Clinical Trial Readiness for the Dystroglycanopathies

Overview

The purpose of the study is to describe the early signs and symptoms of the dystroglycanopathies, and to gather information that will be required for future clinical trials.

Detailed description

Muscular dystrophies are a diverse group of inherited disorders characterized by progressive muscle weakness and wasting. The disorders are caused by mutations, or changes, in genes. Genes are tiny pieces of inherited material (DNA) that direct the body to make certain kinds of proteins.

In this study, researchers will examine the clinical presentation of muscular dystrophy caused by abnormal glycosylation of alpha-dystroglycan. Patients with dystroglycanopathies could have mutations in any one of the more than 20 currently identified genes, or evidence of dystroglycanopathy in biopsied muscle tissue . Symptoms range from congenital muscular dystrophy that may involve the brain and eye, through an adult-onset limb girdle muscular dystrophy.

The study involves a clinical evaluation at the University of Iowa. The evaluation includes muscle strength and motor ability testing, lung function testing, quality of life and activity assessment, and a review of past medical history. Portions of this evaluation will be repeated on a yearly basis. Financial assistance is available for travel to Iowa City. Support is also available for genetic testing for people with a dystroglycanopathy diagnosis based on muscle or skin biopsy analysis.

Knowledge gained from this study will improve healthcare recommendations for people with dystroglycanopathies, and provide a baseline for further study, including potential treatment options.

Primary outcome measures

• 10 meter walk [Time frame: through study completion, an average of 1 yea]

Secondary outcome measures (1)

• 4 stair climb [Time frame: through study completion, an average of 1 yea]

Eligibility criteria

Inclusion criteria

• Elevated CK (creatine kinase)
• Evidence of a dystroglycanopathy as determined by review of muscle pathology OR documented mutation in one of the known genes OR abnormal alpha-dystroglycan glycosylation in cultured fibroblasts
• Dystroglycanopathies are predicted to affect all racial and ethnic backgrounds, and all patients with dystroglycanopathies will be eligible for participation.
• Participants may be of any age, including children, and males and females will be recruited equally.
• Patients will have varying degrees of muscular weakness, but otherwise should be in relatively good health.

Exclusion criteria

• There are no exclusion criteria.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

United States · 1 center

• University of Iowa, 200 Hawkins Drive — Iowa City

Publications

• Crockett CD, Bertrand LA, Cooper CS, Rahhal RM, Liu K, Zimmerman MB, Moore SA, Mathews KD. Urologic and gastrointestinal symptoms in the dystroglycanopathies. Neurology. 2015 Feb 3;84(5):532-9. doi: 10.1212/WNL.0000000000001213. Epub 2015 Jan 7. PMID 25568299
• Mathews KD, Stephan CM, Laubenthal K, Winder TL, Michele DE, Moore SA, Campbell KP. Myoglobinuria and muscle pain are common in patients with limb-girdle muscular dystrophy 2I. Neurology. 2011 Jan 11;76(2):194-5. doi: 10.1212/WNL.0b013e3182061ad4. No abstract available. PMID 21220724
• Jensen BS, Willer T, Saade DN, Cox MO, Mozaffar T, Scavina M, Stefans VA, Winder TL, Campbell KP, Moore SA, Mathews KD. GMPPB-Associated Dystroglycanopathy: Emerging Common Variants with Phenotype Correlation. Hum Mutat. 2015 Dec;36(12):1159-63. doi: 10.1002/humu.22898. Epub 2015 Sep 23. PMID 26310427
• Brun BN, Willer T, Darbro BW, Gonorazky HD, Naumenko S, Dowling JJ, Campbell KP, Moore SA, Mathews KD. Uniparental disomy unveils a novel recessive mutation in POMT2. Neuromuscul Disord. 2018 Jul;28(7):592-596. doi: 10.1016/j.nmd.2018.04.003. Epub 2018 Apr 10. PMID 29759639
• Lee AJ, Jones KA, Butterfield RJ, Cox MO, Konersman CG, Grosmann C, Abdenur JE, Boyer M, Beson B, Wang C, Dowling JJ, Gibbons MA, Ballard A, Janas JS, Leshner RT, Donkervoort S, Bonnemann CG, Malicki DM, Weiss RB, Moore SA, Mathews KD. Clinical, genetic, and pathologic characterization of FKRP Mexican founder mutation c.1387A>G. Neurol Genet. 2019 Mar 1;5(2):e315. doi: 10.1212/NXG.0000000000000315 PMID 31041397
• Gonzalez-Perez P, Smith C, Sebetka WL, Gedlinske A, Perlman S, Mathews KD. Clinical and electrophysiological evaluation of myasthenic features in an alpha-dystroglycanopathy cohort (FKRP-predominant). Neuromuscul Disord. 2020 Mar;30(3):213-218. doi: 10.1016/j.nmd.2020.01.002. Epub 2020 Jan 25. PMID 32115343
• Hagedorn JL, Dunn TM, Bhattarai S, Stephan C, Mathews KD, Pfeifer W, Drack AV. Electroretinogram abnormalities in FKRP-related limb-girdle muscular dystrophy (LGMDR9). Doc Ophthalmol. 2023 Feb;146(1):7-16. doi: 10.1007/s10633-022-09909-4. Epub 2022 Nov 18. PMID 36399172
• Weiss RM, Kerber RE, Jones JK, Stephan CM, Trout CJ, Lindower PD, Staffey KS, Campbell KP, Mathews KD. Exercise-induced left ventricular systolic dysfunction in women heterozygous for dystrophinopathy. J Am Soc Echocardiogr. 2010 Aug;23(8):848-53. doi: 10.1016/j.echo.2010.05.007. Epub 2010 Jun 19. PMID 20646909

Identifiers

NCT: NCT00313677 · 200510743 · U54NS053672

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗