SELENON-Related Myopathy Across the Life Span, a Cross-Sectional Study for Preparing Trial Readiness.

BACKGROUND: SELENON(SEPN1)-related myopathy (SELENON-RM) is a rare congenital neuromuscular disease characterized by proximal and axial muscle weakness, spinal rigidity, scoliosis and respiratory impairment. No curative treatment options exist, but promising preclinical studies are ongoing. Currently, natural history data are lacking, while selection of appropriate clinical and functional outcome measures is needed to reach trial readiness. OBJECTIVE: We aim to identify all Dutch and Dutch-speaking Belgian SELENON-RM patients, deep clinical phenotyping, trial readiness and optimization of clinical care. METHODS: This cross-sectional, single-center, observational study comprised neurological examination, functional measurements including Motor Function Measurement 20/32 (MFM-20/32) and accelerometry, questionnaires, muscle ultrasound, respiratory function tests, electro- and echocardiography, and dual-energy X-ray absorptiometry. RESULTS: Eleven patients with genetically confirmed SELENON-RM were included (20±13 (3-42) years, 73% male). Axial and proximal muscle weakness were most pronounced. The mean MFM-20/32 score was 71.2±15.1%, with domain 1 (standing and transfers) being most severely affected. Accelerometry showed a strong correlation with MFM-20/32. Questionnaires revealed impaired quality of life, pain and problematic fatigue. Muscle ultrasound showed symmetrically increased echogenicity in all muscles. Respiratory function, and particularly diaphragm function, was impaired in all patients, irrespective of the age. Cardiac assessment showed normal left ventricular systolic function in all patients but abnormal left ventricular global longitudinal strain in 43% of patients and QRS fragmentation in 80%. Further, 80% of patients showed decreased bone mineral density on dual-energy X-ray absorptiometry scan and 55% of patients retrospectively experienced fragility long bone fractures. CONCLUSIONS: We recommend cardiorespiratory follow-up as a part of routine clinical care in all patients. Furthermore, we advise vitamin D supplementation and optimization of calcium intake to improve bone quality. We recommend management interventions to reduce pain and fatigue. For future clinical trials, we propose MFM-20/32, accelerometry and muscle ultrasound to capture disease severity and possibly disease progression.

Inspiratory Muscle Training in Nemaline Myopathy.

BACKGROUND: Respiratory muscle weakness is a common feature in nemaline myopathy. Inspiratory muscle training (IMT) is an intervention that aims to improve inspiratory muscle strength. OBJECTIVE: The aim of this controlled before-and-after pilot study was to investigate if IMT improves respiratory muscle strength in patients with nemaline myopathy. METHODS: Nine patients (7 females; 2 males, age 36.6±20.5 years) with respiratory muscle weakness and different clinical phenotypes and genotypes were included. Patients performed eight weeks of sham IMT followed by eight weeks of active threshold IMT. The patients trained twice a day five days a week for 15 minutes at home. The intensity was constant during the training after a gradual increase to 30% of maximal inspiratory pressure (MIP). RESULTS: Active IMT significantly improved MIP from 43±15.9 to 47±16.6 cmH2O (p = 0.019). The effect size was 1.22. There was no significant effect of sham IMT. Sniff nasal inspiratory pressure, maximal expiratory pressure, spirometry, and diaphragm thickness and thickening showed no significant improvements. CONCLUSIONS: This pilot study shows that threshold IMT is feasible in patients with nemaline myopathy and improves inspiratory muscle strength. Our findings provide valuable preliminary data for the design of a larger, more comprehensive trial.

Repeated oral sucrose dosing after the second wind is unnecessary in patients with McArdle disease: Results from a randomized, placebo-controlled, double-blind, cross-over study.

It is well-established that oral sucrose ingested shortly before exercise improves early exercise tolerance in individuals with McArdle disease. This is by supplying blood-borne glucose for muscle metabolism to compensate for the blocked glycogenolysis. The present study investigated if individuals with McArdle disease could benefit further from repeated sucrose ingestion during prolonged exercise. In this double-blind, placebo-controlled, cross-over study, the participants were randomized to ingest either sucrose or placebo first and subsequently the opposite on two separate days. The participants ingested the drink 10 min before and thrice (after 10, 25, and 40 min) during a 60-min submaximal exercise test on a cycle ergometer. The primary outcome was exercise capacity as indicated by heart rate (HR) and perceived exertion (PE) responses to exercise. Secondary outcomes included changes in blood metabolites, insulin and carbohydrate, and fatty acid oxidation rates during exercise. Nine participants with McArdle disease were included in the study. We confirmed improvement of exercise capacity with oral sucrose vs. placebo during early exercise (pre-second wind) indicated by lower peak HR and PE (p < 0.02). We found no further beneficial effect with repeated sucrose versus placebo ingestion during prolonged exercise, as indicated by no difference in HR or PE post-second wind (p > 0.05). Glucose, lactate, insulin, and carbohydrate oxidation rates increased, and fatty acid oxidation decreased with sucrose versus placebo (p ≤ 0.0002). We can conclude that repeated sucrose ingestion is not recommended during prolonged exercise. This finding can prevent excessive caloric intake and reduce the risk of obesity and insulin resistance.

In Vitro Skeletal Muscle Model of PGM1 Deficiency Reveals Altered Energy Homeostasis.

Phosphoglucomutase 1 (PGM1) is a key enzyme for the regulation of energy metabolism from glycogen and glycolysis, as it catalyzes the interconversion of glucose 1-phosphate and glucose 6-phosphate. PGM1 deficiency is an autosomal recessive disorder characterized by a highly heterogenous clinical spectrum, including hypoglycemia, cleft palate, liver dysfunction, growth delay, exercise intolerance, and dilated cardiomyopathy. Abnormal protein glycosylation has been observed in this disease. Oral supplementation with D-galactose efficiently restores protein glycosylation by replenishing the lacking pool of UDP-galactose, and rescues some symptoms, such as hypoglycemia, hepatopathy, and growth delay. However, D-galactose effects on skeletal muscle and heart symptoms remain unclear. In this study, we established an in vitro muscle model for PGM1 deficiency to investigate the role of PGM1 and the effect of D-galactose on nucleotide sugars and energy metabolism. Genome-editing of C2C12 myoblasts via CRISPR/Cas9 resulted in Pgm1 (mouse homologue of human PGM1, according to updated nomenclature) knockout clones, which showed impaired maturation to myotubes. No difference was found for steady-state levels of nucleotide sugars, while dynamic flux analysis based on 13C6-galactose suggested a block in the use of galactose for energy production in knockout myoblasts. Subsequent analyses revealed a lower basal respiration and mitochondrial ATP production capacity in the knockout myoblasts and myotubes, which were not restored by D-galactose. In conclusion, an in vitro mouse muscle cell model has been established to study the muscle-specific metabolic mechanisms in PGM1 deficiency, which suggested that galactose was unable to restore the reduced energy production capacity.

Bone Quality in Patients with a Congenital Myopathy: A Scoping Review.

BACKGROUND: Congenital myopathies are rare neuromuscular disorders presenting with a wide spectrum of clinical features, including long bone fractures (LBFs) that negatively influence functional prognosis, quality of life and survival. Systematic research on bone quality in these patients is lacking. OBJECTIVE: This scoping review aims to summarize all evidence on bone quality and to deduce recommendations for bone quality management in congenital myopathies. METHODS: Five electronic databases (Pubmed, Embase, Cochrane, Web of Science, CINAHL) were searched. All studies on bone quality in congenital myopathies were included. Decreased bone quality was defined as low bone mineral density and/or (fragility) LBFs. Study selection and data extraction were performed by three independent reviewers. RESULTS: We included 244 single cases (mean: 4.1±7.6 years; median: 0 years) diagnosed with a congenital myopathy from 35 articles. Bone quality was decreased in 93 patients (37%) (mean: 2.6±6.8 years; median: 0 years). Low bone mineral density was reported in 11 patients (4.5%) (mean: 10.9±9.7; median: 11 years). Congenital LBFs were reported in 64 patients (26%). (Fragility) LBFs later at life were described in 24 patients (9.8%) (mean: 14.9±11.0; median: 14 years). Four cases (1.6%) were reported to receive vitamin D and/or calcium supplementation or diphosphonate administration. CONCLUSION: LBFs are thus frequently reported in congenital myopathies. We therefore recommend optimal bone quality management through bone mineral density assessment, vitamin D and calcium suppletion, and referral to internal medicine or pediatrics for consideration of additional therapies in order to prevent complications of low bone mineral density.

No effect of oral ketone ester supplementation on exercise capacity in patients with McArdle disease and healthy controls: A randomized placebo-controlled cross-over study.

Patients with glycogen storage disease type V (GSDV), also known as McArdle disease, have blocked glycogen breakdown due to myophosphorylase deficiency, leading to exercise intolerance, muscle pain, and risk of muscle damage. Blood-derived ketone bodies (KBs) constitute an alternative energy source that could fuel the muscle independent of glycogenolysis. However, except for long-time fasting or ketogenic dieting, KBs are present in low quantities. This led us to explore the effects of a drink containing exogenously produced KBs in the form of D-ß-hydroxybutyrate esters (KE) on exercise capacity and metabolism in patients with GSDV. Eight GSDV patients and four healthy controls (HC) were included in this placebo-controlled, cross-over study where subjects were randomized to receive a KE drink with 395 mgKE/kg or placebo drink on two separate days 25 min before a submaximal cycle exercise test. The primary outcome was exercise capacity as indicated by heart rate response (HR) to exercise. Secondary outcomes included perceived exertion (PE) and measures of KB, carbohydrate, and fat metabolism during exercise. In GSDV, the KE drink vs. placebo increased plasma KBs and KB oxidation (p ≤ 0.0001) but did not improve exercise capacity as judged from HR (p = 0.120) and PE (p = 0.109). In addition, the KE drink lowered plasma glucose, free fatty acids, and lowered lipolytic rate and glucose rate of appearance compared with placebo. Similar results were found in the HC group. The present study indicates that an increase in KB oxidation by oral KE supplementation does not improve exercise capacity in GSDV possibly because of KB-induced inhibition of lipolysis and liver glucose output. Thus, oral KE supplementation alone cannot be recommended as a treatment option for patients with GSDV.

Cytidine Diphosphate-Ribitol Analysis for Diagnostics and Treatment Monitoring of Cytidine Diphosphate-l-Ribitol Pyrophosphorylase A Muscular Dystrophy.

BACKGROUND: Many muscular dystrophies currently remain untreatable. Recently, dietary ribitol has been suggested as a treatment for cytidine diphosphate (CDP)-l-ribitol pyrophosphorylase A (CRPPA, ISPD), fukutin (FKTN), and fukutin-related protein (FKRP) myopathy, by raising CDP-ribitol concentrations. Thus, to facilitate fast diagnosis, treatment development, and treatment monitoring, sensitive detection of CDP-ribitol is required. METHODS: An LC-MS method was optimized for CDP-ribitol in human and mice cells and tissues. RESULTS: CDP-ribitol, the product of CRPPA, was detected in all major human and mouse tissues. Moreover, CDP-ribitol concentrations were reduced in fibroblasts and skeletal muscle biopsies from patients with CRPPA myopathy, showing that CDP-ribitol could serve as a diagnostic marker to identify patients with CRPPA with severe Walker-Warburg syndrome and mild limb-girdle muscular dystrophy (LGMD) phenotypes. A screen for potentially therapeutic monosaccharides revealed that ribose, in addition to ribitol, restored CDP-ribitol concentrations and the associated O-glycosylation defect of α-dystroglycan. As the effect occurred in a mutation-dependent manner, we established a CDP-ribitol blood test to facilitate diagnosis and predict individualized treatment response. Ex vivo incubation of blood cells with ribose or ribitol restored CDP-ribitol concentrations in a patient with CRPPA LGMD. CONCLUSIONS: Sensitive detection of CDP-ribitol with LC-MS allows fast diagnosis of patients with severe and mild CRPPA myopathy. Ribose offers a readily testable dietary therapy for CRPPA myopathy, with possible applicability for patients with FKRP and FKTN myopathy. Evaluation of CDP-ribitol in blood is a promising tool for the evaluation and monitoring of dietary therapies for CRPPA myopathy in a patient-specific manner.