The Influence of a Genetic Variant in CCDC78 on LMNA-Associated Skeletal Muscle Disease.

Mutations in the LMNA gene-encoding A-type lamins can cause Limb-Girdle muscular dystrophy Type 1B (LGMD1B). This disease presents with weakness and wasting of the proximal skeletal muscles and has a variable age of onset and disease severity. This variability has been attributed to genetic background differences among individuals; however, such variants have not been well characterized. To identify such variants, we investigated a multigeneration family in which affected individuals are diagnosed with LGMD1B. The primary genetic cause of LGMD1B in this family is a dominant mutation that activates a cryptic splice site, leading to a five-nucleotide deletion in the mature mRNA. This results in a frame shift and a premature stop in translation. Skeletal muscle biopsies from the family members showed dystrophic features of variable severity, with the muscle fibers of some family members possessing cores, regions of sarcomeric disruption, and a paucity of mitochondria, not commonly associated with LGMD1B. Using whole genome sequencing (WGS), we identified 21 DNA sequence variants that segregate with the family members possessing more profound dystrophic features and muscle cores. These include a relatively common variant in coiled-coil domain containing protein 78 (CCDC78). This variant was given priority because another mutation in CCDC78 causes autosomal dominant centronuclear myopathy-4, which causes cores in addition to centrally positioned nuclei. Therefore, we analyzed muscle biopsies from family members and discovered that those with both the LMNA mutation and the CCDC78 variant contain muscle cores that accumulated both CCDC78 and RyR1. Muscle cores containing mislocalized CCDC78 and RyR1 were absent in the less profoundly affected family members possessing only the LMNA mutation. Taken together, our findings suggest that a relatively common variant in CCDC78 can impart profound muscle pathology in combination with a LMNA mutation and accounts for variability in skeletal muscle disease phenotypes.

Management of Select Adverse Events Following Delandistrogene Moxeparvovec Gene Therapy for Patients With Duchenne Muscular Dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a rare, degenerative, recessive X-linked neuromuscular disease. Mutations in the gene encoding dystrophin lead to the absence of functional dystrophin protein. Individuals living with DMD exhibit progressive muscle weakness resulting in loss of ambulation and limb function, respiratory insufficiency, and cardiomyopathy, with multiorgan involvement. Adeno-associated virus vector-mediated gene therapy designed to enable production of functional dystrophin protein is a new therapeutic strategy. Delandistrogene moxeparvovec (Sarepta Therapeutics, Cambridge, MA) is indicated for treatment of ambulatory pediatric patients aged 4 through 5 years with DMD who have an indicated mutation in the DMD gene. OBJECTIVE: Evidence-based considerations for management of potential adverse events following gene therapy treatment for DMD are lacking in clinical literature. Our goal was to provide interdisciplinary consensus considerations for selected treatment-related adverse events (TRAEs) (vomiting, acute liver injury, myocarditis, and immune-mediated myositis) that may arise following gene therapy dosing with delandistrogene moxeparvovec. METHODS: An interdisciplinary panel of 12 specialists utilized a modified Delphi process to develop consensus considerations for the evaluation and management of TRAEs reported in delandistrogene moxeparvovec clinical studies. Panelists completed 2 Questionnaires prior to gathering for an in-person discussion. Consensus was defined as a majority (≥58% ; 7/12) of panelists either agreeing or disagreeing. RESULTS: Panelists agreed that the choice of baseline assessments should be informed by individual clinical indications, the treating provider's judgment, and prescribing information. Corticosteroid dosing for treatment of TRAEs should be optimized by considering individual risk versus benefit for each indication. In all cases involving patients with a confirmed TRAE, consultations with appropriate specialists were suggested. CONCLUSIONS: The Delphi Panel established consensus considerations for the evaluation and management of potential TRAEs for patients receiving delandistrogene moxeparvovec, including vomiting, acute liver injury, myocarditis, and immune-mediated myositis.

Defining clinical endpoints in limb girdle muscular dystrophy: a GRASP-LGMD study.

BACKGROUND: The Limb Girdle Muscular Dystrophies (LGMDs) are characterized by progressive weakness of the shoulder and hip girdle muscles as a result of over 30 different genetic mutations. This study is designed to develop clinical outcome assessments across the group of disorders. METHODS/DESIGN: The primary goal of this study is to evaluate the utility of a set of outcome measures on a wide range of LGMD phenotypes and ability levels to determine if it would be possible to use similar outcomes between individuals with different phenotypes. We will perform a multi-center, 12-month study of 188 LGMD patients within the established Genetic Resolution and Assessments Solving Phenotypes in LGMD (GRASP-LGMD) Research Consortium, which is comprised of 11 sites in the United States and 2 sites in Europe. Enrolled patients will be clinically affected and have mutations in CAPN3 (LGMDR1), ANO5 (LGMDR12), DYSF (LGMDR2), DNAJB6 (LGMDD1), SGCA (LGMDR3), SGCB (LGMDR4), SGCD (LGMDR6), or SGCG (LGMDR5, or FKRP-related (LGMDR9). DISCUSSION: To the best of our knowledge, this will be the largest consortium organized to prospectively validate clinical outcome assessments (COAs) in LGMD at its completion. These assessments will help clinical trial readiness by identifying reliable, valid, and responsive outcome measures as well as providing data driven clinical trial decision making for future clinical trials on therapeutic agents for LGMD. The results of this study will permit more efficient clinical trial design. All relevant data will be made available for investigators or companies involved in LGMD therapeutic development upon conclusion of this study as applicable. TRIAL REGISTRATION: Clinicaltrials.gov NCT03981289; Date of registration: 6/10/2019.

Safety and efficacy of givinostat in boys with Duchenne muscular dystrophy (EPIDYS): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Duchenne muscular dystrophy, the most common childhood muscular dystrophy, is caused by dystrophin deficiency. Preclinical and phase 2 study data have suggested that givinostat, a histone deacetylase inhibitor, might help to counteract the effects of this deficiency. We aimed to evaluate the safety and efficacy of givinostat in the treatment of Duchenne muscular dystrophy. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 3 trial was done at 41 tertiary care sites in 11 countries. Eligible participants were ambulant, male, and aged at least 6 years, had a genetically confirmed diagnosis of Duchenne muscular dystrophy, completed two four-stair climb assessments with a mean of 8 s or less (≤1 s variance), had a time-to-rise of at least 3 s but less than 10 s, and had received systemic corticosteroids for at least 6 months. Participating boys were randomly assigned (2:1, allocated according to a list generated by the interactive response technology provider) to receive either oral givinostat or matching placebo twice a day for 72 weeks, stratified by concomitant steroid use. Boys, investigators, and site and sponsor staff were masked to treatment assignment. The dose was flexible, based on weight, and was reduced if not tolerated. Boys were divided into two groups on the basis of their baseline vastus lateralis fat fraction (VLFF; measured by magnetic resonance spectroscopy): group A comprised boys with a VLFF of more than 5% but no more than 30%, whereas group B comprised boys with a VLFF of 5% or less, or more than 30%. The primary endpoint compared the effects of givinostat and placebo on the change in results of the four-stair climb assessment between baseline and 72 weeks, in the intention-to-treat, group A population. Safety was assessed in all randomly assigned boys who received at least one dose of study drug. When the first 50 boys in group A completed 12 months of treatment, an interim futility assessment was conducted, after which the sample size was adapted using masked data from the four-stair climb assessments. Furthermore, the starting dose of givinostat was reduced following a protocol amendment. This trial is registered with ClinicalTrials.gov, NCT02851797, and is complete. FINDINGS: Between June 6, 2017, and Feb 22, 2022, 359 boys were assessed for eligibility. Of these, 179 were enrolled into the study (median age 9·8 years [IQR 8·1-11·0]), all of whom were randomly assigned (118 to receive givinostat and 61 to receive placebo); 170 (95%) boys completed the study. Of the 179 boys enrolled, 120 (67%) were in group A (81 givinostat and 39 placebo); of these, 114 (95%) completed the study. For participants in group A, comparing the results of the four-stair climb assessment at 72 weeks and baseline, the geometric least squares mean ratio was 1·27 (95% CI 1·17-1·37) for boys receiving givinostat and 1·48 (1·32-1·66) for those receiving placebo (ratio 0·86, 95% CI 0·745-0·989; p=0·035). The most common adverse events in the givinostat group were diarrhoea (43 [36%] of 118 boys vs 11 [18%] of 61 receiving placebo) and vomiting (34 [29%] vs 8 [13%]); no treatment-related deaths occurred. INTERPRETATION: Among ambulant boys with Duchenne muscular dystrophy, results of the four-stair climb assessment worsened in both groups over the study period; however, the decline was significantly smaller with givinostat than with placebo. The dose of givinostat was reduced after an interim safety analysis, but no new safety signals were reported. An ongoing extension study is evaluating the long-term safety and efficacy of givinostat in patients with Duchenne muscular dystrophy. FUNDING: Italfarmaco.

Adaptive Long-Read Sequencing Reveals GGC Repeat Expansion in ZFHX3 Associated with Spinocerebellar Ataxia Type 4.

BACKGROUND: Spinocerebellar ataxia type 4 (SCA4) is an autosomal dominant ataxia with invariable sensory neuropathy originally described in a family with Swedish ancestry residing in Utah more than 25 years ago. Despite tight linkage to the 16q22 region, the molecular diagnosis has since remained elusive. OBJECTIVES: Inspired by pathogenic structural variation implicated in other 16q-ataxias with linkage to the same locus, we revisited the index SCA4 cases from the Utah family using novel technologies to investigate structural variation within the candidate region. METHODS: We adopted a targeted long-read sequencing approach with adaptive sampling on the Oxford Nanopore Technologies (ONT) platform that enables the detection of segregating structural variants within a genomic region without a priori assumptions about any variant features. RESULTS: Using this approach, we found a heterozygous (GGC)n repeat expansion in the last coding exon of the zinc finger homeobox 3 (ZFHX3) gene that segregates with disease, ranging between 48 and 57 GGC repeats in affected probands. This finding was replicated in a separate family with SCA4. Furthermore, the estimation of this GGC repeat size in short-read whole genome sequencing (WGS) data of 21,836 individuals recruited to the 100,000 Genomes Project in the UK and our in-house dataset of 11,258 exomes did not reveal any pathogenic repeats, indicating that the variant is ultrarare. CONCLUSIONS: These findings support the utility of adaptive long-read sequencing as a powerful tool to decipher causative structural variation in unsolved cases of inherited neurological disease. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Prophylactic use of cardiac medications for delay of left ventricular dysfunction in Duchenne muscular dystrophy.

BACKGROUND: Epidemiological support for prophylactic treatment of left ventricular dysfunction (LVD) in Duchenne muscular dystrophy is limited. We used retrospective, population-based surveillance data from the Muscular Dystrophy Surveillance, Tracking and Research Network to evaluate whether prophylaxis delays LVD onset. METHODS: We analyzed 455 males born during 1982-2009. Age at first abnormal echocardiogram (ejection fraction <55% or shortening fraction <28%) determined LVD onset. Prophylaxis was defined as cardiac medication use at least 1 year prior to LVD. Corticosteroid use was also coded. Kaplan-Meier curve estimation and Cox Proportional Hazard modeling with time-varying covariates describe associations. RESULTS: LVD was identified among 40.7%; average onset age was 14.2 years. Prophylaxis was identified for 20.2% and corticosteroids for 57.4%. Prophylaxis showed delayed LVD onset (p < .001) and lower hazard of dysfunction (adjusted hazard ratio [aHR] = 0.39, 95%CL = 0.22, 0.65) compared to untreated. Compared to no treatment, continuous corticosteroids only (aHR = 1.01, 95%CL = 0.66, 1.53) and prophylaxis only (aHR = 0.67, 95%CL = 0.25, 1.50) were not cardioprotective, but prophylaxis plus continuous corticosteroids were associated with lower hazard of dysfunction (aHR = 0.37, 95%CL = 0.15, 0.80). CONCLUSIONS: Proactive cardiac treatment and monitoring are critical aspects of managing Duchenne muscular dystrophy. Consistent with clinical care guidelines, this study supports clinical benefit from cardiac medications initiated prior to documented LVD and suggests further benefit when combined with corticosteroids.

Propensity matched comparison of omaveloxolone treatment to Friedreich ataxia natural history data.

OBJECTIVE: The natural history of Friedreich ataxia is being investigated in a multi-center longitudinal study designated the Friedreich ataxia Clinical Outcome Measures Study (FACOMS). To understand the utility of this study in analysis of clinical trials, we performed a propensity-matched comparison of data from the open-label MOXIe extension (omaveloxolone) to that from FACOMS. METHODS: MOXIe extension patients were matched to FACOMS patients using logistic regression to estimate propensity scores based on multiple covariates: sex, baseline age, age of onset, baseline modified Friedreich Ataxia Rating scale (mFARS) score, and baseline gait score. The change from baseline in mFARS at Year 3 for the MOXIe extension patients compared to the matched FACOMS patients was analyzed as the primary efficacy endpoint using mixed model repeated measures analysis. RESULTS: Data from the MOXIe extension show that omaveloxolone provided persistent benefit over 3 years when compared to an untreated, matched cohort from FACOMS. At each year, in all analysis populations, patients in the MOXIe extension experienced a smaller change from baseline in mFARS score than matched FACOMS patients. In the primary pooled population (136 patients in each group) by Year 3, patients in the FACOMS matched set progressed 6.6 points whereas patients treated with omaveloxolone in MOXIe extension progressed 3 points (difference = -3.6; nominal p value = 0.0001). INTERPRETATION: These results suggest a meaningful slowing of Friedreich ataxia progression with omaveloxolone, and consequently detail how propensity-matched analysis may contribute to understanding of effects of therapeutic agents. This demonstrates the direct value of natural history studies in clinical trial evaluations.

Gastrointestinal and genitourinary symptoms in facioscapulohumeral muscular dystrophy: Prevalence and impact.

INTRODUCTION/AIMS: Anecdotally, patients with facioscapulohumeral muscular dystrophy (FSHD) describe gastrointestinal (GI) and genitourinary (GU) symptoms. We explored the prevalence of GI and GU symptoms and their impact on quality of life (QOL) in people with FSHD compared to healthy household controls. METHODS: In this descriptive, cross-sectional study, we emailed a survey exploring GI and GU symptoms to all FSHD Society patient contacts (n = 3507). We invited those with FSHD and unaffected household controls to respond. Non-parametric statistics were used to compare symptom frequency and impact of symptoms between respondents with FSHD and household controls. Within the FSHD group, symptom frequency was assessed relative to measures of disease progression (need for ambulatory or respiratory support). RESULTS: Surveys from 701 respondents (652 with FSHD) ≥18 years old were included in analysis. Those with FSHD had symptoms affecting both GI and GU systems more frequently than controls using ordinal rating of symptom frequency. Within the FSHD group, more advanced disease was associated with increased symptom frequency. QOL was negatively impacted by the GI and GU symptoms. There was no difference between groups in use of medications to treat these symptoms. DISCUSSION: Recognition and treatment of GI and GU symptoms in people with FSHD, particularly those with more advanced disease, could improve QOL. Additional investigation is required to confirm these findings and understand the physiology.

Thirty-Year Follow-Up of Early Onset Amyotrophic Lateral Sclerosis with a Pathogenic Variant in SPTLC1.

Dominant mutations in serine palmitoyltransferase long chain base subunit 1 (SPTLC1), a known cause of hereditary sensory autonomic neuropathy type 1 (HSAN1), are a recently identified cause of juvenile amyotrophic lateral sclerosis (JALS) with slow progression. We present a case of SPTLC1-associated JALS followed for 30 years. She was initially evaluated at age 22 years for upper extremity weakness. She experienced gradual decline in muscle strength with development of weakness and hyperreflexia in lower extremities and diffuse fasciculations in the upper extremities at 26 years. She lost independent ambulation at age 45 years. Pulmonary function declined from a forced vital capacity of 94% predicted at 27 years to 49% predicted at 47 years, and she was hospitalized twice for respiratory failure. To our knowledge, this is the longest documented follow-up period of JALS caused by a de novo pathogenic variant in SPTLC1.

Pain interference and fatigue in limb-girdle muscular dystrophy R9.

Pain is prevalent in individuals with limb-girdle muscular dystrophy (LGMD) R9, but impact on daily living and correlation with fatigue remain unknown. Patient-Reported Outcomes Measurement Information System (PROMIS) pain interference and fatigue short forms were completed annually by 23 children and 54 adults with biallelic fukutin-related protein (FKRP) variants for up to six years. Concurrent motor and pulmonary function were evaluated. Pain interference T-scores were near the normal mean of 50 by linear mixed model analysis (48.5 in children, 51.6 in adults). 58% of participants experienced pain interference levels greater than the general population on at least one assessment. Fatigue T-scores were elevated in adults but not children (49.0 in children, 55.1 in adults), and 75% had at least one elevated fatigue score. Of participants with at least two visits, serial scores were not consistent across visits, without a clear pattern. Pain interference and fatigue were positively correlated (r = 0.55). Both increased with older age (r = 0.21 and 0.41 respectively). Neither differed by sex or ambulation status. Motor (r=-0.32) and pulmonary (r=-0.25) function correlated with fatigue in adults, not children. Results suggest that pain in those with LGMDR9 is variable and episodic, limiting impact on daily life, while fatigue increases over time.

DMD Gene and Dystrophinopathy Phenotypes Associated With Mutations: A Systematic Review for Clinicians.

ABSTRACT: The diagnosis of Duchenne and Becker muscular dystrophy (DBMD) is made by genetic testing in approximately 95% of cases. Although specific mutations can be associated with skeletal muscle phenotype, pulmonary and cardiac comorbidities (leading causes of death in Duchenne) have not been associated with Duchenne muscular dystrophy mutation type or location and vary within families. Therefore, identifying predictors for phenotype severity beyond frameshift prediction is important clinically. We performed a systematic review assessing research related to genotype-phenotype correlations in DBMD. While there are severity differences across the spectrum and within mild and severe forms of DBMD, few protective or exacerbating mutations within the dystrophin gene were reported. Except for intellectual disability, clinical test results reporting genotypic information are insufficient for clinical prediction of severity and comorbidities and the predictive validity is too low to be useful when advising families. Including expanded information coupled with proposed severity predictions in clinical genetic reports for DBMD is critical for improving anticipatory guidance.

A De Novo Sequence Variant in Barrier-to-Autointegration Factor Is Associated with Dominant Motor Neuronopathy.

Barrier-to-autointegration factor (BAF) is an essential component of the nuclear lamina. Encoded by BANF1, this DNA binding protein contributes to the regulation of gene expression, cell cycle progression, and nuclear integrity. A rare recessive BAF variant, Ala12Thr, causes the premature aging syndrome, Néstor-Guillermo progeria syndrome (NGPS). Here, we report the first dominant pathogenic BAF variant, Gly16Arg, identified in a patient presenting with progressive neuromuscular weakness. Although disease variants carry nearby amino acid substitutions, cellular and biochemical properties are distinct. In contrast to NGPS, Gly16Arg patient fibroblasts show modest changes in nuclear lamina structure and increases in repressive marks associated with heterochromatin. Structural studies reveal that the Gly16Arg substitution introduces a salt bridge between BAF monomers, reducing the conformation ensemble available to BAF. We show that this structural change increases the double-stranded DNA binding affinity of BAF Gly16Arg. Together, our findings suggest that BAF Gly16Arg has an increased chromatin occupancy that leads to epigenetic changes and impacts nuclear functions. These observations provide a new example of how a missense mutation can change a protein conformational equilibrium to cause a dominant disease and extend our understanding of mechanisms by which BAF function impacts human health.

Efficacy of Omaveloxolone in Friedreich's Ataxia: Delayed-Start Analysis of the MOXIe Extension.

BACKGROUND: MOXIe was a two-part study evaluating the safety and efficacy of omaveloxolone in patients with Friedreich's ataxia, a rare, progressive neurological disease with no proven therapy. MOXIe part 2, a randomized double-blind placebo-controlled trial, showed omaveloxolone significantly improved modified Friedreich's Ataxia Rating Scale (mFARS) scores relative to placebo. Patients who completed part 1 or 2 were eligible to receive omaveloxolone in an open-label extension study. OBJECTIVE: The delayed-start study compared mFARS scores at the end of MOXIe part 2 with those at 72 weeks in the open-label extension period (up to 144 weeks) for patients initially randomized to omaveloxolone versus those initially randomized to placebo. METHODS: We performed a noninferiority test to compare the difference between treatment groups (placebo to omaveloxolone versus omaveloxolone to omaveloxolone) using a single mixed model repeated measures (MMRM) model. In addition, slopes of the change in mFARS scores were compared between both groups in the open-label extension. RESULTS: The noninferiority testing demonstrated that the difference in mFARS between omaveloxolone and placebo observed at the end of placebo-controlled MOXIe part 2 (-2.17 ± 1.09 points) was preserved after 72 weeks in the extension (-2.91 ± 1.44 points). In addition, patients previously randomized to omaveloxolone in MOXIe part 2 continued to show no worsening in mFARS relative to their extension baseline through 144 weeks. CONCLUSIONS: These results support the positive results of MOXIe part 2 and indicate a persistent benefit of omaveloxolone treatment on disease course in Friedreich's ataxia. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Electroretinogram abnormalities in FKRP-related limb-girdle muscular dystrophy (LGMDR9).

BACKGROUND: Dystroglycanopathies are a heterogeneous group of membrane-related muscular dystrophies. The dystroglycanopathy phenotype includes a spectrum of severity ranging from severe congenital muscular dystrophy to adult-onset limb-girdle muscular dystrophy (LGMD). LGMDR9 is a dystroglycanopathy caused by mutations in the FKRP gene. Previous studies have characterized electroretinogram findings of dystroglycanopathy mouse models but have not been reported in humans. PURPOSE: This study set out to characterize the electroretinogram in eight participants with LGMDR9. METHODS: Eight participants were recruited from an ongoing dystroglycanopathy natural history study at the University of Iowa (NCT00313677). Inclusion criteria for the current study were children and adults > 6 years old with confirmed LGMDR9. Age similar controls were identified from our electrophysiology service normative control database. Full-field electroretinograms were recorded using ISCEV standards. Six of the eight participants underwent light-adapted ON/OFF testing. RESULTS: The electronegative electroretinogram was not seen in any participants with LGMDR9. An unusual sawtooth pattern in the 30 Hz flicker with faster rise than descent was noted in all 8 participants. Our cases showed a decreased b-wave amplitude in light-adapted ON responses (p = 0.011) and decreased d-wave amplitude in light-adapted OFF responses (p = 0.015). Decreased b-wave amplitude in light-adapted 3.0 testing (p = 0.015) and decreased flicker ERG amplitudes were also detected (p = 0.0018). Additionally, compared to controls, participants with LGMDR9 had decreased a-wave amplitudes on dark-adapted 10 testing (p = 0.026). CONCLUSIONS: Abnormal ON/OFF bipolar cell responses and sawtooth 30 Hz flicker waveforms on full-field electroretinogram may be specific for LGMDR9. If confirmed in a larger population and if related to disease stage, these tests are potential biomarkers which could be useful as endpoints in clinical treatment trials.

Double blind trial of a deuterated form of linoleic acid (RT001) in Friedreich ataxia.

OBJECTIVES: Friedreich ataxia is (FRDA) an autosomal recessive neurodegenerative disorder associated with intrinsic oxidative damage, suggesting that decreasing lipid peroxidation (LPO) might ameliorate disease progression. The present study tested the ability of RT001, a deuterated form of linoleic acid (D2-LA), to alter disease severity in patients with FRDA in a double-blind placebo-controlled trial. METHODS: Sixty-five subjects were recruited across six sites and received either placebo or active drug for an 11-month study. Subjects were evaluated at 0, 4, 9, and 11 months, with the primary outcome measure being maximum oxygen consumption (MVO2) during cardiopulmonary exercise testing (CPET). A key secondary outcome measure was a composite statistical test using results from the timed 1-min walk (T1MW), peak workload, and MVO2. RESULTS: Forty-five subjects completed the protocol. RT001 was well tolerated, with no serious adverse events related to drug. Plasma and red blood cell (RBC) membrane levels of D2-LA and its primary metabolite deuterated arachidonic acid (D2-AA) achieved steady-state concentrations by 4 months. No significant changes in MVO2 were observed for RT001 compared to placebo. Similarly, no differences between the groups were found in secondary or exploratory outcome measures. Post hoc evaluations also suggested minimal effects of RT001 at the dosages used in this study. INTERPRETATIONS: The results of this study provide no evidence for a significant benefit of RT001 at the dosages tested in this Friedreich ataxia patient population.

Selected clinical and demographic factors and all-cause mortality among individuals with Duchenne muscular dystrophy in the Muscular Dystrophy Surveillance, Tracking, and Research Network.

Population-based estimates of survival among individuals with Duchenne muscular dystrophy (DMD) living in the United States are lacking. It is also unclear whether the association between glucocorticoid use and all-cause mortality persists in the context of other common treatments (cardiac medication, cough-assist, bilevel positive airway pressure, and scoliosis surgery) observed to delay mortality. Among 526 individuals identified by the Muscular Dystrophy Surveillance, Tracking, and Research Network, the estimated median survival time from birth was 23.7 years. Current glucocorticoid users had a lower hazard of mortality than non-users. Individuals who ever had scoliosis surgery had a lower hazard of mortality than individuals who did not have scoliosis surgery. Individuals who ever used cough assist had a lower hazard of mortality than individuals who never used cough assist. Non-Hispanic Black individuals had a higher hazard of mortality than non-Hispanic White individuals. No differences in hazards of mortality were observed between ever versus never use of cardiac medication and ever versus never use of bilevel positive airway pressure. The glucocorticoid observation is consistent with the 2018 Care Considerations statement that glucocorticoid use continues in the non-ambulatory phase. Our observations may inform the clinical care of individuals living with DMD.

Randomized phase 2 study of ACE-083, a muscle-promoting agent, in facioscapulohumeral muscular dystrophy.

INTRODUCTION/AIMS: Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive muscular dystrophy without approved therapies. In this study we evaluated whether locally acting ACE-083 could safely increase muscle volume and improve functional outcomes in adults with FSHD. METHODS: Participants were at least 18 years old and had FSHD1/FSHD2. Part 1 was open label, ascending dose, assessing safety and tolerability (primary objective). Part 2 was randomized, double-blind for 6 months, evaluating ACE-083240 mg/muscle vs placebo injected bilaterally every 3 weeks in the biceps brachii (BB) or tibialis anterior (TA) muscles, followed by 6 months of open label. Magnetic resonance imaging measures included total muscle volume (TMV; primary objective), fat fraction (FF), and contractile muscle volume (CMV). Functional measures included 6-minute walk test, 10-meter walk/run, and 4-stair climb (TA group), and performance of upper limb midlevel/elbow score (BB group). Strength, patient-reported outcomes (PROs), and safety were also evaluated. RESULTS: Parts 1 and 2 enrolled 37 and 58 participants, respectively. Among 55 participants evaluable in Part 2, the least-squares mean (90% confidence interval, analysis of covariance) treatment difference for TMV was 16.4% (9.8%-23.0%) in the BB group (P < .0001) and 9.5% (3.2%-15.9%) in the TA group (P = .01). CMV increased significantly in the BB and TA groups and FF decreased in the TA group. There were no consistent improvements in functional or PRO measures in either group. The most common adverse events were mild or moderate injection-site reactions. DISCUSSION: Significant increases in TMV with ACE-083 vs placebo did not result in consistent functional or PRO improvements with up to 12 months of treatment.

Time to diagnosis of Duchenne muscular dystrophy remains unchanged: Findings from the Muscular Dystrophy Surveillance, Tracking, and Research Network, 2000-2015.

INTRODUCTION/AIMS: With current and anticipated disease-modifying treatments, including gene therapy, an early diagnosis for Duchenne muscular dystrophy (DMD) is crucial to assure maximum benefit. In 2009, a study from the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet) showed an average diagnosis age of 5 years among males with DMD born from January 1, 1982 to December 31, 2000. Initiatives were implemented by the US Centers for Disease Control and Prevention (CDC) and patient organizations to reduce time to diagnosis. We conducted a follow-up study in a surveillance cohort born after January 1, 2000 to determine whether there has been an improvement in time to diagnosis. METHODS: We assessed the age of diagnosis among males with DMD born from January 1, 2000 to December 31, 2015 using data collected by six US MD STARnet surveillance sites (Colorado, Iowa, western New York State, the Piedmont region of North Carolina, South Carolina, and Utah). The analytic cohort included 221 males with definite or probable DMD diagnosis without a documented family history. We computed frequency count and percentage for categorical variables, and mean, median, and standard deviation (SD) for continuous variables. RESULTS: The mean [median] ages in years of diagnostic milestones were: first signs, 2.7 [2.0]; first creatine kinase (CK), 4.6 [4.6]; DNA/muscle biopsy testing, 4.9 [4.8]; and time from first signs to diagnostic confirmation, 2.2 [1.4]. DISCUSSION: The time interval between first signs of DMD and diagnosis remains unchanged at 2.2 years. This results in lost opportunities for timely genetic counseling, implementation of standards of care, initiation of glucocorticoids, and participation in clinical trials.

Effect of Denosumab on Bone Health in Adult Patients with Duchenne/Becker Muscular Dystrophy: A Report of 2 Cases.

CASE: Duchenne/Becker muscular dystrophy (DMD/BeMD) is caused by a loss of dystrophin leading to muscular weakness. Glucocorticoids are used to delay loss of muscle strength but frequently result in osteoporosis and fractures. Bisphosphonates are the drug of choice, and there are limited data on the efficacy of denosumab. We describe 2 patients who were treated with denosumab and had stable to improved bone density with no side effects. CONCLUSION: Denosumab can be considered for the treatment of osteoporosis in adults with DMD/BeMD, especially when the response to bisphosphonates is not satisfactory.

Intron mutations and early transcription termination in Duchenne and Becker muscular dystrophy.

DMD pathogenic variants for Duchenne and Becker muscular dystrophy are detectable with high sensitivity by standard clinical exome analyses of genomic DNA. However, up to 7% of DMD mutations are deep intronic and analysis of muscle-derived RNA is an important diagnostic step for patients who have negative genomic testing but abnormal dystrophin expression in muscle. In this study, muscle biopsies were evaluated from 19 patients with clinical features of a dystrophinopathy, but negative clinical DMD mutation analysis. Reverse transcription-polymerase chain reaction or high-throughput RNA sequencing methods identified 19 mutations with one of three pathogenic pseudoexon types: deep intronic point mutations, deletions or insertions, and translocations. In association with point mutations creating intronic splice acceptor sites, we observed the first examples of DMD pseudo 3'-terminal exon mutations causing high efficiency transcription termination within introns. This connection between splicing and premature transcription termination is reminiscent of U1 snRNP-mediating telescripting in sustaining RNA polymerase II elongation across large genes, such as DMD. We propose a novel classification of three distinct types of mutations identifiable by muscle RNA analysis, each of which differ in potential treatment approaches. Recognition and appropriate characterization may lead to therapies directed toward full-length dystrophin expression for some patients.