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.

National Institute of Health (NIH)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZNS1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Iowa
Iowa City
United States
Zip Code
Bönnemann, Carsten G; Wang, Ching H; Quijano-Roy, Susana et al. (2014) Diagnostic approach to the congenital muscular dystrophies. Neuromuscul Disord 24:289-311
Inamori, Kei-ichiro; Willer, Tobias; Hara, Yuji et al. (2014) Endogenous glucuronyltransferase activity of LARGE or LARGE2 required for functional modification of ?-dystroglycan in cells and tissues. J Biol Chem 289:28138-48
Chauveau, Claire; Bonnemann, Carsten G; Julien, Cedric et al. (2014) Recessive TTN truncating mutations define novel forms of core myopathy with heart disease. Hum Mol Genet 23:980-91
Wallace, Stephanie E; Conta, Jessie H; Winder, Thomas L et al. (2014) A novel missense mutation in POMT1 modulates the severe congenital muscular dystrophy phenotype associated with POMT1 nonsense mutations. Neuromuscul Disord 24:312-20
Willer, Tobias; Inamori, Kei-Ichiro; Venzke, David et al. (2014) The glucuronyltransferase B4GAT1 is required for initiation of LARGE-mediated ?-dystroglycan functional glycosylation. Elife 3:
Crockett, Cameron D; Ruggieri, Alessandra; Gujrati, Meena et al. (2014) Late adult-onset of X-linked myopathy with excessive autophagy. Muscle Nerve 50:138-44
Goddeeris, Matthew M; Wu, Biming; Venzke, David et al. (2013) LARGE glycans on dystroglycan function as a tunable matrix scaffold to prevent dystrophy. Nature 503:136-40
Cirak, Sebahattin; Foley, Aileen Reghan; Herrmann, Ralf et al. (2013) ISPD gene mutations are a common cause of congenital and limb-girdle muscular dystrophies. Brain 136:269-81
Yang, Amy C; Ng, Bobby G; Moore, Steven A et al. (2013) Congenital disorder of glycosylation due to DPM1 mutations presenting with dystroglycanopathy-type congenital muscular dystrophy. Mol Genet Metab 110:345-51
Stevens, Elizabeth; Carss, Keren J; Cirak, Sebahattin et al. (2013) Mutations in B3GALNT2 cause congenital muscular dystrophy and hypoglycosylation of *-dystroglycan. Am J Hum Genet 92:354-65

Showing the most recent 10 out of 47 publications