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Metabolic myopathies are a set of rare inborn errors of metabolism leading to disruption in energy production. Relevant to skeletal muscle, glycogen storage disease and fatty acid oxidation defects can lead to exercise intolerance, rhabdomyolysis, and weakness in children and adults, distinct from the severe forms that involve multiple‐organ systems. These nonspecific, dynamic symptoms along with conditions that mimic metabolic myopathies can make diagnosis challenging. Clinicians can shorten the time to diagnosis by recognizing the typical clinical phenotypes and performing next generation sequencing. With improved access and affordability of molecular testing, clinicians need to be well‐versed in resolving variants of uncertain significance relevant to metabolic myopathies. Once identified, patients can improve quality of life, safely engage in exercise, and reduce episodes of rhabdomyolysis by modifying diet and lifestyle habits. [ABSTRACT FROM AUTHOR]

Background: The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension. Methods: Attainment of 'minimal symptom expression' was evaluated using patient-reported outcome measures of gMG symptoms [MG activities of daily living scale (MG-ADL), 15-item MG quality of life questionnaire (MG-QOL15)] at the completion of REGAIN and during the open-label extension. 'Minimal symptom expression' was defined as MG-ADL total score of 0–1 or MG-QOL15 total score of 0–3. Results: At REGAIN week 26, more eculizumab-treated patients achieved 'minimal symptom expression' versus placebo [MG-ADL: 21.4% vs 1.7%; difference 19.8%; 95% confidence interval (CI) 8.5, 31.0; p = 0.0007; MG-QOL15: 16.1% vs 1.7%; difference 14.4%; 95% CI 4.3, 24.6; p = 0.0069]. During the open-label extension, the proportion of patients in the placebo/eculizumab group who achieved 'minimal symptom expression' increased after initiating eculizumab treatment and was sustained through 130 weeks of open-label eculizumab (MG-ADL: 1.7 to 27.8%; MG-QOL15: 1.7 to 19.4%). At extension study week 130, similar proportions of patients in the eculizumab/eculizumab and placebo/eculizumab groups achieved 'minimal symptom expression' (MG-ADL: 22.9% and 27.8%, respectively, p = 0.7861; MG-QOL15: 14.3% and 19.4%, respectively, p = 0.7531). The long-term tolerability of eculizumab was consistent with previous reports. Conclusions: Patients with AChR+ refractory gMG who receive eculizumab can achieve sustained 'minimal symptom expression' based on patient-reported outcomes. 'Minimal symptom expression' may be a useful tool in measuring therapy effectiveness in gMG. Trial registration: ClinicalTrials.gov NCT01997229, NCT02301624. [ABSTRACT FROM AUTHOR]

Objective: The Popeye domain containing 3 (POPDC3) gene encodes a membrane protein involved in cyclic adenosine monophosphate (cAMP) signaling. Besides gastric cancer, no disease association has been described. We describe a new muscular dystrophy associated with this gene.Methods: We screened 1,500 patients with unclassified limb girdle weakness or hyperCKemia for pathogenic POPDC3 variants. Five patients carrying POPDC3 variants were examined by muscle magnetic resonance imaging (MRI), muscle biopsy, and cardiac examination. We performed functional analyses in a zebrafish popdc3 knockdown model and heterologous expression of the mutant proteins in Xenopus laevis oocytes to measure TREK-1 current.Results: We identified homozygous POPDC3 missense variants (p.Leu155His, p.Leu217Phe, and p.Arg261Gln) in 5 patients from 3 ethnically distinct families. Variants affected highly conserved residues in the Popeye (p.Leu155 and p.Leu217) and carboxy-terminal (p.Arg261) domains. The variants were almost absent from control populations. Probands' muscle biopsies were dystrophic, and serum creatine kinase levels were 1,050 to 9,200U/l. Muscle weakness was proximal with adulthood onset in most patients and affected lower earlier than upper limbs. Muscle MRI revealed fat replacement of paraspinal and proximal leg muscles; cardiac investigations were unremarkable. Knockdown of popdc3 in zebrafish, using 2 different splice-site blocking morpholinos, resulted in larvae with tail curling and dystrophic muscle features. All 3 mutants cloned in Xenopus oocytes caused an aberrant modulation of the mechano-gated potassium channel, TREK-1.Interpretation: Our findings point to an important role of POPDC3 for skeletal muscle function and suggest that pathogenic variants in POPDC3 are responsible for a novel type of autosomal recessive limb girdle muscular dystrophy. ANN NEUROL 2019;86:832-843. [ABSTRACT FROM AUTHOR]

Limb girdle muscular dystrophy type 2A is the most common limb girdle muscular dystrophy form worldwide. Although strict recessive inheritance is assumed, patients carrying a single mutation in the calpain 3 gene (CAPN3) are reported. Such findings are commonly attributed to incomplete mutation screening. In this investigation, we report 37 individuals (age range: 21-85 years, 21 females and 16 males) from 10 families in whom only one mutation in CAPN3 could be identified; a 21-bp, in-frame deletion (c.643_663del21). This mutation co-segregated with evidence of muscle disease and autosomal dominant transmission in several generations. Evidence of muscle disease was indicated by muscle pain, muscle weakness and wasting, significant fat replacement of muscles on imaging, myopathic changes on muscle biopsy and loss of calpain 3 protein on western blotting. Thirty-one of 34 patients had elevated creatine kinase or myoglobin. Muscle weakness was generally milder than observed in limb girdle muscular dystrophy type 2A, but affected the same muscle groups (proximal leg, lumbar paraspinal and medial gastrocnemius muscles). In some cases, the weakness was severely disabling. The 21-bp deletion did not affect mRNA maturation. Calpain 3 expression in muscle, assessed by western blot, was below 15% of normal levels in the nine mutation carriers in whom this could be tested. Haplotype analysis in four families from three different countries suggests that the 21-bp deletion is a founder mutation. This study provides strong evidence that heterozygosity for the c.643_663del21 deletion in CAPN3 results in a dominantly inherited muscle disease. The normal expression of mutated mRNA and the severe loss of calpain 3 on western blotting, suggest a dominant negative effect with a loss-of-function mechanism affecting the calpain 3 homodimer. This renders patients deficient in calpain 3 as in limb girdle muscular dystrophy type 2A, albeit in a milder form in most cases. Based on findings in 10 families, our study indicates that a dominantly inherited pattern of calpainopathy exists, and should be considered in the diagnostic work-up and genetic counselling of patients with calpainopathy and single-allele aberrations in CAPN3. [ABSTRACT FROM AUTHOR]

Muscular dystrophies comprise a large group of inherited disorders that lead to progressive muscle wasting. We wanted to investigate if targeting satellite cells can enhance muscle regeneration and thus increase muscle mass. We treated mice with hepatocyte growth factor and leukemia inhibitory factor under three conditions: normoxia, hypoxia and during myostatin deficiency. We found that hepatocyte growth factor treatment led to activation of the Akt/mTOR/p70S6K protein synthesis pathway, up-regulation of the myognic transcription factors MyoD and myogenin, and subsequently the negative growth control factor, myostatin and atrophy markers MAFbx and MuRF1. Hypoxia-induced atrophy was partially restored by hepatocyte growth factor combined with leukemia inhibitory factor treatment. Dividing satellite cells were three-fold increased in the treatment group compared to control. Finally, we demonstrated that myostatin regulates satellite cell activation and myogenesis in vivo following treatment, consistent with previous findings in vitro. Our results suggest, not only a novel in vivo pharmacological treatment directed specifically at activating the satellite cells, but also a myostatin dependent mechanism that may contribute to the progressive muscle wasting seen in severely affected patients with muscular dystrophy and significant on-going regeneration. This treatment could potentially be applied to many conditions that feature muscle wasting to increase muscle bulk and strength. [ABSTRACT FROM AUTHOR]

Abstract: Aims: To estimate the degree of cardiac involvement regarding left ventricular ejection fraction, conduction abnormalities, arrhythmia, risk of sudden cardiac death (SCD) and the associations between cardiac involvement and cytosine–thymine–guanine (CTG)-repeat, neuromuscular involvement, age and gender in patients with myotonic dystrophy type 1 (MD1). Methods and results: A Pub-Med search for the period 1980 to 2010 was performed according to specified criteria. Cardiac parameters including left ventricular ejection fraction (LVEF), conduction abnormalities and arrhythmia were compiled and only studies without ascertainment bias were included. Eighteen studies, 1828 MD1-patients, were included. The prevalence of atrioventricular block grade 1 (AVB1) was 28.2%, QTc>440ms 22%, QRS>120ms 19.9%, frequent ventricular premature contractions (VPC) 14.6%, atrial fibrillation/flutter (AF/AFL) 5%, right/left bundle branch block (RBBB/LBBB) 4.4/5.7% and non-sustained ventricular tachycardia (NSVT) 4.1%. Left ventricular systolic dysfunction (LVSD) was reported in 7.2% of the patients. There was an overall positive association between CTG-repeat size and cardiac involvement and between the degree of neuromuscular and cardiac involvement. Male gender and age were positively associated with arrhythmia and conduction abnormalities. The prevalence of pacemaker- (PM) and implantable cardioverter defibrillator-(ICD) implantations were 4.1% and 1.1%, respectively. The risk of SCD in this MD1-population was 0.56% per year. Conclusion: MD1-patients have a high level of cardiac morbidity and mortality, strongly emphasizing the need of pre-symptomatic screening for arrhythmia and heart failure, as effective and well-documented preventive means are available. [Copyright &y& Elsevier]

• Muscle imaging can provide different biomarkers for FSHD. • Consensus on the diagnostic usefulness of MRI and its role in patients' stratification. • Consensus on the harmonization and improvement of available quantitative MRI protocols. • Proposal of a shared research agenda between the FSHD CTRN and ETN imaging working groups. [ABSTRACT FROM AUTHOR]

Rhythmic auditory stimulation (RAS) has been shown to improve gait parameters in several neurological diseases, both in walk-training interventions and in one-time walking tests, but the effect in myasthenia gravis (MG) is unknown. The aim of this study was to examine if RAS improves walking distance and gait speed in patients with generalised myasthenia gravis (gMG) in the 6-minute walk test (6MWT). Forty-eight patients with gMG walked two 6MWTs under different conditions: (1) walking with RAS with a frequency of 100% of the patient's fastest gait speed, (2) walking with RAS with a frequency of 110% of the patient's fastest gait speed, or (3) walking in silence. RAS with a frequency of 110% of the patient's fastest gait speed increased the walking distance by 8.3 metres in the 6MWT vs standard 6MWT (p = 0.01), without increasing average walking heart rate (HR) or Borg scores. This study indicates that RAS may improve gait speed and walking distance in patients with gMG without additional exertion as judged by HR and Borg scores. Based on these results, RAS could be used as part of a physical rehabilitation program for patients with gMG. [ABSTRACT FROM AUTHOR]

Abstract: Oxygen (O2) extraction is impaired in exercising skeletal muscle of humans with mutations of mitochondrial DNA (mtDNA), but the muscle hemodynamic response to exercise has never been directly investigated. This study sought to examine the extent to which human skeletal muscle perfusion can increase without reductions in blood oxygenation and to determine whether erythrocyte O2 off-loading and related ATP vascular mechanisms are impaired in humans with mutations of mtDNA. Leg vascular hemodynamic, oxygenation and ATP were investigated in ten patients with mtDNA mutations and ten matched healthy control subjects: 1) at rest during normoxia, hypoxia, hyperoxia and intra-femoral artery ATP infusion, and 2) during passive and dynamic one-legged knee-extensor exercises. At rest, blood flow (LBF), femoral arterial and venous blood oxygenation and plasma ATP were similar in the two groups. During dynamic exercise, LBF and vascular conductance increased 9–10 fold in the patients despite erythrocyte oxygenation and leg O2 extraction remained unchanged (p <0.01). In the patients, workload-adjusted LBF was 28% to 62% higher during submaximal- and maximal exercises and was associated with augmented plasma ATP. The appropriate hemodynamic adjustments during severe hypoxia and ATP infusion suggest that erythrocyte O2 off-loading and related ATP vascular mechanisms are intact in patients with mtDNA mutations. Furthermore, greater increase in plasma ATP and LBF at a given metabolic demand in the patients, in concert with unchanged oxyhemoglobin, suggest that erythrocyte O2 off-loading is not obligatory for the exercise-induced increase in blood flow and intravascular ATP concentration. [Copyright &y& Elsevier]

Over 100 mutations in the myophosphorylase gene, which cause McArdle disease, are known. All these mutations have resulted in a complete block of muscle glycogenolysis, and accordingly, no genotype–phenotype correlation has been identified in this condition. We evaluated physiologic and genetic features of two patients with a variant form of McArdle disease, associated with unusually high exercise capacity. Physiologic findings were compared to those in 47 patients with typical McArdle disease, and 17 healthy subjects. Subjects performed an ischaemic forearm exercise test to assess lactate and ammonia production. Peak oxidative capacity (VO2max) and cardiac output were determined, using cycle ergometry as the exercise modality. The two patients with atypical McArdle disease carried common mutations on one allele (R50X and G205S), and novel splice mutations in introns 3 [IVS3-26A>G (c.425-26A>G)] and 5 [IVS5-601G>A (c.856-601G>A)] on the other allele. Plasma lactate after ischaemic exercise decreased in all typical McArdle patients, but increased in the two atypical McArdle patients (10% of that in healthy subjects). Peak workload and oxidative capacity were 2-fold higher in patients with atypical McArdle disease compared to typical McArdle patients. Oxygen uptake, relative to cardiac output, was severely impaired in the 47 patients with typical McArdle disease, and partially normalized in the milder affected McArdle patients. These findings identify the first distinct genotype-phenotype relationship in McArdle disease, and indicate that minimal myophosphorylase activity ameliorates the typical McArdle disease phenotype by augmenting muscle oxidative capacity. The milder form of McArdle disease provides important clues to the level of functional myophosphorylase needed to support muscle oxidative metabolism. [ABSTRACT FROM PUBLISHER]

With the identification of a patient with mutated mitochondrial DNA (mtDNA) of paternal origin, it has been unequivocally proven that not only does paternal mtDNA survive in the zygote, but it can also contribute substantially to the mtDNA pool of adult, human skeletal muscle. The questions are: how often does paternal mtDNA inheritance occur and what mechanisms are involved? In this paper, we will review current knowledge on the fate of sperm mitochondria after fertilization and discuss the impact paternal inheritance may have on our understanding of mitochondrial biology. [Copyright &y& Elsevier]

Presents a study that examined the effect of glycogen on insulin action in the skeletal muscles of patients with McArdle's disease, a kind of glycogen storage disease. Impact of glycogen on insulin-stimulated glucose utilization; Effect of glycogen on glycogen synthase activity; Examination of the activity of insulin-signaling intermediaries.

Background: Regular and consistent disease assessment could provide a clearer picture of burden in generalised myasthenia gravis (gMG) and improve patient care; however, the use of assessment tools in practice lacks standardisation. This modified Delphi approach was taken to review current evidence on assessment tool use in gMG and develop expert‐derived consensus recommendations for good practice. Methods: A European expert panel of 15 experienced gMG neurologists contributed to development of this consensus, four of whom formed a lead Sub‐committee. The PICO (Population, Intervention, Control, Outcomes) framework was used to define six clinical questions on gMG assessment tools, a systematic literature review was conducted, and evidence‐based statements were developed. According to a modified Delphi voting process, consensus was reached when ≥70% of the experts rated agreement with a statement as ≥8 on a scale of 1–10. Results: Eighteen expert‐ and evidence‐based consensus statements based on six themes were developed. Key recommendations include: consistent use of the Myasthenia Gravis Activities of Daily Living score (MG‐ADL) across clinical settings, followed by a simple question (e.g., Patient Acceptable Symptom State [PASS]) or scale to determine patient satisfaction in clinical practice; use of a Quantitative Myasthenia Gravis [QMG] or quality of life [QoL] assessment when the MG‐ADL indicates disease worsening; and consideration of symptom state to determine the timing and frequency of recommended assessments. Expert panel consensus was reached on all 18 statements after two voting rounds. Conclusions: This process provided evidence‐ and expert consensus‐based recommendations for the use of objective and subjective assessment tools across gMG research and care to improve management and outcomes for patients. [ABSTRACT FROM AUTHOR]

Background and purpose Methods Results Conclusions Two novel enzyme replacement therapies (ERTs), studied in phase 3 trials in late‐onset Pompe patients, reached marketing authorization by the European Medicines Agency in 2022 and 2023. The European Pompe Consortium (EPOC) updates and extends the scope of the 2017 recommendations for starting, switching and stopping ERT.The European Pompe Consortium consists of 25 neuromuscular and metabolic experts from eight European countries. This update was performed after an in‐person meeting, three rounds of discussion and voting to provide a consensus recommendation.The patient should be symptomatic, that is, should have skeletal muscle weakness or respiratory muscle involvement. Muscle magnetic resonance imaging findings showing substantial fat replacement can support the decision to start in a patient‐by‐patient scenario. Limited evidence supports switching ERT if there is no indication that skeletal muscle and/or respiratory function have stabilized or improved during standard ERT of 12 months or after severe infusion‐associated reactions. Switching of ERT should be discussed on a patient‐by‐patient shared‐decision basis. If there are severe, unmanageable infusion‐associated reactions and no stabilization in skeletal muscle function during the first 2 years after starting or switching treatment, stopping ERT should be considered. After stopping ERT for inefficacy, restarting ERT can be considered. Six‐monthly European Pompe Consortium muscle function assessments are recommended.The triple‐S criteria on ERT start, switch and stop include muscle magnetic resonance imaging as a supportive finding and the potential option of home infusion therapy. Six‐monthly long‐term monitoring of muscle function is highly recommended to cover insights into the patient's trajectory under ERT. [ABSTRACT FROM AUTHOR]

Background: Generalized myasthenia gravis (MG) with antibodies against the acetylcholine receptor is a chronic disease causing muscle weakness. Access to novel treatments warrants authoritative treatment recommendations. The Nordic countries have similar, comprehensive health systems, mandatory health registers, and extensive MG research. Methods: MG experts and patient representatives from the five Nordic countries formed a working group to prepare treatment guidance for MG based on a systematic literature search and consensus meetings. Results: Pyridostigmine represents the first‐line symptomatic treatment, while ambenonium and beta adrenergic agonists are second‐line options. Early thymectomy should be undertaken if a thymoma, and in non‐thymoma patients up to the age of 50–65 years if not obtaining remission on symptomatic treatment. Most patients need immunosuppressive drug treatment. Combining corticosteroids at the lowest possible dose with azathioprine is recommended, rituximab being an alternative first‐line option. Mycophenolate, methotrexate, and tacrolimus represent second‐line immunosuppression. Plasma exchange and intravenous immunoglobulin are used for myasthenic crises and acute exacerbations. Novel complement inhibitors and FcRn blockers are effective and fast‐acting treatments with promising safety profiles. Their use depends on local availability, refunding policies, and cost–benefit analyses. Adapted physical training is recommended. Planning of pregnancies with optimal treatment, information, and awareness of neonatal MG is necessary. Social support and adaptation of work and daily life activities are recommended. Conclusions: Successful treatment of MG rests on timely combination of different interventions. Due to spontaneous disease fluctuations, comorbidities, and changes in life conditions, regular long‐term specialized follow‐up is needed. Most patients do reasonably well but there is room for further improvement. Novel treatments are promising, though subject to restricted access due to costs. [ABSTRACT FROM AUTHOR]

In the past 20 years, myostatin, a negative regulator of muscle mass, has attracted attention as a potential therapeutic target in muscular dystrophies and other conditions. Preclinical studies have shown potential for increasing muscular mass and ameliorating the pathological features of dystrophic muscle by the inhibition of myostatin in various ways. However, hardly any clinical trials have proven to translate the promising results from the animal models into patient populations. We present the background for myostatin regulation, clinical and preclinical results and discuss why translation from animal models to patients is difficult. Based on this, we put the clinical relevance of future antimyostatin treatment into perspective. [ABSTRACT FROM AUTHOR]

Studies the effect of liver denervation on glucose production during exercise in the guinea pig. Hepatic denervation; Glucose turnover and glycogen metabolism; Hormonal responses; Lactate and glycerol.

Investigates the roles of the group III and IV muscle afferents in the regulation of endocrine and metabolic adjustments to exercise. Electrical stimulation of the muscle branches of the femoral nerves; Measurement of glucose production, plasma glucose and adrenocorticotropic hormone.

Investigates the blood-borne metabolic feedback versus neural feedforward regulation of glucose homeostasis during exercise. Glucose turnover; Glycogen metabolism; Hormonal responses; Plasma glycerol and lactate.

Myotonic dystrophy type 1 (DM1) is a multisystemic neuromuscular disorder caused by the expansion of a CTG repeat in the 3′-UTR of DMPK, which is transcribed to a toxic gain-of-function RNA that affects splicing of a range of genes. The expanded repeat is unstable in both germline and somatic cells. The variable age at disease onset and severity of symptoms have been linked to the inherited CTG repeat length, non-CTG interruptions, and methylation levels flanking the repeat. In general, the genetic biomarkers are investigated separately with specific methods, making it tedious to obtain an overall characterisation of the repeat for a given individual. In the present study, we employed Oxford nanopore sequencing in a pilot study to simultaneously determine the repeat lengths, investigate the presence and nature of repeat interruptions, and quantify methylation levels in the regions flanking the CTG-repeats in four patients with DM1. We determined the repeat lengths, and in three patients, we observed interruptions which were not detected using repeat-primed PCR. Interruptions may thus be more common than previously anticipated and should be investigated in larger cohorts. Allele-specific analyses enabled characterisation of aberrant methylation levels specific to the expanded allele, which greatly increased the sensitivity and resolved cases where the methylation levels were ambiguous. [ABSTRACT FROM AUTHOR]

The article presents the author's views on the study by S. Luo and colleagues on biparental inheritance of mitochondrial DNA in humans. The study reportedly revealed a uniform level of heteroplasmy in people from the same family. Also discussed are the potential mechanisms that underlie paternal inheritance of mitochondrial DNA.

A letter to the editor is presented about the case of a 35-year-old man with muscle glycogenosis resulting from phosphoglucomutase 1 deficiency.

With the publication of a patient with severe exercise intolerance, in whom the mutated mtDNA in muscle was shown to be paternally inherited, the strict maternal inheritance of mtDNA was challenged. Paternal mtDNA inheritance may have gone unrecognized in cases of mitochondrial disease with no clear maternal pattern of inheritance because mitochondrial haplotypes are rarely investigated in diagnostic analyses. To find further evidence for a paternal inheritance of mtDNA, we reinvestigated 12 patients with mitochondrial myopathy, in whom the pathogenic mutation was known to be sporadic. We compared the mtDNA haplotypes from the patient''s muscle with that of the mtDNA haplotypes in blood from either the mother or the patient. No evidence of paternal inheritance of mtDNA was found in this small study. Although these findings indicate that the paternal inheritance of mtDNA is rare, they do not rule out that the phenomenon may occur at a rate that could still affect genetic counselling and anthropological research. [Copyright &y& Elsevier]

Background and purpose: Myotonia congenita (MC) is a muscle channelopathy in which pathogenic variants in a key sarcolemmal chloride channel Gene (CLCN1) cause myotonia. This study used muscle magnetic resonance imaging (MRI) to quantify contractile properties and fat replacement of muscles in a Danish cohort of MC patients. Methods: Individuals with the Thomsen (dominant) and Becker (recessive) variants of MC were studied. Isometric muscle strength, whole‐body MRI, and clinical data were collected. The degree of muscle fat replacement of thigh, calf, and forearm muscles was quantitively calculated on Dixon MRI as fat fractions (FFs). Contractility was evaluated as the muscle strength per contractile muscle cross‐sectional area (PT/CCSA). Muscle contractility was compared with clinical data. Results: Intramuscular FF was increased and contractility reduced in calf and in forearm muscles compared with controls (FF = 7.0–14.3% vs. 5.3–9.6%, PT/CCSA = 1.1–4.9 Nm/cm2 vs. 1.9–5.8 Nm/cm2 [p < 0.05]). Becker individuals also showed increased intramuscular FF and reduced contractility of thigh muscles (FF = 11.9% vs. 9.2%, PT/CCSA = 1.9 Nm/cm2 vs. 3.2 Nm/cm2 [p < 0.05]). Individual muscle analysis showed that increased FF was limited to seven of 18 examined muscles (p < 0.05). There was a weak correlation between reduced contractility and severity of symptoms. Conclusions: Individuals with MC have increased fat replacement and reduced contractile properties of muscles. Nonetheless, changes were small and likely did not impact clinically on their myotonic symptoms. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

• The highest fatigue scores were reported for general - and physical fatigue. • The level of self-reported general- and physical fatigue was equal. • Around 50% of the cohort reported low levels of physical activity. • Physical activity was strongly associated with all fatigue domains. • Higher level of physical activity was associated with lower levels of fatigue. • MG severity, sleep, BMI, comorbidity, job-status and cohabitation were relevant factors. The objective of the study was to examine the association between fatigue (measured by the Multidimensional Fatigue Inventory; MFI-20) and physical activity (measured by the Saltin-Grimby Physical Activity Level Scale; SGPALS) in a large cohort of patients (≥18 years) with myasthenia gravis (MG) including relevant disease - and lifestyle-related factors. A total of 1463 persons, registered at the Danish National Registry of Patients with a MG diagnosis, according to the International Classification of Diseases, received a web-based survey. A total of 779 patients (53% women, mean [SD] age 60.8 [15.5]) responded. The remaining persons were either non-responders (n = 390) or could not confirm the MG diagnosis (n = 294). The most prominent MFI-20 fatigue domains were general fatigue (median [inter-quartile ranges, IQR], 13 [10–16]) and physical fatigue (median [IQR], 13 [9–15]), and 386 (53%) patients reported low levels of physical activity. All fatigue domains were associated with physical activity (p <.01). Higher level of physical activity was associated with lower levels of fatigue. Important factors for the association were myasthenia gravis disease severity (measured by the Myasthenia Gravis Activities of Daily Living profile), body mass index, insomnia (measured by the Insomnia Severity Index) job-status, comorbidity, and cohabitation. [ABSTRACT FROM AUTHOR]

• Patients with spinal muscular atrophy (SMA) may be at increased risk of acetaminophen-induced hepatotoxicity due to low skeletal muscle mass. • Patients with SMA have a lower clearance of acetaminophen compared to healthy controls. • One SMA patient had increased liver biomarkers after only two days of acetaminophen treatment. • We recommend giving pediatric doses of acetaminophen (15 mg/kg/dose) to adult SMA patients with a maximum of 4000 mg/day. • We recommend monitoring standard liver biomarkers of ALT, GGT and LDH after first-time treatment of acetaminophen. Acute liver failure has been reported sporadically in patients with spinal muscular atrophy (SMA) and other neuromuscular disorders with low skeletal muscle mass receiving recommended dosages of acetaminophen. It is suggested that low skeletal muscle mass may add to the risk of toxicity. We aimed to describe the pharmacokinetics and safety of acetaminophen in patients with SMA. We analyzed acetaminophen metabolites and liver biomarkers in plasma from SMA patients and healthy controls (HC) every hour for six or eight hours on day 1 and day 3 of treatment with therapeutic doses of acetaminophen. Twelve patients with SMA (six adults and six children) and 11 HC participated in the study. Adult patients with SMA had significantly lower clearance of acetaminophen compared to HC (14.1 L/h vs. 21.5 L/h). Formation clearance of acetaminophen metabolites, glucuronide, sulfate, and oxidative metabolites were two-fold lower in the patients compared to HC. The liver transaminases and microRNAs increased nine-fold in one adult SMA patient after two days of treatment. The other patients and HC did not develop abnormal liver biomarkers. In this study, patients with SMA had lower clearance and slower metabolism of acetaminophen, and one patient developed liver involvement. We recommend giving 15 mg/kg/dose to SMA adults (with a maximum of 4000 mg/day) and monitoring standard liver biomarkers 48 h after first-time treatment of acetaminophen. [ABSTRACT FROM AUTHOR]

• Individuals with McArdle disease have elevated levels of fatigue. • Disordered sleep correlate with fatigue. • Lower levels of physical activity correlate with fatigue. • Severely perceived McArdle related symptoms correlate with fatigue. • Fatigue, sleep, and mental health assessments should be incorporated in the clinic. McArdle disease is an autosomal recessive inherited disease caused by pathogenic variants in the PYGM gene, resulting in virtual absence of the myophosphorylase enzyme in skeletal muscle. Patients experience physical activity intolerance, muscle pain, and muscle fatigue. This study aimed to investigate other fatigue domains with the Multidimensional Fatigue Inventory (MFI-20) along with an investigation of potential contributing factors, including relevant disease and lifestyle-related factors. We conducted a survey in an international cohort of patients with McArdle disease. The survey included questions on demographics and McArdle disease-related symptoms, and the questionnaires: MFI-20, Insomnia Severity Index (ISI), and International Physical Activity Questionnaire Short-Form (IPAQ-SF). One hundred seventy-four responses were included in the data analyses. We found relatively high fatigue scores in all five domains (general fatigue (12.9 ± 2.2), mental fatigue (10.1 ± 4.1), physical fatigue (13.7 ± 4.1), reduced activity (12.1 ± 4.1), and reduced motivation (10.4 ± 3.4)). Fatigue associated with McArdle symptom severity (p < 0.005), lower levels of physical activity (assessed by IPAQ-SF) (p < 0.05), and poor sleep (assessed by ISI) (p < 0.05). These findings call for clinical focus and future research into fatigue, sleep and mental health in patients with McArdle disease. [ABSTRACT FROM AUTHOR]

Background and objectives: Primary hypokalemic periodic paralysis (HypoPP) is an inherited channelopathy most commonly caused by mutations in CACNA1S. HypoPP can present with different phenotypes: periodic paralysis (PP), permanent muscle weakness (PW), and mixed weakness (MW) with both periodic and permanent weakness. Little is known about the natural history of HypoPP. Methods: In this 3-year follow-up study, we used the MRC scale for manual muscle strength testing and whole-body muscle MRI (Mercuri score) to assess disease progression in individuals with HypoPP-causing mutations in CACNA1S. Results: We included 25 men (mean age 43 years, range 18–76 years) and 12 women (mean age 42 years, range 18–76 years). Two participants were asymptomatic, 21 had PP, 12 MW, and two PW. The median number of months between baseline and follow-up was 42 (range 26–52). Muscle strength declined in 11 patients during follow-up. Four of the patients with a decline in muscle strength had no attacks of paralysis during follow-up, and two of these patients had never had attacks of paralysis. Fat replacement of muscles increased in 27 patients during follow-up. Eight of the patients with increased fat replacement had no attacks of paralysis during follow-up, and two of these patients had never had attacks of paralysis. Discussion: The study demonstrates that HypoPP can be a progressive myopathy in both patients with and without attacks of paralysis. [ABSTRACT FROM AUTHOR]

The purpose of the study was to conduct a nutritional and metabolic assessment of children with cerebral palsy, including an investigation of liver status, body composition, and bone mineral density. In this cross-sectional study we included 22 children with cerebral palsy. By using ultrasound, transient elastography, dual x-ray absorptiometry (DXA) scan, blood samples, anthropometric measurements, and a three-day diet registration, the nutritional and metabolic status was evaluated. Liver fibrosis and steatosis were found in four patients (18.2%), all with severe motor impairments, low skeletal muscle mass, and epilepsy. All patients with liver involvement had normal liver-related blood samples. Decreased bone mineral density was found in 26.3%, and 91.0% had low skeletal muscle mass. Fat mass and muscle mass were significantly lower in the patients with severe motor impairments compared to the patients with less severe motor impairments. Within the children classified as 'underweight' or 'normal' according to body mass index, body fat determined by DXA scan was normal or high in 50% of these patients. Conclusions: This study is the first to report liver fibrosis and steatosis in children with cerebral palsy. Possible causes of liver fibrosis and/or steatosis are altered body composition with low skeletal muscle mass, decreased mobility and medical drug intake. Further investigations of liver involvement and risk factors are needed. What is Known: • Children and adolescents with cerebral palsy are at risk of malnutrition and altered body composition, both of which can lead to fatty liver disease. • It is unknown whether children with cerebral palsy are at increased risk of metabolic disturbances such as fatty liver disease. What is New: • Altered body composition and low skeletal muscle mass, regardless of ambulation is present in 91% of the children with cerebral palsy. • Liver fibrosis and/or steatosis were found in 18.2% of the patients. Possible causes are altered body composition, decreased mobility and medical drug intake. [ABSTRACT FROM AUTHOR]

Genetic confirmation of rare muscle diseases has for long been a tough challenge, using a one-by-one gene Sanger sequencing approach. With the advent of next generation sequencing (NGS), genetic diagnostic work has been considerably facilitated, and several centers around the world have now set up "muscle gene panels" or whole-exome sequencing techniques to diagnose previously undiagnosed patients with myopathy and new cases with no clear phenotype pointing at one disease. The use of NGS has proved particularly fruitful in the diagnostic workup of patients with suspected hereditary myopathies, providing diagnostic yields of close to 50% in many cases, which is a far better yield than for other diseases. Experiences with NGS using "muscle gene panels" in unclassified presumed genetic myopathies will be elaborated on in the talk, and alsothe many limitations of the technique, which include; 1) false-negative results (what type of mutations doesn't NGS cover?), 2) false-positive results, 3) verification of candidate genes that are not certain pathogenic, 4) the experience of the clinician in interpreting results, 5) ethics of accidental findings (what does the patient/family want to know), and 6) what to do with negative results? [ABSTRACT FROM AUTHOR]

Introduction: Bethlem myopathy is caused by dysfunctional collagen VI assembly, leading to varying degrees of hyperlaxity, contractures and muscle weakness. Previous studies demonstrate that cardiovascular training is safe and beneficial in patients with myopathies. However, exercise exacerbates the dystrophic phenotype in collagen VI-knockout mice.Methods: Six men with Bethlem myopathy were included (4 training; 2 controls). After training, 2 patients detrained. Patients performed 10 weeks of home-based, moderate-intensity exercise monitored by a pulse-watch. The primary outcome was change in peak oxygen uptake (VO2peak ). Secondary outcomes were performances in functional tests.Results: VO2peak improved in the training group (16%, P = 0.017). Detraining led to regression of VO2peak toward baseline values (-8%; P = 0.03). No change was seen in the control group (-7%; P = 0.47). Performance in functional tests did not change significantly. Creatine kinase values were stable during the study.Conclusions: Moderate-intensity exercise seems to safely improve oxidative function in patients with Bethlem myopathy. Muscle Nerve 60: 183-188, 2019. [ABSTRACT FROM AUTHOR]

Aim: Conditions related to mutations in the gene encoding the skeletal muscle ryanodine receptor 1 (RYR1) are genetic muscle disorders and include congenital myopathies with permanent weakness, as well as episodic phenotypes such as rhabdomyolysis/myalgia. Although RYR1 dysfunction is the primary mechanism in RYR1‐related disorders, other downstream pathogenic events are less well understood and may include a secondary remodeling of major contractile proteins. Hence, in the present study, we aimed to investigate whether congenital myopathy‐related RYR1 mutations alter the regulation of the most abundant contractile protein, myosin. Methods: We used skeletal muscle tissues from five patients with RYR1‐related congenital myopathy and compared those with five controls and five patients with RYR1‐related rhabdomyolysis/myalgia. We then defined post‐translational modifications on myosin heavy chains (MyHCs) using LC/MS. In parallel, we determined myosin relaxed states using Mant‐ATP chase experiments and performed molecular dynamics (MD) simulations. Results: LC/MS revealed two additional phosphorylations (Thr1309‐P and Ser1362‐P) and one acetylation (Lys1410‐Ac) on the β/slow MyHC of patients with congenital myopathy. This method also identified six acetylations that were lacking on MyHC type IIa of these patients (Lys35‐Ac, Lys663‐Ac, Lys763‐Ac, Lys1171‐Ac, Lys1360‐Ac, and Lys1733‐Ac). MD simulations suggest that modifying myosin Ser1362 impacts the protein structure and dynamics. Finally, Mant‐ATP chase experiments showed a faster ATP turnover time of myosin heads in the disordered–relaxed conformation. Conclusions: Altogether, our results suggest that RYR1 mutations have secondary negative consequences on myosin structure and function, likely contributing to the congenital myopathic phenotype. [ABSTRACT FROM AUTHOR]

The membrane protein, mono carboxylate transporter, mediates lactate transport in skeletal muscle. There is a 1:1 coupling between lactate and H + fluxes, and therefore lactate production is closely coupled to pH regulation. Evidence that lactate/pH may act as a mediator of the pressor response to exercise has been provided by studies in humans and animals that have identified a temporal correlation between the fall in muscle pH during static exercise and the rise in muscle sympathetic nerve activity and pressor responses. Furthermore, conditions with lowered lactate production during exercise, such as glycogen depletion and dichloroacetate treatment, have been shown to be associated with blunted exercise pressor responses, whereas intra-arterial injection of lactate in muscle enhances pressor responses. One observation that challenges the role of muscle pH as a mediator of sympathetic activation is the quick return of blood pressure and muscle sympathetic nerve activity to basal levels after exercise, while pH continues to drop in muscle in the first post-exercise period.

• An intronic variant in the COL6A1 gene causes Ullrich congenital muscular dystrophy. • The variant was found in homozygosity in three patients originating from Turkey. • The variant led to aberrant splicing and loss-of-function of the COL6A1 transcript. • The variant has wrongly been classified as "likely benign" in Clinvar. • The variant led to impaired collagen VI secretion into the extracellular matrix. The three major collagen VI genes: COL6A1, COL6A2 , and COL6A3 encode microfibrillar components of extracellular matrices in multiple tissues including muscles and tendons. Pathogenic variants in the collagen VI genes cause collagen VI-related dystrophies representing a continuum of conditions from Bethlem myopathy at the milder end to Ullrich congenital muscular dystrophy at the more severe end. Here we describe a pathogenic variant in the COL6A1 gene (NM_001848.3; c.1741-6G>A) found in homozygosity in three patients with Ullrich congenital muscular dystrophy. The patients suffered from severe muscle impairment characterised by proximal weakness, distal hyperlaxity, joint contractures, wheelchair-dependency, and use of nocturnal non-invasive ventilation. The pathogenicity was verified by RNA analyses showing that the variant induced aberrant splicing leading to a frameshift and loss of function. The analyses were in line with immunocytochemistry studies of patient-derived skin fibroblasts and muscle tissue demonstrating impaired secretion of collagen VI into the extracellular matrix. Thereby, we add the variant c.1741-6G>A to the list of pathogenic, recessive, splice variants in COL6A1 causing Ullrich congenital muscular dystrophy. The variant is listed in ClinVar as of "uncertain significance" and "likely benign" and may presumably have been overlooked in other patients. [ABSTRACT FROM AUTHOR]

Generalised myasthenia gravis is a chronic, unpredictable, and debilitating autoimmune disease. New treatments for this disease are needed because conventional therapies have limitations, such as side-effects (eg, increased infection risk) or inadequate control of symptoms. Rozanolixizumab is a neonatal Fc receptor blocker that might provide a novel therapeutic option for myasthenia gravis. We aimed to assess the safety and efficacy of rozanolixizumab for generalised myasthenia gravis. MycarinG is a randomised, double-blind, placebo-controlled, adaptive phase 3 study done at 81 outpatient centres and hospitals in Asia, Europe, and North America. We enrolled patients (aged ≥18 years) with acetylcholine receptor (AChR) or muscle-specific kinase (MuSK) autoantibody-positive generalised myasthenia gravis (Myasthenia Gravis Foundation of America class II–IVa), a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of at least 3 (non-ocular symptoms), and a quantitative myasthenia gravis score of at least 11. Patients were randomly assigned (1:1:1) to receive subcutaneous infusions once a week for 6 weeks of either rozanolixizumab 7 mg/kg, rozanolixizumab 10 mg/kg, or placebo. Randomisation was stratified by AChR and MuSK autoantibody status. Investigators, patients, and people assessing outcomes were masked to random assignments. The primary efficacy endpoint was change from baseline to day 43 in MG-ADL score, assessed in the intention-to-treat population. Treatment-emergent adverse events (TEAEs) were assessed in all randomly assigned patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT03971422) and EudraCT (2019-000968-18); an open-label extension study has been completed (NCT04124965 ; EudraCT 2019-000969-21) and another is underway (NCT04650854 ; EudraCT 2020-003230-20). Between June 3, 2019, and June 30, 2021, 300 patients were assessed for eligibility, of whom 200 were enrolled. 66 (33%) were randomly assigned to rozanolixizumab 7 mg/kg, 67 (34%) to rozanolixizumab 10 mg/kg, and 67 (34%) to placebo. Reductions in MG-ADL score from baseline to day 43 were greater in the rozanolixizumab 7 mg/kg group (least-squares mean change –3·37 [SE 0·49]) and in the rozanolixizumab 10 mg/kg group (–3·40 [0·49]) than with placebo (–0·78 [0·49]; for 7 mg/kg, least-squares mean difference −2·59 [95% CI −4·09 to −1·25], p<0·0001; for 10 mg/kg, −2·62 [−3·99 to −1·16], p<0·0001). TEAEs were experienced by 52 (81%) of 64 patients treated with rozanolixizumab 7 mg/kg, 57 (83%) of 69 treated with rozanolixizumab 10 mg/kg, and 45 (67%) of 67 treated with placebo. The most frequent TEAEs were headache (29 [45%] patients in the rozanolixizumab 7 mg/kg group, 26 [38%] in the rozanolixizumab 10 mg/kg group, and 13 [19%] in the placebo group), diarrhoea (16 [25%], 11 [16%], and nine [13%]), and pyrexia (eight [13%], 14 [20%], and one [1%]). Five (8%) patients in the rozanolixizumab 7 mg/kg group, seven (10%) in the rozanolixizumab 10 mg/kg group, and six (9%) in the placebo group had a serious TEAE. No deaths occurred. Rozanolixizumab showed clinically meaningful improvements in patient-reported and investigator-assessed outcomes in patients with generalised myasthenia gravis, for both 7 mg/kg and 10 mg/kg doses. Both doses were generally well tolerated. These findings support the mechanism of action of neonatal Fc receptor inhibition in generalised myasthenia gravis. Rozanolixizumab represents a potential additional treatment option for patients with generalised myasthenia gravis. UCB Pharma. [ABSTRACT FROM AUTHOR]

Background Charcot-Marie-Tooth ( CMT) disease is a hereditary neuropathy associated with impaired walking capacity. Some patients are too weak in the lower extremity muscles to walk at gravity with sufficient intensity or duration to gain benefit. Aim The aim was to investigate the effect of aerobic anti-gravity exercise in weak patients with CMT 1A and X. Methods Five adult patients performed moderate-intensity aerobic anti-gravity exercise 3/week for 10 weeks. Results There was a significant positive difference in Berg balance scale and postural stability test between test occasions, and walking distance in the 6-min walk test trended to increase. Conclusions The study indicates that the anti-gravity treadmill training of patients with CMT should be pursued in larger CMT cohorts. [ABSTRACT FROM AUTHOR]

Introduction: Exercise has not been investigated in myotonia congenita (MC). We investigated whether regular aerobic training can reduce myotonia and improve fitness.Methods: Untrained patients with MC (age: 24-62 years; n = 6) completed 28 ± 3 sessions of 30-minute cycle ergometer training at 75% of maximal capacity for 11 ± 1 weeks. Fitness was evaluated by maximal oxygen uptake. The level of myotonia was assessed by the Myotonia Behavior Scale, 14 step stair test, timed up and go test, and hand and eye closure-open tests.Results: Training increased fitness by 9% (95% confidence interval [CI], 1-17%; P = 0.02) and maximal workload by 10% (95% CI, 3-18%; P = 0.03). None of the myotonia tests changed in a clinically meaningful way.Conclusions: Regular endurance training improves fitness and maximal workload performance in patients with MC. The lack of creatine kinase elevations indicates that muscle damage did not occur. Improved fitness, however, did not change myotonic symptoms in this small cohort. Muscle Nerve 56: 696-699, 2017. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to conduct a metabolic and nutritional assessment of children with neuromuscular disorders, including the investigation of the liver and bone mineral density. Methods: In this observational study, we included 44 children with neuromuscular disorders. The nutritional status, bone health and liver were assessed by ultrasound, transient elastography, dual X‐ray absorptiometry scan, blood samples, anthropometric measurements and 3‐day diet registration. Results: Liver involvement was found in 31.0%: liver enlargement in 7.1%, steatosis in 4.8%, fibrosis in 14.3% and liver enlargement together with steatosis or fibrosis was found in 4.8%. These changes were found in 9/23 patients with Duchenne muscular dystrophy, 4/9 patients with spinal muscular atrophy type II and 0/12 patients with other neuromuscular diagnoses. Low bone mineral density was found in 44.0% of the patients, though the majority used daily vitamin D and calcium supplements. Vitamin D insufficiency or deficiency was found in 22.6%. Conclusion: The metabolic assessment in children with neuromuscular disorders shows an increased risk of liver enlargement, steatosis and fibrosis. Possible causes are obesity, decreased mobility, low skeletal muscle mass and for a subgroup the use of glucocorticoids. The findings suggest that monitoring liver function should be part of the nutritional assessment in patients with neuromuscular disorders. [ABSTRACT FROM AUTHOR]

Skeletal muscle sodium channel disorders give rise to episodic symptoms such as myotonia and/or periodic paralysis. Chronic symptoms with permanent weakness are not considered characteristic of the phenotypes. Muscle fat replacement represents irreversible damage that inevitably will impact on muscle strength. This study investigates muscle fat replacement and contractility in patients with pathogenic SCN4A variants compared to healthy controls. T1-weighted and 2-point Dixon MRI of the legs were conducted to assess fat replacement. Stationary dynamometry was used to assess muscle strength. Contractility was determined by maximal muscle contraction divided by cross-sectional muscle area. The average cross-sectional intramuscular fat fraction was greater in patients compared with controls by 2.5% in the calves (95% CI 0.74–4.29%, p = 0.007) and by 2.0% in the thighs (95% CI 0.75–3.2%, p = 0.003). Muscle contractility was less in patients vs. controls by 14–27% (p < 0.05). Despite greater fat fraction and less contractility, absolute strength was not significantly less. This study quantitatively documents greater fat fraction and additionally describes difference in muscle contractility in a large cohort of patients with skeletal muscle sodium channel disorders. The clinical impact of these abnormal findings is likely limited as muscle hypertrophy in the patients served to preserve absolute muscle strength. Subgroup analysis indicated significant difference in phenotype by genotype, however these findings lack statistical significance and serve as inspiration for future researchers to probe into the geno- phenotype relationship in these disorders. Trial registration: The study was registered at http://clinicaltrials.gov (identifier: NCT04808388). [ABSTRACT FROM AUTHOR]

An abstract of the article "Limitations of muscle biopsy in Pompe disease" by John Vissing is presented.