Spinal muscular atrophy (SMA) is a progressive neuromuscular disorder characterized by loss of motor neurons leading to muscle weakness and atrophy. The United States’ Food and Drug Administration's ...(FDA) approval of nusinersen, onasemnogene abeparvovec, and risdiplam for SMA has challenged existing treatment paradigms with multiple treatment options, a new natural history of the disease, and an emerging understanding of the importance of early and pre-symptomatic treatment. The profound impact of early, pre-symptomatic treatment has led to the creation of a neurogenetics urgency for newly identified patients with SMA, a novel problem for neurologists more accustomed to a more methodical approach to diagnosis and care. Implementation of newborn screening programs has helped facilitate early diagnosis and treatment, but challenges remain in overcoming administrative and procedural hurdles that can lead to treatment delays. Herein I discuss 2 cases that highlight the importance of early treatment, as well as gaps in our understanding of the progression of SMA in pre-symptomatic infants.
Congenital muscular dystrophies and congenital myopathies are a heterogeneous group of disorders resulting in hypotonia, muscle weakness, and dystrophic or myopathic features on muscle biopsy. This ...article summarizes the clinical and genetic aspects of these disorders.
Historically, diagnoses of congenital muscular dystrophy and congenital myopathy have been made by clinical features and histopathology; however, recent advances in genetics have changed diagnostic practice by relying more heavily on genetic findings. This article reviews the clinical and genetic features of the most common congenital muscular dystrophies including laminin subunit alpha 2 (LAMA2)-related (merosin deficient), collagen VI-related, and α-dystroglycan-related congenital muscular dystrophies and reviews the most common congenital myopathies including nemaline rod, core, and centronuclear myopathies. With the increasing accessibility of genetic testing, the number of genes found to be associated with these disorders has increased dramatically. A wide spectrum of severity and onset (from birth to adulthood) exist across all subtypes. Progression and other features are variable depending on the subtype and severity of the specific genetic mutation.
Congenital muscular dystrophy and congenital myopathy are increasingly recognized disorders. A growing appreciation for the breadth of phenotypic variability and overlap between established subtypes has challenged long-standing phenotypic and histopathologic classifications of these disorders but has driven a greater understanding of pathogenesis and opened the door to the development of novel treatments.
To determine whether the genetic prevalence of the CTG expansion in the
gene associated with myotonic dystrophy type 1 (DM1) in an unbiased cohort is higher than previously reported population ...estimates, ranging from 5 to 20 per 100,000 individuals.
This study used a cross-sectional cohort of deidentified dried blood spots from the newborn screening program in the state of New York, taken from consecutive births from 2013 to 2014. Blood spots were screened for the CTG repeat expansion in the
gene using triplet-repeat primed PCR and melt curve analysis. Melt curve morphology was assessed by 4 blinded reviewers to identify samples with possible CTG expansion. Expansion of the CTG repeat was validated by PCR fragment sizing using capillary electrophoresis for samples classified as positive or premutation to confirm the result. Prevalence was calculated as the number of samples with CTG repeat size ≥50 repeats compared to the overall cohort.
Of 50,382 consecutive births, there were 24 with a CTG repeat expansion ≥50, consistent with a diagnosis of DM1. This represents a significantly higher DM1 prevalence of 4.76 per 10,000 births (95% confidence interval 2.86-6.67) or 1 in every 2,100 births. There were an additional 96 samples (19.1 per 10,000 or 1 in 525 births) with a CTG expansion in the
gene in the premutation range (CTG)
.
The prevalence of individuals with CTG repeat expansions in
is up to 5 times higher than previous reported estimates. This suggests that DM1, with multisystemic manifestations, is likely underdiagnosed in practice.
In mammalian embryos, proper zygotic genome activation (ZGA) underlies totipotent development. Double homeobox (DUX)-family factors participate in ZGA, and mouse Dux is required for forming cultured ...two-cell (2C)-like cells. Remarkably, in mouse embryonic stem cells, Dux is activated by the tumor suppressor p53, and Dux expression promotes differentiation into expanded-fate cell types. Long-read sequencing and assembly of the mouse Dux locus reveals its complex chromatin regulation including putative positive and negative feedback loops. We show that the p53-DUX/DUX4 regulatory axis is conserved in humans. Furthermore, we demonstrate that cells derived from patients with facioscapulohumeral muscular dystrophy (FSHD) activate human DUX4 during p53 signaling via a p53-binding site in a primate-specific subtelomeric long terminal repeat (LTR)10C element. In summary, our work shows that p53 activation convergently evolved to couple p53 to Dux/DUX4 activation in embryonic stem cells, embryos and cells from patients with FSHD, potentially uniting the developmental and disease regulation of DUX-family factors and identifying evidence-based therapeutic opportunities for FSHD.
•NURTURE is an ongoing study of nusinersen started in a presymptomatic stage of SMA.•All infants were ≥25 months old, and alive without permanent ventilation.•All infants achieved independent sitting ...and 88% (22/25) were walking alone.•Nusinersen demonstrated durability of effect with a median 2.9 years of follow up.•Nusinersen was well tolerated with no new safety concerns over extended follow up.
Spinal muscular atrophy (SMA) is a neurodegenerative disease associated with severe muscle atrophy and weakness in the limbs and trunk. We report interim efficacy and safety outcomes as of March 29, 2019 in 25 children with genetically diagnosed SMA who first received nusinersen in infancy while presymptomatic in the ongoing Phase 2, multisite, open-label, single-arm NURTURE trial. Fifteen children have two SMN2 copies and 10 have three SMN2 copies. At last visit, children were median (range) 34.8 25.7–45.4 months of age and past the expected age of symptom onset for SMA Types I or II; all were alive and none required tracheostomy or permanent ventilation. Four (16%) participants with two SMN2 copies utilized respiratory support for ≥6 h/day for ≥7 consecutive days that was initiated during acute, reversible illnesses. All 25 participants achieved the ability to sit without support, 23/25 (92%) achieved walking with assistance, and 22/25 (88%) achieved walking independently. Eight infants had adverse events considered possibly related to nusinersen by the study investigators. These results, representing a median 2.9 years of follow up, emphasize the importance of proactive treatment with nusinersen immediately after establishing the genetic diagnosis of SMA in presymptomatic infants and emerging newborn screening efforts.
Introduction
The North Star Ambulatory Assessment (NSAA) tool is a key instrument for measuring clinical outcomes in patients with Duchenne muscular dystrophy (DMD). To gain a better understanding of ...the longitudinal utility of the NSAA, we evaluated NSAA data from a phase II trial of 120 patients with DMD treated with domagrozumab or placebo.
Methods
The NSAA exploratory analyses included assessment of individual skills gained/lost, total skills gained/lost, cumulative loss of function, and the impact of transient loss of function due to a temporary disability on NSAA total score (temporary zero score).
Results
There was no significant difference in the total number of NSAA skills gained (mean 1.41 and 1.04, respectively; p = 0.3314) or lost (3.90 vs. 5.0; p = 0.0998) between domagrozumab- vs. placebo-treated patients at week 49. However, domagrozumab-treated patients were less likely to lose the ability to perform a NSAA item (hazard ratio 0.80, 95% confidence interval CI: 0.65–0.98, p = 0.029) over 48-weeks vs. placebo-treated patients. When temporary zero scores were changed to “not obtainable” (8 values from 7 patients), domagrozumab-treated patients scored higher on the NSAA total score versus placebo-treated patients (difference at week 49: 2.0, 95% CI: 0.1–3.9, p = 0.0359).
Conclusions
These exploratory analyses reveal additional approaches to interpreting the NSAA data beyond just change in NSAA total score. These observations also highlight the importance of reporting items as “not obtainable” for a patient with a temporary/transient physical disability that impacts their ability to perform the NSAA test.
ClinicalTrials.gov identifier
NCT02310763
.
Fascioscapulohumeral muscular dystrophy (FSHD) is caused by a unique genetic mechanism that relies on contraction and hypomethylation of the D4Z4 macrosatellite array on the Chromosome 4q telomere ...allowing ectopic expression of the
gene in skeletal muscle. Genetic analysis is difficult because of the large size and repetitive nature of the array, a nearly identical array on the 10q telomere, and the presence of divergent D4Z4 arrays scattered throughout the genome. Here, we combine nanopore long-read sequencing with Cas9-targeted enrichment of 4q and 10q D4Z4 arrays for comprehensive genetic analysis including determination of the length of the 4q and 10q D4Z4 arrays with base-pair resolution. In the same assay, we differentiate 4q from 10q telomeric sequences, determine A/B haplotype, identify paralogous D4Z4 sequences elsewhere in the genome, and estimate methylation for all CpGs in the array. Asymmetric, length-dependent methylation gradients were observed in the 4q and 10q D4Z4 arrays that reach a hypermethylation point at approximately 10 D4Z4 repeat units, consistent with the known threshold of pathogenic D4Z4 contractions. High resolution analysis of individual D4Z4 repeat methylation revealed areas of low methylation near the CTCF/insulator region and areas of high methylation immediately preceding the
transcriptional start site. Within the
exons, we observed a waxing/waning methylation pattern with a 180-nucleotide periodicity, consistent with phased nucleosomes. Targeted nanopore sequencing complements recently developed molecular combing and optical mapping approaches to genetic analysis for FSHD by adding precision of the length measurement, base-pair resolution sequencing, and quantitative methylation analysis.
To evaluate the cost-effectiveness of nusinersen with and without universal newborn screening for infantile-onset spinal muscular atrophy (SMA).
A Markov model using data from clinical trials with US ...epidemiologic and cost data was developed. The primary interventions studied were nusinersen treatment in a screening setting, nusinersen treatment in a nonscreening setting, and standard care. Analysis was conducted from a societal perspective.
Compared with no screening and no treatment, the incremental cost-effectiveness ratio (ICER) for nusinersen with screening was $330 558 per event-free life year (LY) saved, whereas the ICER for nusinersen treatment without screening was $508 481 per event-free LY saved. For nusinersen with screening to be cost-effective at a willingness-to-pay (WTP) threshold of $50 000 per event-free LY saved, the price would need to be $23 361 per dose, less than one-fifth its current price of $125 000. Preliminary data from the NURTURE trial indicated an 85.7% improvement in expected LYs saved compared with our base results. In probabilistic sensitivity analysis, nusinersen and screening was a preferred strategy 93% of the time at a $500 000 WTP threshold.
Universal newborn screening for SMA provides improved economic value for payers and patients when nusinersen is available.
We evaluated whether whole-body dual-energy X-ray absorptiometry (DXA) measures of lean body mass can be used as biomarkers for disease progression and treatment effects in patients with Duchenne ...muscular dystrophy. This post hoc analysis utilized data from a randomized, 2-period study of domagrozumab versus placebo in 120 ambulatory boys with DMD. DXA measures of lean body mass were obtained from the whole body (excluding head), arms, legs and appendicular skeleton at baseline and every 16 weeks. Treatment effects on DXA measures for domagrozumab versus placebo were assessed at Week 49. At Week 49, domagrozumab statistically significantly increased lean body mass versus placebo in the appendicular skeleton (p = 0.050) and arms (p < 0.001). The relationship between lean body mass at Week 49 and functional endpoints at Week 97 was evaluated. Changes in lean body mass at Week 49 in all regions except arms were significantly correlated with percent change from baseline in 4-stair climb (4SC) at Week 97. DXA-derived percent lean mass at Week 49 also correlated with 4SC and North Star Ambulatory Assessment at Week 97. These data indicate that whole-body DXA measures can be used as biomarkers for treatment effects and disease progression in patients with DMD, and warrant further investigation.Trial registration: ClinicalTrials.gov, NCT02310763; registered 8 December 2014.
The collagen VI related muscular dystrophies (COL6-RD), Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM) are among the most common congenital muscular dystrophies and are ...characterized by distal joint laxity and a combination of distal and proximal joint contractures. Inheritance can be dominant negative (DN) or recessive depending on the type and location of the mutation. DN mutations allow incorporation of abnormal chains into secreted tetramers and are the most commonly identified mutation type in COL6-RD. Null alleles (nonsense, frameshift, and large deletions) do not allow incorporation of abnormal chains and act recessively. To better define the pathways disrupted by mutations in collagen VI, we have used a transcriptional profiling approach with RNA-Seq to identify differentially expressed genes in COL6-RD individuals from controls.
RNA-Seq allows precise detection of all expressed transcripts in a sample and provides a tool for quantification of expression data on a genomic scale. We have used RNA-Seq to identify differentially expressed genes in cultured dermal fibroblasts from 13 COL6-RD individuals (8 dominant negative and 5 null) and 6 controls. To better assess the transcriptional changes induced by abnormal collagen VI in the extracellular matrix (ECM); we compared transcriptional profiles from subjects with DN mutations and subjects with null mutations to transcriptional profiles from controls.
Differentially expressed transcripts between COL6-RD and control fibroblasts include upregulation of ECM components and downregulation of factors controlling matrix remodeling and repair. DN and null samples are differentiated by downregulation of genes involved with DNA replication and repair in null samples.
Differentially expressed genes identified here may help identify new targets for development of therapies and biomarkers to assess the efficacy of treatments.
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