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.
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