There remains a crucial need to address inequalities in genomic research and include populations from low- and middle-income countries (LMIC). Here we present eight consanguineous families from Pakistan, five with neurodevelopmental disorders (NDDs) and three with neuromuscular disorders (NMDs). Affected individuals were clinically characterized, and genetic variants were identified through exome sequencing (ES), followed by family segregation analysis. Affected individuals in six out of eight families (75%) carried homozygous variants that met ACMG criteria for being pathogenic (in the genes ADGRG1, METTL23, SPG11) or likely pathogenic (in the genes GPAA1, MFN2, SGSH). The remaining two families had homozygous candidate variants in the genes (AP4M1 and FAM126A) associated with phenotypes consistent with their clinical presentations, but the variants did not meet the criteria for pathogenicity and were hence classified as variants of unknown significance. Notably, the variants in ADGRG1, AP4M1, FAM126A, and SGSH did not have prior reports in the literature, demonstrating the importance of including diverse populations in genomic studies. We provide clinical phenotyping along with analyses of ES data that support the utility of ES in making accurate molecular diagnoses in these patients, as well as in unearthing novel variants in known disease-causing genes in underrepresented populations from LMIC.

OBJECTIVE: Concentric needle electromyography (CNEMG) is an essential examination for evaluating neuromuscular disorders, although pain is a drawback. Clustering Index (CI) method is a non-invasive quantitative analysis for surface electromyography (SEMG) that evaluates whether the signal area is clustered into the few large motor unit potentials (MUPs) or is evenly distributed. However, the diagnostic yield of the CI method in comparison with CNEMG is not known. In this study, we aimed to compare the sensitivity of the CI method with MUP parameters in CNEMG for diagnosing neurogenic or myogenic disorders.
METHODS: We retrospectively identified patients for whom both SEMG and CNEMG were performed on the same tibialis anterior (TA) muscle. In CNEMG, seven MUP parameters were evaluated, including size index (SI) and revised size indices for neurogenic (rSIn) and myogenic (rSIm) disorders.
RESULTS: Identified were 21 patients with neurogenic and 21 patients with myogenic disorders. Control data were constructed from 30 control subjects. The sensitivities of the CI method for the neurogenic and myogenic groups were 76% and 62%, respectively, which were not significantly different from MUP parameters, except for being significantly higher than those of amplitude and duration for myopathy (24%). Among MUP parameters, the sensitivities of rSIn (62%) and rSIm (57%) for myopathy were significantly higher than those of amplitude and duration. The CI method significantly correlated with the strength of the TA muscle in myopathy.
CONCLUSIONS: The CI method, having comparable diagnostic yields to MUP parameters, is promising as a non-invasive diagnostic measure.

Most neuromuscular disorders are rare, but as a group they are not. Nevertheless, epidemiological data of specific neuromuscular disorders are scarce, especially on the incidence. We applied a capture-recapture approach to a nationwide hospital-based dataset and a patients association-based dataset to estimate the annual incidence rates for fifteen neuromuscular disorders in the Netherlands. The annual incidence rates per 100,000 population varied from 0.03/100,000 (95% CI 0.00 ‒ 0.06) for glycogenosis type 5 to 0.9/100,000 (95% confidence interval 0.7 ‒ 1.0) for myotonic dystrophy type 1. The summed annual incidence rate of these disorders was 4.1 per 100,000 per population. Nine of the provided incidence rates were previously unavailable, three rates were similar to the rates in the literature, and three rates were generally higher compared to previous findings but with overlapping confidence intervals. This study provides nationwide incidence rates for fifteen neuromuscular disorders predominantly diagnosed in adult life, nine which were previously unavailable. The capture-recapture approach provided estimates of the total number of individuals with neuromuscular disorders. To complete the gaps in the knowledge of disease frequencies, there is a need for estimates from an automated, obligatory data collection system of diagnosed and newly diagnosed patients with neuromuscular disorders.

UNASSIGNED: Patients with central core myopathy (CCM) can be at risk of exercise-induced rhabdomyolysis and myalgia. Despite its possible positive effects, physical training has been long avoided in these patients as no population-specific exercise adaption strategies have been developed. Here we present the case of a 17-year-old male CCM patient who underwent a 3-month training program tailored to a preliminary test aimed at assessing his physical exertion tolerance measured via changes in serum creatine kinase (CK).
UNASSIGNED: The preliminary tolerance test consisted of three 25-minute sessions (one session per week) of physical exercise (aerobic, resistance and mixed) at an intensity quantified as level 6 of the Borg Category Ratio (CR) 0-10 scale. A blood sample to assess CK was conducted 36 h following eachsession. The intervention consisted of a training program (three sessions per week) including both resistance and aerobic exercises concomitant with a personalized nutritional plan. Before and after intervention, a battery of metabolic (indirect calorimetry, bioimpedance) and cardiopulmonary (CPET) tests were performed.
UNASSIGNED: After training, improvements of the anaerobic threshold (+6.9%), normalized VO2 max (+15%) and body composition (muscle mass, +1.1 kg; fat mass, -1.1 kg were observed without pain, rhabdomyolysis, and blood CK augmentation compared to pretraining values.
UNASSIGNED: Our results highlight that a mixed aerobic/resistance training, properly tailored and supported by a specific nutritional plan, may safely improve the physical fitness and body composition in a CCM patient. Dosing exercise-induced CK serum change following Borg CR-10 intensity assessment, may be useful to correctly tailor physical exercise in these patients.

This systematic review aims to investigate the relationship between muscle mass and specific health outcomes in pediatric populations with neuromuscular disorders. A search was performed for any relevant studies published in English from 1996 to 2023 in five databases. To be included in this analysis, articles must have had participants with an average age ≤21, focus on children with neuromuscular disabilities, and primarily examine relationships between muscle mass and any functional or health outcomes measure. Studies including typically developing children were used to contrast and enhance findings. Thirty-two studies were included, with 10,129 unique individuals represented: seventeen studies focused on healthy/typically developing children; seven on children with cerebral palsy; three on children with Duchenne muscular dystrophy; two on children with sarcopenia; and one study each on children with osteoporosis, congenital muscular dystrophy, and other various neurologic disorders. Thirteen studies assessed functional outcomes, ten assessed bone outcomes, and nine assessed other cardiovascular/metabolic outcomes. All of the included studies demonstrated relationships between muscle mass and respective outcomes in varying measures. The results of this review demonstrate that there is a consistently recognized relationship between muscle mass and important health outcomes in children, supporting clinically targeting muscle mass as a means to optimize desired outcomes.

Duchenne muscular dystrophy (DMD) is an X-linked progressive disorder and the most common type of muscular dystrophy in children. As newborn screening (NBS) for DMD undergoes evaluation for the Recommended Uniform Screening Panel and is already mandated in multiple states, refining NBS algorithms is of utmost importance. NBS for DMD involves measuring creatine kinase-MM (CK-MM) concentration-a biomarker of muscle damage-in dried blood spots. The current test is FDA-approved for samples obtained less than 72 h after birth. Separate reference ranges are needed for samples collected later than 72 h after birth. In this study, we investigated the relationship between age and CK-MM in presumed healthy newborns to inform NBS algorithm designs. In patients with DMD, CK-MM is persistently elevated in childhood and adolescence, while it may be transiently elevated for other reasons in healthy newborns. CK-MM decrease over time was demonstrated by a population sample of 20,306 presumed healthy newborns tested between 0 and 60 days of life and repeat testing of 53 newborns on two separate days. In the population sample, CK-MM concentration was highest in the second 12 h period of life (median = 318 ng/mL) when only 57.6% of newborns tested below 360 ng/mL, the lowest previously published cutoff. By 72 h of age, median CK-MM concentration was 97 ng/mL, and 96.0% of infants had concentrations below 360 ng/mL. Between 72 h and 60 days, median CK-MM concentration ranged from 32 to 37 ng/mL. Establishing age-related cutoffs is crucial for optimizing the sensitivity and specificity of NBS for DMD.

UNASSIGNED: The Facioscapulohumeral Muscular Dystrophy Health Index (FSHD-HI) is a patient-reported outcome measure developed for patients with FSHD. This study aimed to translate the FSHD-HI into Japanese (FSHD-HI-J), evaluate cultural adaptation, and examine its psychometric properties.
UNASSIGNED: We created two forward translations, integrated them into a single Japanese version, and evaluated the back-translated version of the FSHD-HI. After finalizing the translation and cultural adaptation, we conducted a survey of 66 patients with FSHD to examine the reliability and validity of the FSHD-HI-J. For psychometric evaluations, we used Cronbach\'s alpha to assess internal consistency, the intraclass correlation coefficient (ICC) for test-retest reliability, and assessed validity based on the associations between FSHD-HI-J, clinical variables, and quality of life measures.
UNASSIGNED: The FSHD-HI-J was found to be clinically relevant, indicating high internal consistency and test-retest reliability (ICC = 0.92 [95% confidence interval: 0.86-0.95] for the total score), as well as significant associations with clinical variables (D4Z4 repeats and functional impairment) and other quality of life measures (|rho| = 0.25-0.73).
UNASSIGNED: The FSHD-HI-J is a valid and reliable patient-reported outcome measure for Japanese patients with FSHD. This validated, disease-specific patient-reported outcome is essential for future clinical practice and clinical trials.
Facioscapulohumeral muscular dystrophy (FSHD) affects not only a patient’s physical abilities but also their social activities, participation, and overall quality of life.The FSHD-Health Index (FSHD-HI) is an instrument developed as a disease-specific patient-reported outcome measure to evaluate the burden experienced by patients.The Japanese version of the FSHD-HI has been established as a reliable and validated measure for Japanese-speaking patients with FSHD.The Japanese version of the FSHD-HI can serve as a useful instrument for evaluating the effectiveness of interventions in future trials.

The HOXB1 gene encodes a homeobox transcription factor pivotal in the development of rhombomere 4. Biallelic pathogenic variants in this gene are associated with congenital facial paresis type 3 (HCFP3). Only seven single nucleotide variants have been reported in the literature to date. Here, we report a 27-year-old female with a unique presentation of HCFP3 with two novel compound-heterozygous missense variants: c.763C>G, p.(Arg255Gly), which arose de novo and an inherited c.781C>T, p.(Arg261Cys) variant. The patient exhibited HCFP3 symptoms with mild upward esodeviation and lacked the documented ear malformations common in HCFP. For many years, she was misdiagnosed with facio-scapulo-humeral muscular dystrophy, due to complaints of shoulder girdle and neck muscle weakness. No alternative genetic or acquired causes of neck and shoulder girdle weakness were found, suggesting its potential inclusion in the phenotypic spectrum.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a genetic muscle disorder that manifests during early childhood and is ultimately fatal. Recently approved treatments targeting the genetic cause of DMD are limited to specific subpopulations of patients, highlighting the need for therapies with wider applications. Pharmacologic inhibition of myostatin, an endogenous inhibitor of muscle growth produced almost exclusively in skeletal muscle, has been shown to increase muscle mass in several species, including humans. Taldefgrobep alfa is an anti-myostatin recombinant protein engineered to bind to and block myostatin signaling. Preclinical studies of taldefgrobep alfa demonstrated significant decreases in myostatin and increased lower limb volume in three animal species, including dystrophic mice.
METHODS: This manuscript reports the cumulative data from three separate clinical trials of taldefgrobep alfa in DMD: a phase 1 study in healthy adult volunteers (NCT02145234), and two randomized, double-blind, placebo-controlled studies in ambulatory boys with DMD-a phase 1b/2 trial assessing safety (NCT02515669) and a phase 2/3 trial including the North Star Ambulatory Assessment (NSAA) as the primary endpoint (NCT03039686).
RESULTS: In healthy adult volunteers, taldefgrobep alfa was generally well tolerated and resulted in a significant increase in thigh muscle volume. Treatment with taldefgrobep alfa was associated with robust dose-dependent suppression of free myostatin. In the phase 1b/2 trial, myostatin suppression was associated with a positive effect on lean body mass, though effects on muscle mass were modest. The phase 2/3 trial found that the effects of treatment did not meet the primary endpoint pre-specified futility analysis threshold (change from baseline of ≥ 1.5 points on the NSAA total score).
CONCLUSIONS: The futility analysis demonstrated that taldefgrobep alfa did not result in functional change for boys with DMD. The program was subsequently terminated in 2019. Overall, there were no safety concerns, and no patients were withdrawn from treatment as a result of treatment-related adverse events or serious adverse events.
BACKGROUND: NCT02145234, NCT02515669, NCT03039686.
The goal of this program was to develop a treatment to improve muscle function in patients with Duchenne muscular dystrophy (DMD). Muscle weakness in patients with DMD is progressive, leading to the irreversible loss of walking ability and eventually death due to cardiorespiratory failure. One potential way of improving muscle function is to target a protein known as myostatin that acts in healthy muscle to regulate muscle size. Studies in animals have shown that blocking myostatin can increase muscle size. Taldefgrobep alfa is a drug designed to block myostatin and it was shown to induce muscle growth in animals. A study in healthy volunteers found that taldefgrobep alfa was able to increase muscle size in humans and was not associated with safety concerns. Following this, a study was conducted in boys with DMD who were either treated with taldefgrobep alfa or a placebo. This first study in patients found that treatment was able to reduce myostatin levels and had a small effect on muscle size, supporting a larger trial in more patients with DMD. The aim of the larger trial was to test if taldefgrobep alfa had a meaningful effect on muscle function in patients with DMD. Results from this key trial did not meet the targeted improvement in function and a decision was made to end the trial and halt the use of taldefgrobep alfa as a potential treatment for DMD. No patients stopped treatment with taldefgrobep alfa as a result of adverse safety effects and no safety concerns were identified.

Neuromuscular disorders, characterized by progressive muscle degeneration and weakness, present substantial challenges to both affected individuals and their families. Genetic testing assumes a pivotal role in facilitating early diagnosis, intervention, treatment, and informed family planning for these conditions. The objective of this qualitative study is to delve into the knowledge, awareness, and perceptions surrounding genetic testing within the cohort of parents caring for individuals with neuromuscular disorders in Malaysia. A semi-structured interview approach was employed to elicit data from parents of individuals diagnosed with neuromuscular disorders, encompassing those with clinical diagnoses and those diagnosed through genetic testing. Examination of the interview responses yielded nine overarching themes, which furnish invaluable insights into the perspectives of Malaysian parents concerning genetic testing. The study discerned several challenges associated with genetic testing, notably encompassing the limited awareness among parents, the financial constraints associated with genetic testing, and the perceived significance of genetic testing in the context of neuromuscular disorders. The findings suggest that the level of knowledge and awareness pertaining to genetic testing for neuromuscular disorders among parents in Malaysia varies, with initial levels of awareness ranging from relatively low to reasonably sufficient prior to and following the birth of an affected child. However, the investigation revealed that parents tended to cultivate more favorable perceptions regarding genetic testing subsequent to their experience with genetic counseling. This underscores the potential for heightened awareness and comprehension as a consequence of the personal experience of parenting an affected child confirmed through genetic testing and genetic counseling, ultimately influencing parental awareness.