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Predicting the severity of Duchenne muscular dystrophy Implications for treatment

Neurology (Impact Factor: 8.3). 01/2011; 76(3):208-9. DOI: 10.1212/WNL.0b013e3182074c0e
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    ABSTRACT: To test the effect of the single nucleotide polymorphism -66 T>G (rs28357094) in the osteopontin gene (SPP1) on functional measures over 12 months in Duchenne muscular dystrophy (DMD). This study was conducted on a cohort of ambulatory patients with DMD from a network of Italian neuromuscular centers, evaluated longitudinally with the north star ambulatory assessment (NSAA) and the 6-minute walk test (6MWT) at study entry and after 12 months. Genotype at rs28357094 was determined after completion of the clinical evaluations. Patients were stratified in 2 groups according to a dominant model (TT homozygotes vs TG heterozygotes and GG homozygotes) and clinical data were retrospectively compared between groups. Eighty patients were selected (age 4.1-19.3 years; mean 8.3 ± 2.7 SD). There were no differences in age or steroid treatment between the 2 subgroups. Paired t test showed a significant difference in both NSAA (p = 0.013) and 6MWT (p = 0.03) between baseline and follow-up after 12 months in patients with DMD carrying the G allele. The difference was not significant in the T subgroup. The analysis of covariance using age and baseline values as covariate and SPP1 genotype as fixed effect showed that these parameters are significantly correlated with the 12-month values. These data provide evidence of the role of SPP1 genotype as a disease modifier in DMD and support its relevance in the selection of homogeneous groups of patients for future clinical trials.
    Neurology 06/2012; 79(2):159-62. DOI:10.1212/WNL.0b013e31825f04ea · 8.30 Impact Factor
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    ABSTRACT: We studied the effects of LTBP4 and SPP1 polymorphisms on age at loss of ambulation (LoA) in a multiethnic Duchenne muscular dystrophy cohort (DMD).We genotyped SPP1 rs28357094 and LTBP4 haplotype in 283/340 participants in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG-DNHS). Median ages at LoA were compared by Kaplan-Meier analysis and log-rank test. We controlled polymorphism analyses for concurrent effects of glucocorticoid corticosteroid (GC) treatment (time-varying Cox regression), and for population stratification (multidimensional scaling of genome-wide markers).Hispanic and South Asian participants (n = 18, 41) lost ambulation 2.7 and 2 years earlier than Caucasian (p = 0.003, <0.001). The TG/GG genotype at SPP1 rs28357094 was associated to 1.2-year earlier median LoA (p = 0.048). This difference was greater (1.9 years, p = 0.038) in GC-treated participants, whereas no difference was observed in untreated. Cox regression confirmed a significant effect of SPP1 genotype in GC-treated participants (HR 1.61, p = 0.016). LTBP4 genotype showed a direction of association with age at LoA as previously reported, but not statistically significant. After controlling for population stratification, we confirmed a strong effect of LTBP4 genotype in Caucasians (2.4 years, p = 0.024). Median age at LoA with the protective LTBP4 genotype in this cohort was 15.0 years, 16.0 if GC-treated.In conclusion, SPP1 rs28357094 acts as a pharmacodynamic biomarker of GC response, and LTBP4 haplotype modifies age at LoA in the CINRG-DNHS cohort. Adjustment for GC treatment and population stratification appears crucial in assessing genetic modifiers in DMD. This article is protected by copyright. All rights reserved.
    Annals of Neurology 01/2015; DOI:10.1002/ana.24370 · 11.91 Impact Factor
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    ABSTRACT: Abstract Background: The measurement of time and compensatory movements for functional tasks is not frequently used to evaluate children with Duchenne muscular dystrophy (DMD). As muscle weakness progresses, new synergies (compensatory movements) are selected to perform the tasks, demanding higher times. Objectives: The present study aimed to describe the timed motor performance of rising from the floor to standing, sitting down on the floor from standing, climbing up four steps and climbing down four steps 18 and 6 months prior to gait loss and to investigate possible relationships between these timed performances, the compensatory movements and the Vignos Scale (VS) scores. Method: Fourteen children with DMD (mean age: 9.6) were videotaped performing the tasks. Spearman correlation tests investigated the relationships between the times, compensatory movements (scored by FES-DMD) and VS. Results: The timed performance and the compensatory movements for rising from the floor, climbing up and climbing down steps varied broadly and were correlated to each other among patients with DMD at 18 and 6 months prior to gait loss. The relationship was not found for sitting on the floor. The timed performance and compensatory movements for climbing up and down steps also correlated to the VS. Conclusion: Rising from the floor, climbing up, and climbing down steps have some components in common, such as the demand for muscle strength and the recruitment of compensatory muscle synergies, as DMD progresses. To sit down on the floor, some children let themselves fall, resulting in a faster performance, but more compensatory movements.
    Physiotherapy Theory and Practice 12/2014; DOI:10.3109/09593985.2014.989294