Clinical Trial Readiness for the Dystroglycanopathies

该项目的目的是收集信息，并建立所需的基础设施，计划和开展临床试验的患者缺乏糖基化的α -三磷酸腺苷。这些患者有肌营养不良，伴或不伴多系统累及（糖营养不良症）。到目前为止，已知6个基因（POMTl、P0MT2、POMGnTI、FKTN、FKRP和LARGE）的突变可导致糖营养不良症。有几种临床亚型，这些亚型具有重叠的表型。糖代谢异常人群在考虑治疗试验时面临着特殊的挑战，因为他们的临床严重程度差别很大。此外，在某些亚型中看到的认知障碍限制了患者配合测试的能力。

The purpose of this project is to gather the information and create the infrastructure needed to plan and carry out clinical trials for patients with deficient glycosylation of alpha-dystroglycan. These patients have muscular dystrophy, with or without multisystem involvement (the dystroglycanopathies). Thus far, mutafions in six genes (POMTl, P0MT2, POMGnTI, FKTN, FKRP, and LARGE) are known to result in dystroglycanopathies. There are several clinical subtypes, and these have overiapping phenotypes. The dystroglycanopathy population poses special challenges in thinking about treatment trials due to the wide range in clinical severity. In addition, the cognitive impairment seen in some of the subtypes limits patients' ability to cooperate with testing. In Aim 1, we will recruit patients with suspected or proven dystroglycanopathies and define their clinical phenotypes using historical information, standardized functional tests, and muscle ultrasound. In cooperation with Core B, we will evaluate muscle biopsies, define patients' alpha-dystroglycan glycosylation status in cultured fibroblasts, and determine their genotype. In Aim 2, we will follow patients with dystroglycanopathy longitudinally using a battery of potential clinical trial outcome measures. This will provide us with natural history information and determine optimal outcome measures for use in therapeutic trials. In Aim 3, we will develop the infrastructure for a proposed clinical trial of corticosteroids, using the data collected in Aims 1 and 2 to guide trial design. Anecdotes and case reports suggest corticosteroids are beneficial in patients with the dystroglycanopathies. In this proposal, we will develop the patient cohort, outcome markers and infrastructure to test this hypothesis. We expect that the results of these three aims will prepare us to evaluate novel treatments for these rare forms of muscular dystrophy as they become available.