Glucocorticoid treatment is recommended as a standard of care in Duchenne muscular dystrophy; however, few studies have assessed the long-term benefits of this treatment. We examined the long-term ...effects of glucocorticoids on milestone-related disease progression across the lifespan and survival in patients with Duchenne muscular dystrophy.
For this prospective cohort study, we enrolled male patients aged 2–28 years with Duchenne muscular dystrophy at 20 centres in nine countries. Patients were followed up for 10 years. We compared no glucocorticoid treatment or cumulative treatment duration of less than 1 month versus treatment of 1 year or longer with regard to progression of nine disease-related and clinically meaningful mobility and upper limb milestones. We used Kaplan-Meier analyses to compare glucocorticoid treatment groups for time to stand from supine of 5 s or longer and 10 s or longer, and loss of stand from supine, four-stair climb, ambulation, full overhead reach, hand-to-mouth function, and hand function. Risk of death was also assessed. This study is registered with ClinicalTrials.gov, number NCT00468832.
440 patients were enrolled during two recruitment periods (2006–09 and 2012–16). Time to all disease progression milestone events was significantly longer in patients treated with glucocorticoids for 1 year or longer than in patients treated for less than 1 month or never treated (log-rank p<0·0001). Glucocorticoid treatment for 1 year or longer was associated with increased median age at loss of mobility milestones by 2·1–4·4 years and upper limb milestones by 2·8–8·0 years compared with treatment for less than 1 month. Deflazacort was associated with increased median age at loss of three milestones by 2·1–2·7 years in comparison with prednisone or prednisolone (log-rank p<0·012). 45 patients died during the 10-year follow-up. 39 (87%) of these deaths were attributable to Duchenne-related causes in patients with known duration of glucocorticoids usage. 28 (9%) deaths occurred in 311 patients treated with glucocorticoids for 1 year or longer compared with 11 (19%) deaths in 58 patients with no history of glucocorticoid use (odds ratio 0·47, 95% CI 0·22–1·00; p=0·0501).
In patients with Duchenne muscular dystrophy, glucocorticoid treatment is associated with reduced risk of losing clinically meaningful mobility and upper limb disease progression milestones across the lifespan as well as reduced risk of death.
US Department of Education/National Institute on Disability and Rehabilitation Research; US Department of Defense; National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases; and Parent Project Muscular Dystrophy.
Broad A-band myopathy is an ultra-rare morphological diagnosis with only two prior cases reported in the literature. The apparent broadening of the A-band on light and electron microscopy is ...attributed to myosin thick filament misalignment leading to loss of distinct A- and I-bands with preservation of the Z-line. The first two patients described by Mrak et al. presented with hypotonia in infancy and delayed milestones but by 5 years old had minimal gross motor deficits and near normal neuromuscular exams. One of the patients had progressive blindness attributed to Leber's congenital amaurosis. Neither patient had a formal genetic diagnosis as both presented ∼30 years ago, before genetic testing was widely available, without further follow up. We present a third case of broad A-band myopathy in a patient with 3 variants in TTN (titin). Our patient is a now 19-year-old female who had delayed walking (2 ½ to 3 years old), increased falls for age and a clumsy appearing walk-run in childhood. Exam was notable for a high arched palate, mild diffuse proximal and distal weakness with reduced muscle stretch reflexes. CK was 167 units/L and electromyogram and nerve conduction studies at 14 years old were normal. MRI of the bilateral legs showed mild diffuse fatty atrophy of the muscles, most prominent in the rectus femoris and biceps femoris. Biopsy of the right rectus femoris muscle at 18 years old showed moderate variability in fiber size, increased endomysial connective tissue and numerous moth-eaten fibers. Ultrastructural analysis showed multifocal sarcomeric disorganization with broadened A-bands, loss of the I-bands, with and without associated Z-disc streaming. This finding supports that these mutations in titin can be associated with the ultrastructural finding of broad A-bands on muscle biopsy which may correlate with neuromuscular disease.
To determine whether pentoxifylline (PTX) slows the decline of muscle strength and function in ambulatory boys with Duchenne muscular dystrophy (DMD).
This was a multicenter, randomized, ...double-blinded, controlled trial comparing 12 months of daily treatment with PTX or placebo in corticosteroid-treated boys with DMD using a slow-release PTX formulation (~20 mg/kg/day). The primary outcome was the change in mean total quantitative muscle testing (QMT) score. Secondary outcomes included changes in QMT subscales, manual muscle strength, pulmonary function, and timed function tests. Outcomes were compared using Student t tests and a linear mixed-effects model. Adverse events (AEs) were compared using the Fisher exact test.
A total of 64 boys with DMD with a mean age of 9.9 ± 2.9 years were randomly assigned to PTX or placebo in 11 participating Cooperative International Neuromuscular Research Group centers. There was no significant difference between PTX and the placebo group in total QMT scores (p = 0.14) or in most of the secondary outcomes after a 12-month treatment. The use of PTX was associated with mild to moderate gastrointestinal or hematologic AEs.
The addition of PTX to corticosteroid-treated boys with DMD at a moderate to late ambulatory stage of disease did not improve or halt the deterioration of muscle strength and function over a 12-month study period.
This study provides Class I evidence that treatment with PTX does not prevent deterioration in muscle function or strength in corticosteroid-treated boys with DMD.
Spinal muscular atrophy (SMA) characterized by progressive muscle weakness and atrophy results in loss of function. Most outcomes assess motor function without assessing fatigue, a common clinical ...feature that may change with treatment. To assess feasibility and effectiveness of a performance-based evaluation using the Assisted 6 Minute Cycle Test (A6MCT) for non-ambulatory patients with SMA and to determine the relationship of A6MCT with the RULM and ATEND measures. Prospective data was collected on patients who were on disease modifying treatments for an average of 3.0 years. Outcomes used for analysis include: A6MCT total revolutions(TR) and % fatigue, RULM, ATEND, Fatigue Severity Score (FSS) and EK2. Analysis included association of A6MCT revolutions and fatigue with disease characteristics and outcomes. Two separate linear mixed models were utilized to analyze the interaction and change over time between visits (Significance ɑlevel of 0.05). Thirty-two participants were recruited (sitters=8.31.8±13.8 yrs; non-sitters=24.28.9±.5 yrs) who had 35 follow up evaluations (avg baseline to follow up=0.92 yrs). No differences in revolutions between functional groups or SMA type was found. No significant correlations with fatigue and RULM, ATEND, FSS; moderate correlations (r-0.6; p>0.05) with functional status and EK2 for both sitters (r=-0.7; p=0.005) and non-sitters (r=0.76; p=0.024). There was a statistically significant positive interaction between time and fatigue (β=7.136, p=0.0127). Sitters showed a statistically significant negative relationship with fatigue (β=-18.647, p=0.0055) showing less fatigue than the non-sitter group. TR showed a significantly positive interaction with time (β=46.455, p=0.0096). These results suggest that both time and functional status are predictors of fatigue, and TR shows change over time. The A6MCT test may be used in clinical settings for patients with SMA to evaluate endurance and fatigability.
Abstract High-throughput – next generation sequencing technologies constitute the most promising current development in the field of human genomics given its potential tool to study even sporadic ...patients with undefined genetic conditions. Next generation sequencing techniques allow researchers to produce over 100 times more data compared to the most sophisticated capillary sequencers based on the Sanger method. In our lab we have developed nextgen-sequencing strategies, where all candidate muscular disorders genes are sequenced in parallel through either targeted re-sequencing or exome sequencing. We compared three approaches to nextgen sequencing in patients with suspected neuromuscular disorders; RainDance targeted amplification of 1841 amplimers covering the exons and exon/intron boundaries of 46 neuromuscular disorders genes, and exomic sequencing (with and without a 46 gene filtering step). The RainDance unit fuses individual microbubbles of the amplimer mix with patient DNA. The emulsion is then PCR amplified, and amplimers were sequenced using 2nd generation sequencing (Illumina HiScan SQ). In parallel, whole exome sequencing was done on muscular dystrophy patients and was analyzed with or without the 46 gene filter. Data was assembled and analyzed using the NextGENe software and variants were called and reported accordingly. This strategy has two main issues: (1) each subject shows a huge number of DNA private sequence variations and (2) copy number variations are usually not detected. Incorporating SNP haplotype analysis or the concomitant analysis of entire nuclear families with apparent autosomal recessive or de novo dominant patterns of inheritance helps address some of these problems. Using this highly parallel, rapid, and relatively inexpensive genotyping strategy we have identified a number of disease associated and novel mutations. Results confirm a high degree of genetic heterogeneity in neuromuscular disorders, and reaffirm the promise targeted.
Muscle disease shows extensive genetic and allelic heterogeneity, with many genes causing related phenotypes. Some of the gene loci causing muscular dystrophy are the largest in the human genome ...(e.g. titin, dystrophin) making molecular diagnostics particularly challenging and expensive. Next generation sequencing promises single-test approach to diagnostics. A commonly utilized nextgen approach is whole exome sequence (WES), where hybrid capture of exons enables parallel sequencing of most exons in a single sequencing run. However, WES has an exonic drop-out rate of about 10% – 1 in 10 dystrophin, nebulin, titin or other gene exons would remain ‘non-sequenced’ with the WES approach. Thus, a negative result on WES does not necessarily rule out common genetic causes of muscle disease. An alternative approach is targeted sequencing panels. Here, each exon of specific candidate myopathy genes is individually amplified by microbubble PCR (RainDance), and this highly enriched DNA is then subjected to nextgen sequencing. Here, we develop and test a targeted muscle disease gene panel for 45 of the most common myopathy genes (1851 amplimers). We report our experience with this panel in 89 myopathy patients. We found greater consistency in depth of coverage (average 1000-fold coverage), less drop-out (2% instead of 10% in exomes), and genotype/phenotype concordance with clinician-determined differential diagnosis. Overall, targeted re-sequencing panels allow for more definitive testing of known muscular dystrophy genes. We give some specific case examples, with mutation in titin (TTN), ryanodine receptor (RYR1), and nebulin (NEB) genes. Both WES and targeted sequencing panels permit more centralized testing at greatly reduced cost and more rapid turn-around compared to single gene testing. The routine implementation of nextgen sequencing approaches should streamline molecular diagnostics, genetic counseling, and patient navigation for clinical trials.
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