Male Reproduction in Spinal Muscular Atrophy (SMA) and the Potential Impact of Oral Survival of Motor Neuron 2 (SMN2) Pre-mRNA Splicing Modifiers.

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by deletions or mutations in the survival of motor neuron 1 (SMN1) gene resulting in reduced levels of SMN protein. SMN protein is produced by cells throughout the body, and evidence suggests that low SMN protein can have systemic implications, including in male reproductive organs. However, a paucity of research exists on this important topic. This article will discuss findings from non-clinical studies on the role of SMN in the male reproductive system; additionally, real-world observational reports of individuals with SMA will be examined. Furthermore, we will review the non-clinical reproductive findings of risdiplam, a small-molecule SMN2 splicing modifier approved for the treatment of SMA, which has widespread distribution in both the central nervous system and peripheral organs. Specifically, the available non-clinical evidence of the effect of risdiplam on male reproductive organs and spermatogenesis is examined. Lastly, the article will highlight available capabilities to assess male fertility as well as the advanced reproductive technologies utilized to treat male infertility. This article demonstrates the need for further research to better understand the impacts of SMA on male fertility and reproduction.

Lenalidomide in the treatment of anti-myelin-associated glycoprotein neuropathy: A phase 1 study to identify the maximum tolerated dose.

BACKGROUND: Anti-myelin-associated glycoprotein (MAG) neuropathy is a debilitating demyelinating polyneuropathy with no approved therapies. Our primary objective was to ascertain lenalidomide safety and maximum tolerated dose (MTD) in anti-MAG neuropathy. METHODS: This phase 1b, open-label, single-arm, dose-finding trial was conducted from 2019 through 2022. The original design included a dose-escalation/extension phase followed by a dose-expansion phase. Three doses of lenalidomide were evaluated: 10, 15, and 25 mg. The main outcome was the MTD. RESULTS: Eleven patients enrolled (10 men), with a mean age of 67.6 years (SD = 6.18, range 58-77 years) and mean disease duration of 8.5 years (SD = 10.9, range 1-40 years). The study terminated early due to higher-than-expected non-dose-limiting toxicity venous thromboembolism (VTE) events. The calculated MTD was 25 mg (posterior mean of toxicity probability was 0.01 with a 95% credible interval of 0.00, 0.06), but a recommended phase 2 dose of 15 mg was advised. For secondary exploratory outcomes, only EQ-5D (-0.95, 95% CI -1.81 to -0.09) and total IgM (-162 mg/dL, 95% CI -298 to -26) showed signs of improvement by month 12. CONCLUSIONS: Lenalidomide was associated with higher-than-expected VTE events in anti-MAG neuropathy patients, despite a calculated MTD of 25 mg. A recommended phase 2 dose of 15 mg was advised. Lenalidomide did not improve disability or impairment at 12 months, although this study was not powered for efficacy. The risks of long term lenalidomide may outweigh benefit for patients with anti-MAG neuropathy. Any future efficacy study should address VTE risk, as current myeloma guidelines appear inadequate. TRIAL REGISTRATION: Lenalidomide in Anti-MAG Neuropathy: Phase 1b Study, ClinicalTrials.gov Identifier: NCT03701711, https://clinicaltrials.gov/ct2/show/NCT03701711. First submitted October 10, 2018. First patient enrolled in January 2019.

Differential impact on motor unit characteristics across severities of adult spinal muscular atrophy.

OBJECTIVE: To test the hypotheses that decomposition electromyography (dEMG) motor unit action potential (MUAP) amplitude and firing rate are altered in SMA; dEMG parameters are associated with strength and function; dEMG parameters are correlated with traditional electrophysiological assessments. METHODS: Ambulatory and non-ambulatory adults with SMA on nusinersen and healthy controls were enrolled. MUAPs were decomposed from multielectrode surface recordings during 30-s maximum contraction of the abductor digiti minimi (ADM). Isometric strength, upper limb function, patient-reported function, and standard electrophysiologic measures of the ADM (compound muscle action potential [CMAP], single motor unit potential [SMUP], motor unit number estimation [MUNE]) were collected. RESULTS: dEMG MUAP amplitudes were higher in ambulatory versus control and non-ambulatory groups and were higher in controls versus non-ambulatory SMA. In contrast, dEMG firing rates were higher in ambulatory versus non-ambulatory and control groups but similar between non-ambulatory and control. dEMG parameters showed moderate to strong positive correlation with strength and function whereas CMAP and MUNE better correlated with function than strength. SMUP did not correlate with strength, function, or dEMG MUAP amplitude. dEMG parameters show overall good test-retest reliability. INTERPRETATION: dEMG provided reliable, noninvasive measure of MUAP amplitude size and firing rate and revealed divergent patterns across disease severity in adults with SMA. Firing rate enhancement, as seen in milder SMA, may provide a therapeutic avenue for improving function in more severe SMA, where firing rates appear preserved. MUAP amplitude size and firing rate, quantified with dEMG, may be promising monitoring biomarker candidates for noninvasive assessment of SMA.

Anti-myelin-associated glycoprotein neuropathy: Where do we stand?

Myelin-associated glycoprotein (MAG) is a transmembrane glycoprotein concentrated in periaxonal Schwann cell and oligodendroglial membranes of myelin sheaths that serves as an antigen for immunoglobulin M (IgM) monoclonal antibodies. Individuals who harbor anti-MAG antibodies classically develop a progressive autoimmune peripheral neuropathy characterized clinically by ataxia, distal sensory loss, and gait instability, and electrophysiologically by distally accentuated conduction velocity slowing. Although off-label immunotherapy is common, there are currently no proven effective disease-modifying therapeutics, and most patients experience slow accumulation of disability over years and decades. The typically slowly progressive nature of this neuropathy presents unique challenges when trying to find effective anti-MAG therapeutic agents. Drug development has also been hampered by the lack of validated outcome measures that can detect clinically meaningful changes in a reasonable amount of time as well as by the lack of disease activity biomarkers. In this invited review, we provide an update on the state of clinicometric outcome measures and disease activity biomarkers in anti-MAG neuropathy. We highlight the insensitivity of widely used existing clinicometric outcome measures such as the Inflammatory Neuropathy Cause and Treatment (INCAT) disability score as well as the INCAT sensory subscore in anti-MAG neuropathy, referencing the two previous negative randomized controlled clinical trials evaluating rituximab. We then discuss newly emerging candidate therapeutic agents, including tyrosine kinase inhibitors and enhanced B-cell-depleting agents, among others. We conclude with a practical approach to the evaluation and management of anti-MAG neuropathy patients.

Lean tissue mass measurements by dual-energy X-ray absorptiometry and associations with strength and functional outcome measures in facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive disease of skeletal muscle. Dual energy X-ray absorptiometry (DEXA) is a widely available, cost-effective and sensitive technique for measuring whole body and regional lean tissue mass and has been used in prior clinical trials in neuromuscular diseases. The Clinical Trial Readiness to Solve Barriers to Drug Development in FSHD (ReSolve) study is a prospective, longitudinal, observational multisite study. We obtained concurrent DEXA scans and functional outcome measurements in 185 patients with FSHD at the baseline visit. We determined the associations between lean tissue mass in the upper and lower extremities and corresponding clinical outcome measures. There were moderate correlations between upper and lower extremity lean tissue mass and their corresponding strengths and function. Lean tissue mass obtained by DEXA scan may be useful as a biomarker in future clinical trials in FSHD.

Identifying Biomarkers of Spinal Muscular Atrophy for Further Development.

BACKGROUND: Spinal muscular atrophy (SMA) is caused by bi-allelic, recessive mutations of the survival motor neuron 1 (SMN1) gene and reduced expression levels of the survival motor neuron (SMN) protein. Degeneration of alpha motor neurons in the spinal cord causes progressive skeletal muscle weakness. The wide range of disease severities, variable rates of decline, and heterogenous clinical responses to approved disease-modifying treatment remain poorly understood and limit the ability to optimize treatment for patients. Validation of a reliable biomarker(s) with the potential to support early diagnosis, inform disease prognosis and therapeutic suitability, and/or confirm response to treatment(s) represents a significant unmet need in SMA. OBJECTIVES: The SMA Multidisciplinary Biomarkers Working Group, comprising 11 experts in a variety of relevant fields, sought to determine the most promising candidate biomarker currently available, determine key knowledge gaps, and recommend next steps toward validating that biomarker for SMA. METHODS: The Working Group engaged in a modified Delphi process to answer questions about candidate SMA biomarkers. Members participated in six rounds of reiterative surveys that were designed to build upon previous discussions. RESULTS: The Working Group reached a consensus that neurofilament (NF) is the candidate biomarker best poised for further development. Several important knowledge gaps were identified, and the next steps toward filling these gaps were proposed. CONCLUSIONS: NF is a promising SMA biomarker with the potential for prognostic, predictive, and pharmacodynamic capabilities. The Working Group has identified needed information to continue efforts toward the validation of NF as a biomarker for SMA.

Characterizing Ventilatory Muscle Dysfunction in Inclusion Body Myositis.

OBJECTIVE: Investigation of the frequency and progression of ventilatory muscle dysfunction in patients with inclusion body myositis, the most common myopathy after age of 50 yrs. Prior research is limited to case series and cross-section studies. DESIGN: This is a retrospective review of pulmonary function tests, respiratory symptoms, and muscle strength testing. RESULTS: Of the 54 patients reviewed (mean age: 65 ± 9 yrs and disease duration: 7 ± 7 yrs), the majority ( n = 32, 59%) had restrictive forced vital capacity deficits at initial visit. Patients with reduced forced vital capacity showed higher prevalence of respiratory symptoms; but age, body mass index, and limb strength were similar when compared with patients without restrictive forced vital capacity. Mean rate of forced vital capacity decline of 0.108 l/yr in inclusion body myositis patients. Lower baseline limb strength correlated with longer disease duration and future forced vital capacity decline (eg, weaker patients experienced faster decline). CONCLUSIONS: Based on forced vital capacity, there is a high frequency of ventilatory pump muscle weakness in inclusion body myositis, which is associated with a higher burden of respiratory symptoms. Baseline strength may indicate risk of respiratory decline and need for vigilant screening. Importantly, ventilatory and limb muscle decline may not progress in a corresponding manner, highlighting the importance of pulmonary function surveillance.

Neurofilament Levels in CSF and Serum in an Adult SMA Cohort Treated with Nusinersen.

OBJECTIVE: To retrospectively evaluate the utility of serum and cerebrospinal fluid (CSF) levels of neurofilament light chain (NfL) and phosphorylated neurofilament heavy chain (pNfH) as biomarkers for spinal muscular atrophy (SMA) progression and response to nusinersen treatment. METHODS: NfL and pNfH levels were quantified using single molecular array (SIMOA) in CSF of 33 adult SMA patients (SMN copy number 3-5) before and in response to nusinersen treatment. In 11 of the patients, blood serum samples were also collected. CSF NfL and pNfH from patients were compared to CSF Nfs from age-matched controls without neurological disease (n = 6). For patients, pearson correlation coefficients (r) were calculated to investigate associations between Nf levels and other functional outcome measures. RESULTS: Nf levels were similar between SMA and control adults and showed no change in response to nusinersen treatment in CSF or serum. Cross-sectional analyses showed an increase in CSF NfL and pNfH with age in patients (NfL p = 0.0013; pNfH p = 0.0035) and an increase in CSF NfL in controls (p = 0.002). In non-ambulatory patients, baseline serum pNfH showed a negative correlation with multiple strength and functional assessment metrics including Revised Upper Limb Module (r = -0.822, p = 0.04), upper extremity strength (r = -0.828, p = 0.042), lower extremity strength (r = -0.860, p = 0.028), and total strength (r = -0.870, p = 0.024). CONCLUSIONS: Nf levels did not change in response to nusinersen in adults with SMA and were not different from controls. In patients and controls, we detected an age-related increase in baseline CSF NfL and pNfH levels. Though some associations were identified, our results suggest Nf levels are not preditive or prognostic biomarkers in this population.

Persistent neuromuscular junction transmission defects in adults with spinal muscular atrophy treated with nusinersen.

OBJECTIVE: Spinal muscular atrophy (SMA) is a motor neuron disease caused by low levels of survival motor neuron (SMN) protein. Prior work in models and patients has demonstrated electrophysiological and morphological defects at the neuromuscular junction (NMJ). Therapeutic development has resulted in clinically available therapies to increase SMN protein levels in patients and improve muscle function. Here we aimed to investigate the effect of SMN restoration (via nusinersen) on NMJ transmission in adults with SMA. METHODS: Participants undergoing nusinersen treatment underwent 3 Hz repetitive nerve stimulation (RNS) of the spinal accessory nerve to assess compound muscle action potential amplitude decrement. Maximum voluntary isometric contraction (MVICT), Revised Upper Limb Module (RULM), and 6 min walk test (6MWT) were assessed for correlations with decrement. RESULTS: Data from 13 ambulatory (7 men/6 women, mean age 40±11 years) and 11 non-ambulatory (3 men/8 women, mean age 38±12 years) participants were analysed. Cross-sectional analyses of RNS decrement were similar at 14 months of nusinersen (-14.2%±11.5%, n=17) vs baseline (-11.9%±8.3%, n=15) (unpaired t-test, p=0.5202). Longitudinal comparison of decrement in eight participants showed no change at 14 months (-13.9%±6.7%) vs baseline (-16.9%±13.4%) (paired t-test, p=0.5863). Decrement showed strong correlations with measures of MVICT, RULM and 6MWT but not age or disease duration. CONCLUSION: Adults with SMA had significant NMJ transmission defects that were not corrected with 14 months of nusinersen treatment. NMJ defects were negatively associated with physical function, and thus may represent a promising target for additive or combinatorial treatments.

Recurrent Miller Fisher: A Case Report Along With a Literature and an EMG/NCS Review.

MFS has been reported to recur in 10-12% of patients. There may be a genetic component related to HLA-DR2. Anti-GAD antibodies can be present in MFS along with anti-GQ1b. Common EMG/NCS associations consist of a predominantly axonal, sensory polyneuropathy and absent H reflexes. A 32-year-old female with a history of hypothyroidism presented to our institution twice with symptoms of diplopia, lower extremity weakness and distal paresthesias occurring a year apart. She had ophthalmoplegia, reduced reflexes, and ataxia on exam. CSF showed a borderline elevated protein of 47 and white blood cells <3. She was positive for anti-GQ1b both times. Her anti-GAD65 antibody was elevated during both admissions. EMG/NCS on her first admission revealed comparatively reduced sensory nerve action potentials (SNAPs) and a normal blink reflex. Her SNAPs improved on the second admission, however, the EMG was performed only 2 days after the onset of her symptoms, limiting some early findings that may have not matured electrophysiologically. She was treated with IVIG on both occasions with rapid recovery within 5 days. This case highlights the fact that MFS can be recurrent. It also provides further evidence that anti-GAD antibodies may be associated with MFS. Reported findings of the blink reflex in MFS are diverse and further data is needed to determine if certain findings are more predominant than others. Treatment typically consists of IVIG, though steroids may also be considered for recurrence. Prognosis is generally favorable, regardless of treatment.

Safety, Tolerability, and Effect of Nusinersen Treatment in Ambulatory Adults With 5q-SMA.

Objective: To determine the safety and tolerability of nusinersen treatment in ambulatory adults with spinal muscular atrophy (SMA) and investigate the treatment effect on muscle strength, physical function, and motor unit physiology. Methods: Individuals aged 18 years or older with genetically confirmed 5q SMA, three or more copies of the SMN2 gene, and the ability to ambulate 30 feet were enrolled. Safety outcomes included the number of adverse events and serious adverse events, clinically significant vital sign or laboratory parameter abnormalities. Outcome assessments occurred at baseline (prior to the first dose of nusinersen) and then 2, 6, 10, and 14 months post-treatment. Results: Six women, seven men (mean age: 37 ± 11, range: 18-59 years) were included for analyses. The most common side effects were headache and back pain, but overall procedures and treatments were well-tolerated. No serious adverse events were reported. Maximal Voluntary Isometric Muscle Contraction Testing (MVICT) and 6-min walk test (6MWT) both showed overall stability with significant increases at 2, 6, and 10 months for the 6MWT. More consistent significant treatment effects were noted on the Hammersmith Functional Motor Scale Expanded, SMA-Functional Rating Scale, and forced vital capacity. Treatment resulted in progressively increased ulnar compound muscle action potential and average single motor unit potential amplitudes, but motor unit number estimation remained stable. Conclusions: Nusinersen treatment is safe and well-tolerated in ambulatory adults with SMA. Treatment resulted in improved motor function and electrophysiological findings suggest that this improvement may be occurring via improved motor unit reinnervation capacity.

Safety, Tolerability, and Effect of Nusinersen in Non-ambulatory Adults With Spinal Muscular Atrophy.

Objective: Investigation of the safety, tolerability, and treatment effect of nusinersen treatment in non-ambulatory adults with spinal muscular atrophy (SMA). Methods: Non-ambulatory individuals, aged 18 years or older with genetically confirmed 5q SMA were enrolled. In participants with spinal fusion, fluoroscopy guided cervical C1-C2 lateral approach was used. Outcomes at 2, 6, 10, and 14 months post-treatment were compared with baseline assessment. Forced vital capacity (FVC) was the primary outcome, and RULM, HFMSE, the modified SMA-FRS, and ulnar nerve electrophysiology [compound muscle action potential (CMAP), single motor unit size, and motor unit number] were secondary. Adverse and serious adverse events and clinically significant vital sign or lab abnormalities were recorded. Results: Results from 12 women and 7 men (mean age: 39.7 ± 13.9, range: 21-64 years) were analyzed. No clinically significant changes of vital signs or laboratory parameters were observed. Five participants were hospitalized for pneumonia. Other adverse events included headache, back pain, cervical injection site pain, and upper respiratory and urinary tract infections. High baseline protein/creatinine ratio without significant change on treatment noted in 4 participants. FVC was feasible in all participants. HFMSE and RULM were not feasible in the majority of participants. FVC and functional outcomes were stable without improvement. CMAP and single motor unit potential sizes showed enlargement while motor unit numbers were stable. Conclusions: Nusinersen, including C1/C2 delivery, was safe overall and well-tolerated. Several outcome measures were limited by floor effect. Overall, treatment resulted in stability of motor outcomes, but motor unit and CMAP size were increased.

Elevated Creatinine Kinase in Peripheral Neuropathy Is Associated With Muscle Cramping.

Introduction: Serum Creatinine Kinase (CK) is a non-specific marker of muscle damage. There has been limited investigation of the association between peripheral neuropathy and CK elevation (hyperCKemia). Methods: We performed a chart review to investigate the CK level in peripheral neuropathies. Demographics, clinical history, physical exam, electrodiagnostic data, CK level, statin use, etiology of neuropathy, and concomitant neuromuscular disorders were recorded. HyperCKemia was defined using our laboratory cutoff values of >180 U/L (women) and >220 U/L (men). Results: We identified 450 patients with peripheral neuropathy who had CK testing, 92 (20.4%) of whom had hyperCKemia. Sixty-one of those patients (13.5% of the total figure) had a concomitant etiology that could explain the CK elevation. Thirty-one patients (6.9%) had no other identifiable etiology for their hyperCKemia beyond the neuropathy. The average CK level in the latter cohort with hyperCKemia was 376 U/L (women: 312 U/L; men: 444 U/L). The frequency of cramping was greater in patients with elevated vs. normal CK (p < 0.0001). Discussion: HyperCKemia can occur in patients with peripheral neuropathy and appears to associate with cramping.

Cerebrospinal Fluid Protein Level and Mechanical Ventilation in Guillain-Barré Syndrome patients.

The prognostic value of cerebrospinal fluid (CSF) protein in Guillain Barré Syndrome (GBS) is unclear. We aimed to explore the potential association between CSF protein level and mechanical ventilation in GBS. We undertook a retrospective study of GBS patients from January 2000 to November 2019 at the University of Michigan. 94 patients were ultimately included for evaluation. After adjusting for the Erasmus GBS Respiratory Insufficiency Scale (EGRIS), we did not find a significant difference in CSF protein between ventilated and non-ventilated patients. Elevated CSF protein level does not appear to portend an increased likelihood of mechanical ventilation in GBS patients.

Novel heterozygous truncating titin variants affecting the A-band are associated with cardiomyopathy and myopathy/muscular dystrophy.

BACKGROUND: Variants in TTN are frequently identified in the genetic evaluation of skeletal myopathy or cardiomyopathy. However, due to the high frequency of TTN variants in the general population, incomplete penetrance, and limited understanding of the spectrum of disease, interpretation of TTN variants is often difficult for laboratories and clinicians. Currently, cardiomyopathy is associated with heterozygous A-band TTN variants, whereas skeletal myopathy is largely associated with homozygous or compound heterozygous TTN variants. Recent reports show pathogenic variants in TTN may result in a broader phenotypic spectrum than previously recognized. METHODS: Here we report the results of a multisite study that characterized the phenotypes of probands with variants in TTN. We investigated TTN genotype-phenotype correlations in probands with skeletal myopathy and/or cardiomyopathy. Probands with TTN truncating variants (TTNtv) or pathogenic missense variants were ascertained from two academic medical centers. Variants were identified via clinical genetic testing and reviewed according to the American College of Medical Genetics criteria. Clinical and family history data were documented via retrospective chart review. Family studies were performed for probands with atypical phenotypes. RESULTS: Forty-nine probands were identified with TTNtv or pathogenic missense variants. Probands were classified by clinical presentation: cardiac (n = 30), skeletal muscle (n = 12), or both (cardioskeletal, n = 7). Within the cardioskeletal group, 5/7 probands had heterozygous TTNtv predicted to affect the distal (3') end of the A-band. All cardioskeletal probands had onset of proximal-predominant muscle weakness before diagnosis of cardiovascular disease, five pedigrees support dominant transmission. CONCLUSION: Although heterozygous TTNtv in the A-band is known to cause dilated cardiomyopathy, we present evidence that these variants may in some cases cause a novel, dominant skeletal myopathy with a limb-girdle pattern of weakness. These findings emphasize the importance of multidisciplinary care for patients with A-band TTNtv who may be at risk for multisystem disease.

Spinal Muscular Atrophy in the Treatment Era.

Spinal muscular atrophy is an autosomal-recessive degenerative neuromuscular disease that has historically been categorized into 5 types based on the individual's best functional ability. Two rather remarkable treatments have recently been approved for commercial use, and both have markedly changed the natural history of this disease. Here the authors report several cases of individuals, ranging from infants to adults, to highlight diagnostic considerations, along with initial and long-term treatment considerations in these individuals who now have the potential for stabilization to significant improvement in functional outcomes.

Clinical Effects of the Self-administered Subcutaneous Complement Inhibitor Zilucoplan in Patients With Moderate to Severe Generalized Myasthenia Gravis: Results of a Phase 2 Randomized, Double-Blind, Placebo-Controlled, Multicenter Clinical Trial.

Importance: Many patients with generalized myasthenia gravis (gMG) have substantial clinical disability, persistent disease burden, and adverse effects attributable to chronic immunosuppression. Therefore, there is a significant need for targeted, well-tolerated therapies with the potential to improve disease control and enhance quality of life. Objective: To evaluate the clinical effects of zilucoplan, a subcutaneously (SC) self-administered macrocyclic peptide inhibitor of complement component 5, in a broad population of patients with moderate to severe gMG. Design, Setting, and Participants: This randomized, double-blind, placebo-controlled phase 2 clinical trial at 25 study sites across North America recruited participants between December 2017 and August 2018. Fifty-seven patients were screened, of whom 12 did not meet inclusion criteria and 1 was lost to follow-up after randomization but before receiving study drug, resulting in a total of 44 acetylcholine receptor autoantibody (AChR-Ab)-positive patients with gMG with baseline Quantitative Myasthenia Gravis (QMG) scores of at least 12, regardless of treatment history. Interventions: Patients were randomized 1:1:1 to a daily SC self-injection of placebo, 0.1-mg/kg zilucoplan, or 0.3-mg/kg zilucoplan for 12 weeks. Main Outcomes and Measures: The primary and key secondary end points were the change from baseline to week 12 in QMG and MG Activities of Daily Living scores, respectively. Significance testing was prespecified at a 1-sided α of .10. Safety and tolerability were also assessed. Results: The study of 44 patients was well balanced across the 3 treatment arms with respect to key demographic and disease-specific variables. The mean age of patients across all 3 treatment groups ranged from 45.5 to 54.6 years and most patients were white (average proportions across 3 treatment groups: 78.6%-86.7%). Clinically meaningful and statistically significant improvements in primary and key secondary efficacy end points were observed. Zilucoplan at a dose of 0.3 mg/kg SC daily resulted in a mean reduction from baseline of 6.0 points in the QMG score (placebo-corrected change, -2.8; P = .05) and 3.4 points in the MG Activities of Daily Living score (placebo-corrected change, -2.3; P = .04). Clinically meaningful and statistically significant improvements were also observed in other secondary end points, the MG Composite and MG Quality-of-Life scores. Outcomes for the 0.1-mg/kg SC daily dose were also statistically significant but slower in onset and less pronounced than with the 0.3-mg/kg dose. Rescue therapy (intravenous immunoglobulin or plasma exchange) was required in 3 of 15, 1 of 15, and 0 of 14 participants in the placebo, 0.1-mg/kg zilucoplan, and 0.3-mg/kg zilucoplan arms, respectively. Zilucoplan was observed to have a favorable safety and tolerability profile. Conclusions and Relevance: Zilucoplan yielded rapid, meaningful, and sustained improvements over 12 weeks in a broad population of patients with moderate to severe AChR-Ab-positive gMG. Near-complete complement inhibition appeared superior to submaximal inhibition. The observed safety and tolerability profile of zilucoplan was favorable. Trial Registration: ClinicalTrials.gov Identifier: NCT03315130.

Outcome measures in a cohort of ambulatory adults with spinal muscular atrophy.

INTRODUCTION: With the advent of disease-altering therapies for spinal muscular atrophy (SMA), there is a requirement to better characterize outcome measures, particularly in milder forms of disease. METHODS: Maximal voluntary isometric contraction testing and 6-minute walk test (6MWT) performed in ambulatory SMA adults as part of the SMA-VALIANT trial were analyzed. Test-retest reliability and correlation with other candidate biomarkers and outcomes were investigated. RESULTS: Maximal voluntary isometric contraction testing and 6MWT showed good test-retest reliability (intraclass correlation coefficient = 0.98 and 0.85, respectively). Maximal voluntary isometric contraction testing and 6MWT demonstrated very strong correlation (r = 0.83, P <. 0001), and each correlated with the SMA Functional Rating Scale (r = 0.7, P < .0001 and r = 0.65, P = .0001, respectively), lean muscle mass (r = 0.68, P < .0001 and r = 0.56, P = .001, respectively), and ulnar compound muscle action potential (r = 0.57, P = .0008 and r = 0.47, P = .008, respectively). DISCUSSION: Maximal voluntary isometric contraction testing and 6MWT are suitable outcomes for use in ambulatory adults with SMA. Maximal voluntary isometric contraction testing may be preferable because of superior test-retest reliability and closer associations with other outcomes and biomarkers of neuromuscular function.

A novel TTN deletion in a family with skeletal myopathy, facial weakness, and dilated cardiomyopathy.

BACKGROUND: Pathogenic variants in TTN (OMIM 188840), encoding the largest human protein, are known to cause dilated cardiomyopathy and several forms of skeletal myopathy. The clinical interpretation of TTN variants is challenging, however, due to the frequency of missense changes, variable testing and reporting practices in commercial laboratories, and incomplete understanding of the spectrum of TTN-related disease. METHODS: We report a heterozygous TTN deletion segregating in a family with an unusual skeletal myopathy phenotype associated with facial weakness, gait abnormality, and dilated cardiomyopathy. RESULTS: A novel 16.430 kb heterozygous deletion spanning part of the A- and M-bands of TTN was identified in the proband and his symptomatic son, as well as in an additional son whose symptoms were identified on clinical evaluation. The deletion was found to be de novo in the proband. CONCLUSION: Pathogenic variants in TTN may be an unrecognized cause of skeletal myopathy phenotypes, particularly when accompanied by dilated cardiomyopathy.