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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54NS053672-10
Application #
8675962
Study Section
Special Emphasis Panel (ZNS1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Iowa
Department
Type
DUNS #
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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Jerber, Julie; Zaki, Maha S; Al-Aama, Jumana Y et al. (2016) Biallelic Mutations in TMTC3, Encoding a Transmembrane and TPR-Containing Protein, Lead to Cobblestone Lissencephaly. Am J Hum Genet 99:1181-1189

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