Myopathic manifestations across the adult lifespan of patients with malignant hyperthermia susceptibility: a narrative review.

Malignant hyperthermia susceptibility (MHS) designates individuals at risk of developing a hypermetabolic reaction triggered by halogenated anaesthetics or the depolarising neuromuscular blocking agent suxamethonium. Over the past few decades, beyond the operating theatre, myopathic manifestations impacting daily life are increasingly recognised as a prevalent phenomenon in MHS patients. At the request of the European Malignant Hyperthermia Group, we reviewed the literature and gathered the opinion of experts to define MHS-related myopathy as a distinct phenotype expressed across the adult lifespan of MHS patients unrelated to anaesthetic exposure; this serves to raise awareness about non-anaesthetic manifestations, potential therapies, and management of MHS-related myopathy. We focused on the clinical presentation, biochemical and histopathological findings, and the impact on patient well-being. The spectrum of symptoms of MHS-related myopathy encompasses muscle cramps, stiffness, myalgias, rhabdomyolysis, and weakness, with a wide age range of onset mainly during adulthood. Histopathological analysis can reveal nonspecific abnormalities suggestive of RYR1 involvement, while metabolic profiling reflects altered energy metabolism in MHS muscle. Myopathic manifestations can significantly impact patient quality of life and lead to functional limitations and socio-economic burden. While currently available therapies can provide symptomatic relief, there is a need for further research into targeted treatments addressing the underlying pathophysiology. Counselling early after establishing the MHS diagnosis, followed by multidisciplinary management involving various medical specialties, is crucial to optimise patient care.

Individuals and Families Affected by RYR1-Related Diseases - The Patient/Caregiver Perspective.

Background and objective: Pathogenic variants of RYR1, the gene encoding the principal sarcoplasmic reticulum calcium release channel (RyR1) with a crucial role in excitation-contraction coupling, are among the most common genetic causes of non-dystrophic neuromuscular disorders. We recently conducted a questionnaire study focusing on functional impairments, fatigue, and quality of life (QoL) in patients with RYR1-related diseases (RYR1-RD) throughout the recognized disease spectrum. In this previous questionnaire study the medical perspective was taken, reflective of a study protocol designed by neurologists and psychologists. With this present study we wanted to specifically address the patient perspective. Methods: Together with affected individuals, family members, and advocates concerned with RYR1-RD, we developed an online patient survey that was completed by 227 patients or their parents/other caretakers (143 females and 84 males, 0-85 years). We invited 12 individuals, representing most of the patient group based on age, sex, race, and type and severity of diagnosis, to share their personal experiences on living with a RYR1-RD during an international workshop in July 2022. Data were analyzed through a mixed-methods approach, employing both a quantitative analysis of the survey results and a qualitative analysis of the testimonials. Results: Data obtained from the combined quantitative and qualitative analyses provide important insights on six topics: 1) Diagnosis; 2) Symptoms and impact of the condition; 3) Physical activity; 4) Treatment; 5) Clinical research and studies; and 6) Expectations. Conclusions: Together, this study provides a unique patient perspective on the RYR1-RD spectrum, associated disease impact, suitable physical activities and expectations of future treatments and trials, and thus, offers an essential contribution to future research.

Population-based incidence rates of 15 neuromuscular disorders: a nationwide capture-recapture study in the Netherlands.

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.

A cross-sectional study in 18 patients with typical and mild forms of nemaline myopathy in the Netherlands.

Nemaline myopathy (NM) is a congenital myopathy with generalised muscle weakness, most pronounced in neck flexor, bulbar and respiratory muscles. The aim of this cross-sectional study was to assess the Dutch NM patient cohort. We assessed medical history, physical examination, quality of life (QoL), fatigue severity, motor function (MFM), and respiratory muscle function. We included 18 of the 28 identified patients (13 females (11-67 years old); five males (31-74 years old)) with typical or mild NM and eight different genotypes. Nine patients (50 %) used a wheelchair, eight patients (44 %) used mechanical ventilation, and four patients (22 %) were on tube feeding. Spinal deformities were found in 14 patients (78 %). The median Medical Research Council (MRC) sum score was 38/60 [interquartile range 32-51] in typical and 48/60 [44-50] in mild NM. The experienced QoL was lower and fatigue severity was higher than reference values of the healthy population. The total MFM score was 55 % [49-94] in typical and 88 % [72-93] in mild NM. Most of the patients who performed spirometry had a restrictive lung function pattern (11/15). This identification and characterisation of the Dutch NM patient cohort is important for international collaboration and can guide the design of future clinical trials.

Cardiac Involvement in LAMA2-Related Muscular Dystrophy and SELENON-Related Congenital Myopathy: A Case Series.

Background: LAMA2-related muscular dystrophy (LAMA2-MD) and SELENON-related myopathy (SELENON-RM) are two rare neuromuscular diseases characterized by proximal and axial muscle weakness, scoliosis, spinal rigidity, low bone quality and respiratory impairment. Cardiac involvement has previously been described in retrospective studies and case reports, but large case series and prospective studies in unselected cohorts are lacking. Objective: The objective of this study is to conduct prevalence estimations, perform cardiac phenotyping, and provide recommendations for clinical care. Methods: In this case series including two time points, we conducted comprehensive assessments with electrocardiography (ECG) and transthoracic echocardiography (TTE). ECGs were systematically assessed for a large subset of variables. TTE included left and right ventricular ejection fraction (LVEF/RVEF) and left ventricular global longitudinal strain (GLS), the latter being a more early and sensitive marker of left ventricular dysfunction. Results: 21 LAMA2-MD (M = 5; 20±14 years) and 10 SELENON-RM patients (M = 7; 18±12 years) were included. In most patients, QRS fragmentation and Q waves, markers of heterogeneous ventricular activation, were present both at baseline and at follow-up. GLS was abnormal (age specific in children, > -18% in adults) in 33% of LAMA2-MD and 43% of SELENON-RM patients at baseline. Reduced LVEF (<52% in males, <54% in females and <55% in pediatric population) was observed in three LAMA2-MD patients at baseline and in none of the SELENON-RM patients. GLS and LVEF did not change between baseline and follow-up. RVEF was normal in all patients. Conclusion: ECG abnormalities and abnormal GLS are prevalent in LAMA2-MD and SELENON-RM, yet abnormal LVEF was only seen in LAMA2-MD patients. One LAMA2-MD patient had a clinically relevant deterioration in LVEF during 1.5-year follow-up. We advise routine screening of all patients with LAMA2-MD or SELENON-RM with ECG and echocardiography at diagnosis, minimally every two years from second decade of life and if new cardiac signs arise.

274th ENMC international workshop: Recommendations for optimizing bone strength in neuromuscular disorders. Hoofddorp, The Netherlands, 19-21 January 2024.

The 274th ENMC workshop for optimizing bone strength in neuromuscular disorders (NMDs) was held on January 19-21, 2024. The group of participants included experts in the fields of bone health and neuromuscular medicine along with the patient voice. Bone strength represents a crucial aspect of the management of pediatric and adult patients with NMDs. Bone strength may be compromised due to different pathophysiologic mechanisms, including disrupted bone-muscle "cross-talk", loss of biomechanical loading, nutritional insufficiency, inadequate weight-bearing physical activity, muscle weakness and/or immobility, and drug treatment. While for Duchenne muscular dystrophy recommendations for evaluation and treatment of bone strength have been published, evidence on bone strength in other hereditary and acquired NMDs is scarce. Enhanced knowledge is needed to understand the development and maintenance of bone strength in patients with NMDs. This workshop aimed to develop a strategy to improve bone strength and thus prevent fractures in patients with NMDs.

Nerve enlargement in patients with Noonan syndrome: A retrospective cohort study.

Noonan syndrome (NS) is an autosomal dominant condition characterized by facial dysmorphism, congenital heart disease, development delay, growth retardation and lymphatic disease. It is caused by germline pathogenic variants in genes encoding proteins in the Ras/mitogen-activated protein kinase signaling pathway. Nerve enlargement is not generally considered as a feature of NS, although some cases have been reported. High-resolution nerve ultrasound enables detailed anatomical assessment of peripheral nerves and can show enlarged nerves. This retrospective cohort study aims to describe the sonographic findings of patients with NS performed during a 1-year time period. Data on the degree of enlargement, the relation to increasing age, pain in extremities, genotype on the gene level and clinical features were collected. Twenty-nine of 93 patients visiting the NS Center of Expertise of the Radboud University Medical Center Nijmegen underwent high-resolution ultrasound. In 24 patients (83%) nerve enlargement was found. Most of them experienced pain. We observed a weak correlation with increasing age and the degree of nerve enlargement but no association with pain, genotype at the gene level or clinical features. This study shows that patients with NS have a high predisposition for sonographic nerve enlargement and that the majority experience pain.

An open-label pilot study of losmapimod to evaluate the safety, tolerability, and changes in biomarker and clinical outcome assessments in participants with facioscapulohumeral muscular dystrophy type 1.

INTRODUCTION: Facioscapulohumeral muscular dystrophy (FSHD) is a genetic disease caused by aberrant DUX4 expression, leading to progressive muscle weakness. No effective pharmaceutical treatment is available. Losmapimod, a small molecule selective inhibitor of p38 α/ß MAPK, showed promising results in a phase 1 trial for the treatment of FSHD, prompting additional studies. We report the findings of an open-label phase 2 trial (NCT04004000) investigating the safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of losmapimod in participants with FSHD1. METHODS: This study was conducted at a single site in the Netherlands from August 2019 to March 2021, with an optional, ongoing open-label extension. Participants aged 18 to 65 years with FSHD1 took 15 mg of losmapimod twice daily for 52 weeks. Primary endpoints were measures of losmapimod safety and tolerability. Secondary endpoints were assessments of losmapimod pharmacokinetics and pharmacodynamics. RESULTS: Fourteen participants were enrolled. No deaths, serious treatment-emergent adverse events (TEAEs), or discontinuations due to TEAEs were reported. Losmapimod achieved blood concentrations and target engagements that were previously associated with decreased DUX4 expression in vitro. Clinical outcome measures showed a trend toward stabilization or improvement. CONCLUSIONS: Losmapimod was well tolerated and may be a promising new treatment for FSHD; a larger phase 3 study is ongoing.

The expanding clinical and genetic spectrum of DYNC1H1-related disorders.

Intracellular trafficking involves an intricate machinery of motor complexes including the dynein complex to shuttle cargo for autophagolysosomal degradation. Deficiency in dynein axonemal chains as well as cytoplasmic light and intermediate chains have been linked with ciliary dyskinesia and skeletal dysplasia. The cytoplasmic dynein 1 heavy chain protein (DYNC1H1) serves as a core complex for retrograde trafficking in neuronal axons. Dominant pathogenic variants in DYNC1H1 have been previously implicated in peripheral neuromuscular disorders (NMD) and neurodevelopmental disorders (NDD). As heavy-chain dynein is ubiquitously expressed, the apparent selectivity of heavy-chain dyneinopathy for motor neuronal phenotypes remains currently unaccounted for. Here, we aimed to evaluate the full DYNC1H1-related clinical, molecular and imaging spectrum, including multisystem features and novel phenotypes presenting throughout life. We identified 47 cases from 43 families with pathogenic heterozygous variants in DYNC1H1 (aged 0-59 years) and collected phenotypic data via a comprehensive standardized survey and clinical follow-up appointments. Most patients presented with divergent and previously unrecognized neurological and multisystem features, leading to significant delays in genetic testing and establishing the correct diagnosis. Neurological phenotypes include novel autonomic features, previously rarely described behavioral disorders, movement disorders, and periventricular lesions. Sensory neuropathy was identified in nine patients (median age of onset 10.6 years), of which five were only diagnosed after the second decade of life, and three had a progressive age-dependent sensory neuropathy. Novel multisystem features included primary immunodeficiency, bilateral sensorineural hearing loss, organ anomalies, and skeletal manifestations, resembling the phenotypic spectrum of other dyneinopathies. We also identified an age-dependent biphasic disease course with developmental regression in the first decade and, following a period of stability, neurodegenerative progression after the second decade of life. Of note, we observed several cases in whom neurodegeneration appeared to be prompted by intercurrent systemic infections with double-stranded DNA viruses (Herpesviridae) or single-stranded RNA viruses (Ross-River fever, SARS-CoV-2). Moreover, the disease course appeared to be exacerbated by viral infections regardless of age and/or severity of NDD manifestations, indicating a role of dynein in anti-viral immunity and neuronal health. In summary, our findings expand the clinical, imaging, and molecular spectrum of pathogenic DYNC1H1 variants beyond motor neuropathy disorders and suggest a life-long continuum and age-related progression due to deficient intracellular trafficking. This study will facilitate early diagnosis and improve counselling and health surveillance of affected patients.

Future Directions for Respiratory Muscle Training in Neuromuscular Disorders: A Scoping Review.

BACKGROUND: Respiratory muscle training (RMT) aims to improve inspiratory and/or expiratory muscle function in neuromuscular disorders (NMDs). A comprehensive overview of the available literature is lacking. This scoping review explores methodological characteristics, (adverse) effects, and adherence of RMT studies in NMDs. Moreover, it identifies limitations and research gaps in the literature and provides future research directions. SUMMARY: Eligible studies were identified using MEDLINE, Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials databases. Three reviewers independently selected articles. Inclusion criteria were English language, original research articles on RMT using a device, patients with an NMD, and pulmonary function tests or respiratory muscle strength as outcome measures. We included NMDs with slow, intermediate and fast progression. Exclusion criteria were critically ill patients, weaning from mechanical ventilation, other neurological disorders, and RMT combined with non-respiratory interventions. One reviewer extracted the data on patients' characteristics, methodological characteristics, results of outcome measures, adverse events, and patient adherence. Forty-five studies were identified. We found a large diversity in study designs and training protocols. The effects of RMT on respiratory muscle strength and/or endurance are variable. Patient adherence was high and no serious adverse events were reported. KEY MESSAGES: The diversity in studies across the available literature precludes definitive conclusions regarding the effects of RMT on respiratory muscle function and clinically relevant outcomes in NMDs. Therefore, well-powered and -designed studies that focus on clinically relevant outcomes and assess whether RMT can improve or offset deterioration of respiratory muscle weakness in NMDs are needed.

Quality of life and support needs in children, adolescents, and young adults with facioscapulohumeral dystrophy, a mixed-method study.

BACKGROUND AND OBJECTIVES: Quality of life (QoL) in children with facioscapulohumeral dystrophy (FSHD) seems plausible decreased. Little is known about factors influencing QoL in children with FSHD. Our objective is to explore factors contributing to the QoL of children, adolescents, and young adults with FSHD, to describe how they experience life with FSHD, and to report their support needs. METHODS: We performed a mixed-method study with individual age-appropriate semi-structured interviews assessing QoL in children, adolescents, and young adults with FSHD and their parents. To characterize the sample, quantitative data on QoL, pain, fatigue, and participation were collected. Interview data was analyzed using a thematic analysis. RESULTS: Fourteen patients participated (age between 9 and 26 years old, eight males and six females). The degree of FSHD severity, as indicated by the FSHD-score, did not correlate with QoL. Older children had a lower QoL than younger children. Children and adolescents strived for normality regardless of physical discomfort. Phenotypical features of FSHD led to insecurity aggravated by hurtful comments of others. The unpredictability of disease progression and its implications for career and parenthood choices led to a generalized feeling of uncertainty about the future. Support was found within family and friends. Participants expressed a need for peer support and psychological support as well as recommending it to others. DISCUSSION: Quality of life in childhood FSHD is diminished caused by their physical limitations, altered appearance, fear of social rejection, and uncertainty of the disease progression in the future. A fear of social rejection most likely contributes to striving for normality regardless of physical discomfort. Support should be focused on acceptance and coping with hurtful comments. It should preferably be individualized, easily accessible and not offered as therapy but rather as tutoring for children.

Best practice guidelines on genetic diagnostics of facioscapulohumeral muscular dystrophy: Update of the 2012 guidelines.

The gold standard for facioscapulohumeral muscular dystrophy (FSHD) genetic diagnostic procedures was published in 2012. With the increasing complexity of the genetics of FSHD1 and 2, the increase of genetic testing centers, and the start of clinical trials for FSHD, it is crucial to provide an update on our knowledge of the genetic features of the FSHD loci and renew the international consensus on the molecular testing recommendations. To this end, members of the FSHD European Trial Network summarized the evidence presented during the 2022 ENMC meeting on Genetic diagnosis, clinical outcome measures, and biomarkers. The working group additionally invited genetic and clinical experts from the USA, India, Japan, Australia, South-Africa, and Brazil to provide a global perspective. Six virtual meetings were organized to reach consensus on the minimal requirements for genetic confirmation of FSHD1 and FSHD2. Here, we present the clinical and genetic features of FSHD, specific features of FSHD1 and FSHD2, pros and cons of established and new technologies (Southern blot in combination with either linear or pulsed-field gel electrophoresis, molecular combing, optical genome mapping, FSHD2 methylation analysis and FSHD2 genotyping), the possibilities and challenges of prenatal testing, including pre-implantation genetic testing, and the minimal requirements and recommendations for genetic confirmation of FSHD1 and FSHD2. This consensus is expected to contribute to current clinical management and trial-readiness for FSHD.

Lessons Learned From Clinical Studies in Centronuclear Myopathies: The Patient Perspective-A Qualitative Study.

BACKGROUND: Since 2014, several clinical studies focusing on centronuclear myopathies have been conducted, including a prospective natural history study, a gene transfer clinical trial and a clinical trial using an antisense oligonucleotide. Dedicated patient organizations have played an important role in this process. The experience of members of these organizations, either as a study participant, parent or as a patient organization member communicating with the sponsors are potentially very informative for future trial design. METHODS: We investigated the burden of and the lessons learned from the first natural history studies and clinical trials from a patient perspective using a qualitative approach. We arranged 4 focus groups with a total of 37 participants from 3 large international patient organizations: ZNM-ZusammenStark!, the Myotubular Trust, and the MTM-CNM Family Connection. 4 themes, based on a systematic literature search were discussed: Expectations and preparation, Clinical study participation, Communication and Recommendations for future clinical trials. The focus group recordings were transcribed, anonymized, and uploaded to Atlas-ti version 8.1 software. The data were analyzed using a thematic content analysis. RESULTS: Overall, participants were realistic in their expectations, hoping for small improvements of function and quality of life. The realization that trial participation does not equate to a treatment was challenging. Participating in a clinical study had a huge impact on many aspects of daily life, both for patients and their immediate families. First-hand insights into the burden of the design and its possible effect on performance were provided, resulting in numerous compelling recommendations for future clinical studies. Furthermore, participants stressed the importance of clear communication, which was considered to be especially vital in cases of severe adverse events. Finally, while patients were understanding of the importance of adhering to the regulations of good clinical practice, they indicated that they would strongly appreciate a greater understanding and/or acknowledgment of the patient perspective and a reflection of this perspective in future clinical trial design. CONCLUSION: The acknowledgment and inclusion of patients' perspectives and efficient and effective communication is expected to improve patient recruitment and retention in future clinical studies, as well as more accurate assessment of the patient performance related to suitable planning of the study visits.

Treatment Approaches for Altered Facial Expression: A Systematic Review in Facioscapulohumeral Muscular Dystrophy and Other Neurological Diseases.

Background: Facial weakness is a key feature of facioscapulohumeral muscular dystrophy (FSHD) and may lead to altered facial expression and subsequent psychosocial impairment. There is no cure and supportive treatments focus on optimizing physical fitness and compensation of functional disabilities. Objective: We hypothesize that symptomatic treatment options and psychosocial interventions for other neurological diseases with altered facial expression could be applicable to FSHD. Therefore, the aim of this review is to collect symptomatic treatment approaches that target facial muscle function and psychosocial interventions in various neurological diseases with altered facial expression in order to discuss the applicability to FSHD. Methods: A systematic search was performed. Selected studies had to include FSHD, Bell's palsy, Moebius syndrome, myotonic dystrophy type 1, or Parkinson's disease and treatment options which target altered facial expression. Data was extracted for study and patients' characteristics, outcome assessment tools, treatment, outcome of facial expression and or psychosocial functioning. Results: Forty studies met the inclusion criteria, of which only three studies included FSHD patients exclusively. Most, twenty-one, studies were performed in patients with Bell's palsy. Studies included twelve different therapy categories and results were assessed with different outcomes measures. Conclusions: Five therapy categories were considered applicable to FSHD: training of (non-verbal) communication compensation strategies, speech training, physical therapy, conference attendance, and smile restoration surgery. Further research is needed to establish the effect of these therapies in FSHD. We recommend to include outcome measures in these studies that cover at least cosmetic, functional, communication, and quality of life domains.

The complementary use of muscle ultrasound and MRI in FSHD: Early versus later disease stage follow-up.

OBJECTIVES: Muscle MRI and ultrasound provide complementary techniques for characterizing muscle changes and tracking disease progression in facioscapulohumeral muscular dystrophy (FSHD). In this cohort study, we provide longitudinal data that compares both imaging modalities head-to-head. METHODS: FSHD patients were assessed at baseline and after five years. Standardized muscle MRI and ultrasound images of five leg muscles were assessed bilaterally. Fat replacement was quantified using MRI fat-fraction (FF) and ultrasound Heckmatt and echogenicity z-scores (EZ-score). Muscle edema was evaluated using T2-weighted turbo inversion recovery magnitude (TIRM) MRI. RESULTS: Twenty FSHD patients were included. Muscles with normal baseline imaging showed increases in ultrasound EZ-scores (≥1; in 17%) more often than MRI FF increases (≥10%; in 7%) over time. Muscles with only baseline ultrasound abnormalities often showed considerable FF increases (in 22%), and TIRM positivity at follow-up (44%). Muscles with increased FF at baseline showed stable (80%) or increasing FF (20%) over time. EZ-scores of those muscles either increased (23%), decreased (33%) or remained stable (44%). CONCLUSIONS: Muscle ultrasound may capture accelerated pathological muscle changes in FSHD in early disease, while muscle MRI appears better-suited to detecting and monitoring pathology in later stages. SIGNIFICANCE: Our results help establish each techniques' optimal use as imaging biomarker.

An up-to-date myopathologic characterisation of facioscapulohumeral muscular dystrophy type 1 muscle biopsies shows sarcolemmal complement membrane attack complex deposits and increased skeletal muscle regeneration.

The aim of this study was to identify key routinely used myopathologic biomarkers of FSHD1. Needle muscle biopsies were taken in 34 affected muscles (m. quadriceps femoris (QF), n = 20, m. tibialis anterior (TA), n = 13, m. biceps brachii, n = 1) from 22 patients (age, 53.5 (10) years; M = 12, F = 10). Eleven patients had more than one biopsy (2xQF, n = 1; QF+TA, n = 9; 2xQF+TA, n = 1). Histochemistry, immunoperoxidase, and immunofluorescence stainings were performed and compared to age and muscle type matched muscle specimens of 11 healthy controls. Myopathologic features observed in our FSHD1 cohort were internalized nuclei, type 1 fibre hypertrophy and NADH central clearances/cores. We observed a prominent inflammatory response with MAC deposits, MHC I expression, and muscle regeneration that correlated with the inflammatory score. Our up-to-date characterization of FSHD1 points towards MHC I, MAC, and embryonic Myosin Heavy Chain/muscle regeneration as useful myopathologic readouts of FSHD1.