明，相对较少的 基因校正的成肌细胞可能能够在表型上校正很多 更多的细胞。

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. The final study in the endeavor turned up the curious finding that the disease in an in-bred Swedish family from a small village was due to the propagation through a number of generations of two different disease-related mutations. Together with the fact that the largest reservoir of patients, Ashkenazi Jews, also derives from the same geographic region along the Baltic (although the mutations are different), this raises the interesting possibility that the heterozygous carrier state is advantageous in this region. Because this is a mild as well as an infrequent condition, we have ceased work on it. 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. 2) Analysis of the mutations in clinical variants. Studies in the atypical juvenile form has turned up a disabled form of the enzyme. Studies in patients from West Africa (presenting at Children's Hospital in Washington) has shown they share the same mutation, and it is the same mutation identified in the only Afro-American patients studied. This mutation appears, therefore, to be a marker of origin from a particular West African tribe. This is being pursued in collaboration with scholars in other disciplines. 3) Gene transfer with a retroviral vector. Since acid maltase deficiency is a lysosomal storage disease, it is an attractive candidate for gene replacement. A retroviral vector has been shown not only to act in myoblasts and fibroblasts to remove lysosomal glycogen, but also to provide a similar phenotypic improvement in other affected muscle cells through the secretion-mannose-6-phosphate re-uptake pathway and through cell fusion. This suggests that a relatively small number of gene-corrected myoblasts may be able to phenotypically correct a much larger number of cells.