RNA mis-splicing in children with congenital myotonic dystrophy is associated with physical function.

OBJECTIVES: Dysregulated RNA alternative splicing is the hallmark of myotonic dystrophy type 1 (DM1). However, the association between RNA mis-splicing and physical function in children with the most severe form of disease, congenital myotonic dystrophy (CDM), is unknown. METHODS: Eighty-two participants (42 adults with DM1 and 40 children with CDM) with muscle biopsies and measures of myotonia, motor function, and strength were combined from five observational studies. Data were normalized and correlated with an aggregate measure of alternative splicing dysregulation, [MBNL]inferred, in skeletal muscle biopsies. Multiple linear regression analysis was performed to predict [MBNL]inferred using clinical outcome measures alone. Similar analyses were performed to predict 12-month physical function using baseline metrics. RESULTS: Myotonia (measured via vHOT) was significantly correlated with RNA mis-splicing in our cross-sectional population of all DM1 individuals; CDM participants alone displayed no myotonia despite a similar range of RNA mis-splicing. Measures of motor performance and muscle strength were significantly associated with [MBNL]inferred in our cohort of all DM1 individuals and when assessing children with CDM independently. Multiple linear regression analyses yielded two models capable of predicting [MBNL]inferred from select clinical outcome assessments alone in all subjects (adjusted R2 = 0.6723) or exclusively in children with CDM (adjusted R2 = 0.5875). INTERPRETATION: Our findings establish significant correlations between skeletal muscle performance and a composite measure of alternative splicing dysregulation, [MBNL]inferred, in DM1. The strength of these correlations and the development of predictive models will assist in designing efficacious clinical trials for individuals with DM1, particularly CDM.

Parental diagnostic delay and developmental outcomes in congenital and childhood-onset myotonic dystrophy type 1.

AIM: To investigate the timing of type 1 myotonic dystrophy (DM1) diagnosis in parents of affected children and describe children's perinatal characteristics and developmental outcomes. METHOD: This was a descriptive case series of children with congenital myotonic dystrophy (CDM) and childhood-onset myotonic dystrophy (ChDM). Parental timing of DM1 diagnosis and the perinatal, motor, and cognitive outcomes of paediatric patients were recorded. RESULTS: A total of 139 children followed by 12 highly specialized tertiary care neuromuscular centres in Italy and one tertiary neuromuscular centre in the USA were included: 105 children with CDM and 34 children with ChDM (mean age 8 years 8 months and 12 years 2 months respectively; 49 males and 17 males respectively). Seventy (50%) parents were diagnosed with adult-onset DM1 after the affected child was diagnosed. Only 12 (17%) of the 69 parents known to be affected had prenatal testing. Of the 105 children with CDM, 98% had maternally inherited CDM, 36% were born preterm, 83% required a stay in the neonatal intensive care unit for more than 48 hours, 84% and 79% had ambulation and speech delay, and 84% had an IQ lower than 70. Of the 34 children with ChDM, 59% had paternally inherited ChDM, 91% were born at term, and 36% had an IQ lower than 70. INTERPRETATION: Delay in diagnosing DM1 affects family planning. The prenatal and perinatal outcomes of the affected offspring emphasize the need for proactive counselling as parents may be reluctant to conduct prenatal testing.

Association between Reported Sleep Disorders and Behavioral Issues in Children with Myotonic Dystrophy Type 1-Results from a Retrospective Analysis in Italy.

Background: Sleep disorders have been poorly described in congenital (CDM) and childhood (ChDM) myotonic dystrophy despite being highly burdensome. The aims of this study were to explore sleep disorders in a cohort of Italian CDM and ChDM and to assess their association with motor and respiratory function and disease-specific cognitive and behavioral assessments. Methods: This was an observational multicenter study. Reported sleep quality was assessed using the Pediatric Daytime Sleepiness Scale (PDSS) and Pediatric Sleep Questionnaire (PSQ). Sleep quality was correlated to motor function (6 min walk test, 6MWT and grip strength; pulmonary function (predicted Forced Vital Capacity%, FVC% pred.); executive function assessed by BRIEF-2; autism traits assessed by Autism Spectrum Screening Questionnaire (ASSQ) and Repetitive Behavior Scale-revised (RBS-R); Quality of life (PedsQL) and disease burden (Congenital Childhood Myotonic Dystrophy Health Index, CCMDHI). Results: Forty-six patients were included, 33 CDM and 13 ChDM, at a median age of 10.4 and 15.1 years. Daytime sleepiness and disrupted sleep were reported by 30% children, in both subgroups of CDM and ChDM. Daytime sleepiness correlated with autism traits in CDM (p < 0.05). Disrupted sleep correlated with poorer executive function (p = 0.04) and higher disease burden (p = 0.03). Conclusions: Sleep issues are a feature of both CDM and ChDM. They correlate with behavioral issues and impact on disease burden.

RNA mis-splicing in children with myotonic dystrophy is associated with physical function.

Objectives: Dysregulated RNA alternative splicing is the hallmark of myotonic dystrophy type 1 (DM1). However, the association between RNA mis-splicing and physical function in children with the most severe form of disease, congenital myotonic dystrophy (CDM), is unknown. Methods: 82 participants (42 DM1 adults & 40 CDM children) with muscle biopsies and measures of myotonia, motor function, and strength were combined from five observational studies. Data were normalized and correlated with an aggregate measure of alternative splicing dysregulation, [MBNL] inferred in skeletal muscle biopsies. Multiple linear regression analysis was performed to predict [MBNL] inferred using clinical outcome measures alone. Similar analyses were performed to predict 12-month physical function using baseline metrics. Results: Myotonia (measured via vHOT) was significantly correlated with RNA mis-splicing in our cross-sectional population of all DM1 individuals; CDM participants alone displayed no myotonia despite a similar range of RNA mis-splicing. Measures of motor performance and muscle strength were significantly associated with [MBNL] inferred in our cohort of all DM1 individuals and when assessing CDM children independently. Multiple linear regression analyses yielded two models capable of predicting [MBNL] inferred from select clinical outcome assessments alone in all subjects (adjusted R 2 = 0.6723) or exclusively in CDM children (adjusted R 2 = 0.5875). Interpretation: Our findings establish significant correlations between skeletal muscle performance and a composite measure of alternative splicing dysregulation, [MBNL] inferred, in DM1. The strength of these correlations and the development of the predictive models will assist in designing efficacious clinical trials for individuals with DM1, particularly CDM.

The Limb Girdle Muscular Dystrophy Health Index (LGMD-HI).

Limb girdle muscular dystrophy (LGMD) is a debilitating disease and the fourth most common muscular dystrophy. This study describes the development of the LGMD-Health Index (LGMD-HI). Participants were aged >18 years and recruited from three LGMD registries and GRASP-LGMD consortium. The initial instrument, comprised of 16 thematic subscales and 161 items, underwent expert review resulting in item removal as well as confirmatory factor analysis followed by inter-rater reliability and internal consistency of the subscales. Following expert review, one subscale and 59 items were eliminated. Inter-rater reliability was assessed and five items were removed due to Cohen's kappa <0.5. The final subscales had high internal consistencies with an average Cronbach alpha of 0.92. Test re-test reliability of the final instrument was high (intraclass correlation coefficient=0.97). Known groups validity testing showed a statistically significant difference in LGMD-HI scores amongst subjects based on ambulation status (28.7 vs 50.0, p < 0.0001), but not sex, employment status, or genetic subtype. The final instrument is comprised of 15 subscales and 97 items. The LGMD-HI is a disease-specific, patient-reported outcome measure designed in compliance with published FDA guidelines. This instrument is capable of measuring burden of disease with no significant variation based on LGMD subtype.

Diagnosis and Management of Myotonic Dystrophy Type 1.

This JAMA Insights discusses the signs and symptoms, diagnosis, and treatment of myotonic dystrophy type 1.

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.

Neurobehavioral Phenotype of Children With Congenital Myotonic Dystrophy.

BACKGROUND AND OBJECTIVES: To describe the neurobehavioral phenotype of congenital myotonic dystrophy. Congenital myotonic dystrophy (CDM) is the most severe form of myotonic dystrophy, characterized by symptom presentation at birth and later, cognitive impairment, autistic features, and disordered sleep. METHODS: The neurobehavioral phenotype was assessed in this cross-sectional study by a neuropsychological battery consisting of the Wechsler Preschool and Primary Scale of Intelligence, Third Edition, Weschler Intelligence Scale for Children, Fourth Edition, Vineland Adaptive Behavior Scale, Second Edition (Vineland-II), Behavior Rating Inventory of Executive Function including preschool and teacher reports, Autism Spectrum Screening Questionnaire, Social Communication Scale, and Repetitive Behavior Scale-Revised. Sleep quality was evaluated with the Pediatric Sleep Questionnaire and Pediatric Daytime Sleepiness Scale. RESULTS: Fifty-five children with CDM, ages 5 weeks to 14 years, were enrolled. The mean age and (CTG)n repeats (±SD) were 6.4 ± 3.8 years and 1,263 ± 432, respectively. The mean IQ was 64.1 ± 14.9 on the Weschler scales with 65.6% of participants falling in the extremely low range for IQ. Adaptive functioning was significantly low for 57.1% of participants (n = 20). Caregiver report of executive functioning indicated 23.1% (9/39) of participants had clinically elevated levels of dysfunction, though teacher report was discrepant and indicated 53.3% of participants with CDM fell in this range (8/15). Spearman correlations were strongly positive (p ≤ 0.05) for estimated full scale IQ, overall adaptive functioning and with daily living and socialization domain standard scores on the Vineland-II ranging from r = 0.719 to r = 0.849 for all ages. Aspects of executive function were directly related to features of autism and sleep quality. Social communication was inversely related to all aspects of daily functioning, except communication, and directly related to aspects of autism behavior. DISCUSSION: Depressed IQ, adaptive skills, and executive functioning, poor sleep quality, and features of autism and altered social functioning individually describe different aspects of the neurobehavioral phenotype in CDM. These neurobehavioral and sleep measures could help quantitatively measure and assess the burden of cognitive impairment in CDM.

Genetic Patterns of Selected Muscular Dystrophies in the Muscular Dystrophy Surveillance, Tracking, and Research Network.

Background and Objectives: To report the genetic etiologies of Emery-Dreifuss muscular dystrophy (EDMD), limb-girdle muscular dystrophy (LGMD), congenital muscular dystrophy (CMD), and distal muscular dystrophy (DD) in 6 geographically defined areas of the United States. Methods: This was a cross-sectional, population-based study in which we studied the genes and variants associated with muscular dystrophy in individuals who were diagnosed with and received care for EDMD, LGMD, CMD, and DD from January 1, 2008, through December 31, 2016, in the 6 areas of the United States covered by the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet). Variants of unknown significance (VUSs) from the original genetic test reports were reanalyzed for changes in interpretation. Results: Among 243 individuals with definite or probable muscular dystrophy, LGMD was the most common diagnosis (138 cases), followed by CMD (62 cases), DD (22 cases), and EDMD (21 cases). There was a higher proportion of male individuals compared with female individuals, which persisted after excluding X-linked genes (EMD) and autosomal genes reported to have skewed gender ratios (ANO5, CAV3, and LMNA). The most common associated genes were FKRP, CAPN3, ANO5, and DYSF. Reanalysis yielded more definitive variant interpretations for 60 of 144 VUSs, with a mean interval between the original clinical genetic test of 8.11 years for all 144 VUSs and 8.62 years for the 60 reclassified variants. Ten individuals were found to have monoallelic pathogenic variants in genes known to be primarily recessive. Discussion: This study is distinct for being an examination of 4 types of muscular dystrophies in selected geographic areas of the United States. The striking proportion of resolved VUSs demonstrates the value of periodic re-examinations of these variants. Such re-examinations will resolve some genetic diagnostic ambiguities before initiating repeat testing or more invasive diagnostic procedures such as muscle biopsy. The presence of monoallelic pathogenic variants in recessive genes in our cohort indicates that some individuals with muscular dystrophy continue to face incomplete genetic diagnoses; further refinements in genetic knowledge and diagnostic approaches will optimize diagnostic information for these individuals.

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.

Antisense oligonucleotide targeting DMPK in patients with myotonic dystrophy type 1: a multicentre, randomised, dose-escalation, placebo-controlled, phase 1/2a trial.

BACKGROUND: Myotonic dystrophy type 1 results from an RNA gain-of-function mutation, in which DM1 protein kinase (DMPK) transcripts carrying expanded trinucleotide repeats exert deleterious effects. Antisense oligonucleotides (ASOs) provide a promising approach to treatment of myotonic dystrophy type 1 because they reduce toxic RNA levels. We aimed to investigate the safety of baliforsen (ISIS 598769), an ASO targeting DMPK mRNA. METHODS: In this dose-escalation phase 1/2a trial, adults aged 20-55 years with myotonic dystrophy type 1 were enrolled at seven tertiary referral centres in the USA and randomly assigned via an interactive web or phone response system to subcutaneous injections of baliforsen 100 mg, 200 mg, or 300 mg, or placebo (6:2 randomisation at each dose level), or to baliforsen 400 mg or 600 mg, or placebo (10:2 randomisation at each dose level), on days 1, 3, 5, 8, 15, 22, 29, and 36. Sponsor personnel directly involved with the trial, participants, and all study personnel were masked to treatment assignments. The primary outcome measure was safety in all participants who received at least one dose of study drug up to day 134. This trial is registered with ClinicalTrials.gov (NCT02312011), and is complete. FINDINGS: Between Dec 12, 2014, and Feb 22, 2016, 49 participants were enrolled and randomly assigned to baliforsen 100 mg (n=7, one patient not dosed), 200 mg (n=6), 300 mg (n=6), 400 mg (n=10), 600 mg (n=10), or placebo (n=10). The safety population comprised 48 participants who received at least one dose of study drug. Treatment-emergent adverse events were reported for 36 (95%) of 38 participants assigned to baliforsen and nine (90%) of ten participants assigned to placebo. Aside from injection-site reactions, common treatment-emergent adverse events were headache (baliforsen: ten [26%] of 38 participants; placebo: four [40%] of ten participants), contusion (baliforsen: seven [18%] of 38; placebo: one [10%] of ten), and nausea (baliforsen: six [16%] of 38; placebo: two [20%] of ten). Most adverse events (baliforsen: 425 [86%] of 494; placebo: 62 [85%] of 73) were mild in severity. One participant (baliforsen 600 mg) developed transient thrombocytopenia considered potentially treatment related. Baliforsen concentrations in skeletal muscle increased with dose. INTERPRETATION: Baliforsen was generally well tolerated. However, skeletal muscle drug concentrations were below levels predicted to achieve substantial target reduction. These results support the further investigation of ASOs as a therapeutic approach for myotonic dystrophy type 1, but suggest improved drug delivery to muscle is needed. FUNDING: Ionis Pharmaceuticals, Biogen.

Dynamics and variability of transcriptomic dysregulation in congenital myotonic dystrophy during pediatric development.

Myotonic dystrophy type 1 (DM1) is a multi-systemic disorder caused by expansion of CTG microsatellite repeats within DMPK. The most severe form, congenital myotonic dystrophy (CDM), has symptom onset at birth due to large intergenerational repeat expansions. Despite a common mutation, CDM individuals present with a distinct clinical phenotype and absence of common DM1 symptoms. Given the clinical divergence, it is unknown if the hallmark of DM1 pathology, dysregulation of alternative splicing (AS) due to sequestration of MBNL proteins within toxic CUG repeat RNAs, contributes to disease throughout pediatric development. To evaluate global transcriptomic dysregulation, RNA-seq was performed on 36 CDM skeletal muscle biopsies ages 2 weeks to 16 years, including two longitudinal samples. Fifty DM1 and adult/pediatric controls were also sequenced as comparative groups. Despite a large CTG expansion and shared age of onset, CDM individuals presented with a heterogenous, MBNL-dependent mis-splicing signature. Estimation of intracellular MBNL concentrations from splicing responses of select events correlated with total spliceopathy and revealed a distinct, triphasic pattern of AS dysregulation across pediatric development. CDM infants (< 2 years) possess severe mis-splicing that significantly improves in early childhood (2-8 years) independent of sex or CTG repeat load. Adolescent individuals (8-16 years) stratified into two populations with a full range of global splicing dysregulation. DMPK expression changes correlated with alterations in splicing severity during development. This study reveals the complex dynamics of the CDM muscle transcriptome and provides insights into new therapeutic strategies, timing of therapeutic intervention, and biomarker development.

The Limb-Girdle Muscular Dystrophies.

PURPOSE OF REVIEW: The limb-girdle muscular dystrophies (LGMDs) are a group of inherited muscle disorders with a common feature of limb-girdle pattern of weakness, caused by over 29 individual genes. This article describes the classification scheme, common subtypes, and the management of individuals with LGMD. RECENT FINDINGS: Advances in genetic testing and next-generation sequencing panels containing all of the LGMD genes have led to earlier genetic confirmation, but also to more individuals with variants of uncertain significance. The LGMDs include disorders with autosomal recessive inheritance, which are often due to loss-of-function mutations in muscle structural or repair proteins and typically have younger ages of onset and more rapidly progressive presentations, and those with autosomal dominant inheritance, which can have older ages of presentation and chronic progressive disease courses. All cause progressive disability and potential loss of ability to walk or maintain a job due to progressive muscle wasting. Certain mutations are associated with cardiac or respiratory involvement. No disease-altering therapies have been approved by the US Food and Drug Administration (FDA) for LGMDs and standard treatment uses a multidisciplinary clinic model, but recessive LGMDs are potentially amenable to systemic gene replacement therapies, which are already being tested in clinical trials for sarcoglycan and FKRP mutations. The dominant LGMDs may be amenable to RNA-based therapeutic approaches. SUMMARY: International efforts are underway to better characterize LGMDs, help resolve variants of uncertain significance, provide consistent and improved standards of care, and prepare for future clinical trials.

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.

Patient reported quality of life in limb girdle muscular dystrophy.

This study determined the frequency and impact of symptoms on quality of life in patients diagnosed with limb girdle muscular dystrophy (LGMD). Participants with a diagnosis of LGMD in registries based at the Coalition to Cure Calpain-3, the Jain foundation, and the Global FKRP Registry competed a survey to report the frequency and relative impact of themes and symptoms of LGMD. Frequency, mean impact, and population impact scores were calculated, and responses were categorized by age, symptom duration, gender, employment status, use of assistive devices, and LGMD subtypes. 134 participants completed the survey. The most prevalent themes included an inability to do activities (100%), limitation with mobility (99.3%), and lower extremity weakness (97.0%). Themes with the greatest impact were: limitations with mobility, lower extremity weakness, and an inability to do activities. Symptom duration and the use of assistive devices were associated with the presence of multiple themes. Employment was associated with the impact of several themes with no differences in frequency. The prevalence and impact of these themes vary in the LMGD population. The most prevalent and impactful themes were related to weakness, but additional concerns related to emotional challenges should also be considered in clinical and research settings.

Neurologic Therapeutics in 2035: The Neurology Future Forecasting Series.

Therapeutic development has accelerated rapidly in the past 5 years in many neurologic and neurodegenerative diseases. The therapeutic categories of development include small molecules, genetic therapies, and cell-based therapies. Current development has provided novel treatment approaches to disorders without available treatment. However, the regulatory procedures to allow for access to these therapies is challenging, as is the ability to provide wide access to increasingly expensive therapies. By 2035, these challenges are likely to have accelerated and have the potential to create bottlenecks in drug approval and reduced access to patients. Innovative regulatory and payer solutions are required. In addition, ethical considerations around genetic therapies should be considered in current and future development. These approaches will ensure that patients with neurologic disease have broad access to highly innovative therapies.

p53 convergently activates Dux/DUX4 in embryonic stem cells and in facioscapulohumeral muscular dystrophy cell models.

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.

Long-term efficacy and safety of dichlorphenamide for treatment of primary periodic paralysis.

INTRODUCTION/AIM: Long-term efficacy and safety of dichlorphenamide (DCP) were characterized in patients with primary periodic paralysis (PPP). METHODS: Patients with PPP in a double-blind, placebo-controlled study were randomly assigned to receive DCP 50 mg twice daily or placebo for 9 weeks, followed by a 52-week open-label DCP treatment phase (DCP/DCP and placebo/DCP populations). Efficacy (attack rate, severity-weighted attack rate) and safety were assessed in patients completing the study (61 weeks). In this post hoc analysis, efficacy and safety data were pooled from hyperkalemic and hypokalemic substudies. RESULTS: Sixty-three adults (age, 19-76 years) completed the double-blind phase; 47 (74.6%) of these patients completed 61 weeks. There were median decreases in weekly attack and severity-weighted attack rates from baseline to week 61 (DCP/DCP [n = 25], -1.00 [P < .0001]; placebo/DCP [n = 20], -0.63 [P = .01] and DCP/DCP, -2.25 [P < .0001]; placebo/DCP, -1.69 [P = .01]). Relatively smaller median decreases in weekly attack and severity-weighted attack rates occurred from weeks 9 to 61 among patients receiving DCP continuously (n = 26; -0.14 [P = .1] and -0.24 [P = .09]) than among those switching from placebo to DCP after 9 weeks (n = 16; -1.04 [P = .049] and -2.72 [P = .08]). Common adverse events (AEs) were paresthesia and cognition-related events, which typically first occurred within 1 month of blinded treatment initiation and in rare cases led to treatment discontinuation. Dose reductions were frequently associated with common AE resolution. DISCUSSION: One-year open-label DCP treatment after a 9-week randomized, controlled study confirmed long-term DCP remains safe and effective for chronic use. Tolerability issues (paresthesia, cognition-related AEs) were manageable in most patients.