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, mutations in six genes (POMT1, P0MT2, POMGnT1, FKTN, FKRP, and LARGE) are known to result in dystroglycanopathies. There are several clinical subtypes, and these have overlapping 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.
The dystroglycanopathies are a group of muscular dystrophies with a wide range of severity. This clinical spectrum presents special challenges in planning treatment trials for this population. In this proposal, we will collect data and create an infrastructure that will facilitate translation of possible treatments to clinical trials.
|Lee, Angela J; Buckingham, Edward T; Kauer, Aaron J et al. (2018) Descriptive Phenotype of Obsessive Compulsive Symptoms in Males With Duchenne Muscular Dystrophy. J Child Neurol 33:572-579|
|González Coraspe, José Andrés; Weis, Joachim; Anderson, Mary E et al. (2018) Biochemical and pathological changes result from mutated Caveolin-3 in muscle. Skelet Muscle 8:28|
|Martinez-Thompson, Jennifer M; Niu, Zhiyv; Tracy, Jennifer A et al. (2018) Autosomal dominant calpainopathy due to heterozygous CAPN3 C.643_663del21. Muscle Nerve 57:679-683|
|Brun, Brianna N; Willer, Tobias; Darbro, Benjamin W et al. (2018) Uniparental disomy unveils a novel recessive mutation in POMT2. Neuromuscul Disord 28:592-596|
|Larson, Austin A; Baker 2nd, Peter R; Milev, Miroslav P et al. (2018) TRAPPC11 and GOSR2 mutations associate with hypoglycosylation of ?-dystroglycan and muscular dystrophy. Skelet Muscle 8:17|
|Carlson, Courtney R; Moore, Steven A; Mathews, Katherine D (2018) Dystrophinopathy muscle biopsies in the genetic testing ERA: One center's data. Muscle Nerve :|
|Brun, Brianna N; Mockler, Shelley R H; Laubscher, Katie M et al. (2017) Comparison of brain MRI findings with language and motor function in the dystroglycanopathies. Neurology 88:623-629|
|Carlson, Courtney R; McGaughey, Steven D; Eskuri, Jamie M et al. (2017) Illness-associated muscle weakness in dystroglycanopathies. Neurology 89:2374-2380|
|Donkervoort, Sandra; Chan, Sophelia H S; Hayes, Leslie H et al. (2017) Cytoplasmic body pathology in severe ACTA1-related myopathy in the absence of typical nemaline rods. Neuromuscul Disord 27:531-536|
|Wilson, Kristin; Faelan, Crystal; Patterson-Kane, Janet C et al. (2017) Duchenne and Becker Muscular Dystrophies: A Review of Animal Models, Clinical End Points, and Biomarker Quantification. Toxicol Pathol 45:961-976|
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