Jeffrey M Statland1, Colleen M Donlin-Smith2, Stephen J Tapscott2, Richard J L F Lemmers2, Silvère M van der Maarel2, Rabi Tawil2. 1. From the Department of Neurology (J.M.S.), University of Kansas Medical Center, Kansas City; the Department of Neurology (C.M.D., R.T.), University of Rochester Medical Center, NY; the Division of Human Biology (S.J.T.), Fred Hutchinson Cancer Research Center, Seattle, WA; and the Department of Human Genetics (R.J.L.F.L., S.M.v.d.M.), Leiden University Medical Center, the Netherlands. jstatland@kumc.edu. 2. From the Department of Neurology (J.M.S.), University of Kansas Medical Center, Kansas City; the Department of Neurology (C.M.D., R.T.), University of Rochester Medical Center, NY; the Division of Human Biology (S.J.T.), Fred Hutchinson Cancer Research Center, Seattle, WA; and the Department of Human Genetics (R.J.L.F.L., S.M.v.d.M.), Leiden University Medical Center, the Netherlands.
Abstract
OBJECTIVE: To examine the relationship of clinical and genetic features of patients with facioscapulohumeral muscular dystrophy (FSHD) with 7-10 residual D4Z4 repeats in a large genetically defined FSHD1 cohort. METHODS: We performed a prospective cross-sectional observational study of 74 clinically affected patients with FSHD1. Measures of clinical severity were compared between patients with 1-6 D4Z4 repeats and 7-10 repeats, and included D4Z4 CpG methylation, age at diagnosis, age-adjusted clinical severity score, a muscle pathology grade of quadriceps biopsies (0 = normal, 12 = severe dystrophic changes), quantitative myometry of biopsied muscles, global manual muscle testing scores, and frequency of wheelchair use. RESULTS: Twenty-eight (37.8%) participants had 7-10 D4Z4 repeats, and compared to participants with 1-6 repeats, were diagnosed 6.6 years older (p = 0.17); had lower CpG methylation than would be predicted by D4Z4 repeat size (p = 0.04); had age-adjusted clinical severity 39.8 points lower (p = 0.004); had muscle pathology grades that were 2.4 points less severe (p < 0.0001); had quantitative myometry 28.3% predicted of normal higher (p = 0.002); had global manual muscle testing scores 0.6 higher (p = 0.005); and did not require wheelchairs. CONCLUSION: Patients with FSHD with 7-10 D4Z4 repeats have milder disease than other genetically defined patients with FSHD1. The lower than predicted methylation in the 7-10 residual repeat group may suggest that additional epigenetic factors play a role in the severity of disease expression.
OBJECTIVE: To examine the relationship of clinical and genetic features of patients with facioscapulohumeral muscular dystrophy (FSHD) with 7-10 residual D4Z4 repeats in a large genetically defined FSHD1 cohort. METHODS: We performed a prospective cross-sectional observational study of 74 clinically affected patients with FSHD1. Measures of clinical severity were compared between patients with 1-6 D4Z4 repeats and 7-10 repeats, and included D4Z4 CpG methylation, age at diagnosis, age-adjusted clinical severity score, a muscle pathology grade of quadriceps biopsies (0 = normal, 12 = severe dystrophic changes), quantitative myometry of biopsied muscles, global manual muscle testing scores, and frequency of wheelchair use. RESULTS: Twenty-eight (37.8%) participants had 7-10 D4Z4 repeats, and compared to participants with 1-6 repeats, were diagnosed 6.6 years older (p = 0.17); had lower CpG methylation than would be predicted by D4Z4 repeat size (p = 0.04); had age-adjusted clinical severity 39.8 points lower (p = 0.004); had muscle pathology grades that were 2.4 points less severe (p < 0.0001); had quantitative myometry 28.3% predicted of normal higher (p = 0.002); had global manual muscle testing scores 0.6 higher (p = 0.005); and did not require wheelchairs. CONCLUSION:Patients with FSHD with 7-10 D4Z4 repeats have milder disease than other genetically defined patients with FSHD1. The lower than predicted methylation in the 7-10 residual repeat group may suggest that additional epigenetic factors play a role in the severity of disease expression.
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