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.
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