Multi-parametric MR in Becker muscular dystrophy patients

Quantitative MRI and MRS of muscle are increasingly being used to measure individual pathophysiological processes in Becker muscular dystrophy (BMD). In particular, muscle fat fraction was shown to be highly associated with functional tests in BMD. However, the muscle strength per unit of contractile cross-sectional area is lower in patients with BMD compared with healthy controls. This suggests that the quality of the non-fat-replaced (NFR) muscle tissue is lower than in healthy controls. Consequently, a measure that reflects changes in muscle tissue itself is needed. Here, we explore the potential of water T2 relaxation times, diffusion parameters and phosphorus metabolic indices as early disease markers in patients with BMD. For this purpose, we examined these measures in fat-replaced (FR) and NFR lower leg muscles in patients with BMD and compared these values with those in healthy controls. Quantitative proton MRI (three-point Dixon, multi-spin-echo and diffusion-weighted spin-echo echo planar imaging) and 2D chemical shift imaging 31P MRS data were acquired in 24 patients with BMD (age 18.8-66.2 years) and 13 healthy controls (age 21.3-63.6 years). Muscle fat fractions, phosphorus metabolic indices, and averages and standard deviations (SDs) of the water T2 relaxation times and diffusion tensor imaging (DTI) parameters were assessed in six individual leg muscles. Phosphodiester levels were increased in the NFR and FR tibialis anterior, FR peroneus and FR gastrocnemius lateralis muscles. No clear pattern was visible for the other metabolic indices. Increased T2 SD was found in the majority of FR muscles compared with NFR and healthy control muscles. No differences in average water T2 relaxation times or DTI indices were found between groups. Overall, our results indicate that primarily muscles that are further along in the disease process showed increases in T2 heterogeneity and changes in some metabolic indices. No clear differences were found for the DTI indices between groups

Multi‐parametric MR in Becker muscular dystrophy patients

Quantitative MRI and MRS of muscle are increasingly being used to measure individual pathophysiological processes in Becker muscular dystrophy (BMD). In particular, muscle fat fraction was shown to be highly associated with functional tests in BMD. However, the muscle strength per unit of contractile cross-sectional area is lower in patients with BMD compared with healthy controls. This suggests that the quality of the non-fat-replaced (NFR) muscle tissue is lower than in healthy controls. Consequently, a measure that reflects changes in muscle tissue itself is needed. Here, we explore the potential of waterT(2)relaxation times, diffusion parameters and phosphorus metabolic indices as early disease markers in patients with BMD. For this purpose, we examined these measures in fat-replaced (FR) and NFR lower leg muscles in patients with BMD and compared these values with those in healthy controls. Quantitative proton MRI (three-point Dixon, multi-spin-echo and diffusion-weighted spin-echo echo planar imaging) and 2D chemical shift imaging(31)P MRS data were acquired in 24 patients with BMD (age 18.8-66.2 years) and 13 healthy controls (age 21.3-63.6 years). Muscle fat fractions, phosphorus metabolic indices, and averages and standard deviations (SDs) of the waterT(2)relaxation times and diffusion tensor imaging (DTI) parameters were assessed in six individual leg muscles. Phosphodiester levels were increased in the NFR and FR tibialis anterior, FR peroneus and FR gastrocnemius lateralis muscles. No clear pattern was visible for the other metabolic indices. IncreasedT(2)SD was found in the majority of FR muscles compared with NFR and healthy control muscles. No differences in average waterT(2)relaxation times or DTI indices were found between groups. Overall, our results indicate that primarily muscles that are further along in the disease process showed increases inT(2)heterogeneity and changes in some metabolic indices. No clear differences were found for the DTI indices between groups.Neuro Imaging Researc

TCTEX1D1 is a genetic modifier of disease progression in Duchenne muscular dystrophy

International audienceDuchenne muscular dystrophy (DMD) is caused by pathogenic variants in the DMD gene leading to the lack of dystrophin. Variability in the disease course suggests that other factors influence disease progression. With this study we aimed to identify genetic factors that may account for some of the variability in the clinical presentation. We compared whole-exome sequencing (WES) data in 27 DMD patients with extreme phenotypes to identify candidate variants that could affect disease progression. Validation of the candidate SNPs was performed in two independent cohorts including 301 (BIO-NMD cohort) and 109 (CINRG cohort of European ancestry) DMD patients, respectively. Variants in the Tctex1 domain containing 1 (TCTEX1D1) gene on chromosome 1 were associated with age of ambulation loss. The minor alleles of two independent variants, known to affect TCTEX1D1 coding sequence and induce skipping of its exon 4, were associated with earlier loss of ambulation. Our data show that disease progression of DMD is affected by a new locus on chromosome 1 and demonstrate the possibility to identify genetic modifiers in rare diseases by studying WES data in patients with extreme phenotypes followed by multiple layers of validatio

TCTEX1D1 is a genetic modifier of disease progression in Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is caused by pathogenic variants in the DMD gene leading to the lack of dystrophin. Variability in the disease course suggests that other factors influence disease progression. With this study we aimed to identify genetic factors that may account for some of the variability in the clinical presentation. We compared whole-exome sequencing (WES) data in 27 DMD patients with extreme phenotypes to identify candidate variants that could affect disease progression. Validation of the candidate SNPs was performed in two independent cohorts including 301 (BIO-NMD cohort) and 109 (CINRG cohort of European ancestry) DMD patients, respectively. Variants in the Tctex1 domain containing 1 (TCTEX1D1) gene on chromosome 1 were associated with age of ambulation loss. The minor alleles of two independent variants, known to affect TCTEX1D1 coding sequence and induce skipping of its exon 4, were associated with earlier loss of ambulation. Our data show that disease progression of DMD is affected by a new locus on chromosome 1 and demonstrate the possibility to identify genetic modifiers in rare diseases by studying WES data in patients with extreme phenotypes followed by multiple layers of validation