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BACKGROUND: Giant axonal neuropathy is a rare, autosomal recessive, pediatric, polysymptomatic, neurodegenerative disorder caused by biallelic loss-of-function variants in GAN, the gene encoding gigaxonin. METHODS: We conducted an intrathecal dose-escalation study of scAAV9/JeT-GAN (a self-complementary adeno-associated virus-based gene therapy containing the GAN transgene) in children with giant axonal neuropathy. Safety was the primary end point. The key secondary clinical end point was at least a 95% posterior probability of slowing the rate of change (i.e., slope) in the 32-item Motor Function Measure total percent score at 1 year after treatment, as compared with the pretreatment slope. RESULTS: One of four intrathecal doses of scAAV9/JeT-GAN was administered to 14 participants - 3.5×1013 total vector genomes (vg) (in 2 participants), 1.2×1014 vg (in 4), 1.8×1014 vg (in 5), and 3.5×1014 vg (in 3). During a median observation period of 68.7 months (range, 8.6 to 90.5), of 48 serious adverse events that had occurred, 1 (fever) was possibly related to treatment; 129 of 682 adverse events were possibly related to treatment. The mean pretreatment slope in the total cohort was -7.17 percentage points per year (95% credible interval, -8.36 to -5.97). At 1 year after treatment, posterior mean changes in slope were -0.54 percentage points (95% credible interval, -7.48 to 6.28) with the 3.5×1013-vg dose, 3.23 percentage points (95% credible interval, -1.27 to 7.65) with the 1.2×1014-vg dose, 5.32 percentage points (95% credible interval, 1.07 to 9.57) with the 1.8×1014-vg dose, and 3.43 percentage points (95% credible interval, -1.89 to 8.82) with the 3.5×1014-vg dose. The corresponding posterior probabilities for slowing the slope were 44% (95% credible interval, 43 to 44); 92% (95% credible interval, 92 to 93); 99% (95% credible interval, 99 to 99), which was above the efficacy threshold; and 90% (95% credible interval, 89 to 90). Between 6 and 24 months after gene transfer, sensory-nerve action potential amplitudes increased, stopped declining, or became recordable after being absent in 6 participants but remained absent in 8. CONCLUSIONS: Intrathecal gene transfer with scAAV9/JeT-GAN for giant axonal neuropathy was associated with adverse events and resulted in a possible benefit in motor function scores and other measures at some vector doses over a year. Further studies are warranted to determine the safety and efficacy of intrathecal AAV-mediated gene therapy in this disorder. (Funded by the National Institute of Neurological Disorders and Stroke and others; ClinicalTrials.gov number, NCT02362438.).
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Técnicas de Transferencia de Gen , Terapia Genética , Neuropatía Axonal Gigante , Niño , Humanos , Proteínas del Citoesqueleto/genética , Terapia Genética/efectos adversos , Terapia Genética/métodos , Neuropatía Axonal Gigante/genética , Neuropatía Axonal Gigante/terapia , Transgenes , Inyecciones EspinalesRESUMEN
Background: RYR1-related myopathies (RYR1-RM) are caused by pathogenic variants in the RYR1 gene which encodes the type 1 ryanodine receptor (RyR1). RyR1 is the sarcoplasmic reticulum (SR) calcium release channel that mediates excitation-contraction coupling in skeletal muscle. RyR1 sub-conductance, SR calcium leak, reduced RyR1 expression, and oxidative stress often contribute to RYR1-RM pathogenesis. Loss of RyR1-calstabin1 association, SR calcium leak, and increased RyR1 open probability were observed in 17 RYR1-RM patient skeletal muscle biopsies and improved following ex vivo treatment with Rycal compounds. Thus, we initiated a first-in-patient trial of Rycal S48168 (ARM210) in ambulatory adults with genetically confirmed RYR1-RM. Methods: Participants received 120 mg (n = 3) or 200 mg (n = 4) S48168 (ARM210) daily for 29 days. The primary endpoint was safety and tolerability. Exploratory endpoints included S48168 (ARM210) pharmacokinetics (PK), target engagement, motor function measure (MFM)-32, hand grip and pinch strength, timed functional tests, PROMIS fatigue scale, semi-quantitative physical exam strength measurements, and oxidative stress biomarkers. The trial was registered with clinicaltrials.gov (NCT04141670) and was conducted at the National Institutes of Health Clinical Center between October 28, 2019 and December 12, 2021. Findings: S48168 (ARM210) was well-tolerated, did not cause any serious adverse events, and exhibited a dose-dependent PK profile. Three of four participants who received the 200 mg/day dose reported improvements in PROMIS-fatigue at 28 days post-dosing, and also demonstrated improved proximal muscle strength on physical examination. Interpretation: S48168 (ARM210) demonstrated favorable safety, tolerability, and PK, in RYR1-RM affected individuals. Most participants who received 200 mg/day S48168 (ARM210) reported decreased fatigue, a key symptom of RYR1-RM. These results set the foundation for a randomized, double-blind, placebo-controlled proof of concept trial to determine efficacy of S48168 (ARM210) in RYR1-RM. Funding: NINDS and NINR Intramural Research Programs, NIH Clinical Center Bench to Bedside Award (2017-551673), ARMGO Pharma Inc., and its development partner Les Laboratoires Servier.
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BACKGROUND: Acute myocardial infarction complicated by cardiogenic shock (AMI-CS) is associated with significant morbidity and mortality. Mechanical circulatory support (MCS) devices increase systemic blood pressure and end organ perfusion while reducing cardiac filling pressures. METHODS AND RESULTS: The National Cardiogenic Shock Initiative (NCT03677180) is a single-arm, multicenter study. The purpose of this study was to assess the feasibility and effectiveness of utilizing early MCS with Impella in patients presenting with AMI-CS. The primary end point was in-hospital mortality. A total of 406 patients were enrolled at 80 sites between 2016 and 2020. Average age was 64±12 years, 24% were female, 17% had a witnessed out-of-hospital cardiac arrest, 27% had in-hospital cardiac arrest, and 9% were under active cardiopulmonary resuscitation during MCS implantation. Patients presented with a mean systolic blood pressure of 77.2±19.2 mm Hg, 85% of patients were on vasopressors or inotropes, mean lactate was 4.8±3.9 mmol/L and cardiac power output was 0.67±0.29 watts. At 24 hours, mean systolic blood pressure improved to 103.9±17.8 mm Hg, lactate to 2.7±2.8 mmol/L, and cardiac power output to 1.0±1.3 watts. Procedural survival, survival to discharge, survival to 30 days, and survival to 1 year were 99%, 71%, 68%, and 53%, respectively. CONCLUSIONS: Early use of MCS in AMI-CS is feasible across varying health care settings and resulted in improvements to early hemodynamics and perfusion. Survival rates to hospital discharge were high. Given the encouraging results from our analysis, randomized clinical trials are warranted to assess the role of utilizing early MCS, using a standardized, multidisciplinary approach.
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Corazón Auxiliar , Infarto del Miocardio , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ácido Láctico , Infarto del Miocardio/complicaciones , Infarto del Miocardio/terapia , Choque Cardiogénico/diagnóstico , Choque Cardiogénico/etiología , Choque Cardiogénico/terapia , Resultado del TratamientoRESUMEN
BACKGROUND AND OBJECTIVES: Retinopathy of prematurity is an increasingly important cause of blindness in children in low- and middle-income countries. Timely screening and treatment greatly reduce blindness. This study assessed the impact of the COVID-19 pandemic on ROP services in low- and middle-income countries. METHODS: An online survey with closed and open-ended questions in Microsoft Teams was sent to 304 ophthalmologists providing screening, treatment and/or vitreoretinal services (January 15 to March 12 2021). Categories were used to report impact on services. 28 participants were purposively selected for interview. RESULTS: 184/201 completed forms from 32 countries were received. Two thirds of participants worked in government facilities and 45.6% were paediatric ophthalmologists. A moderate to severe impact was reported by 13% for screening, 9% for treatment and 16% for vitreoretinal surgery with some variation between government, private and not-for-profit sectors. 22% thought services would take a year to recover. Fifteen ophthalmologists from 12 countries were interviewed. Many reported fewer neonatal admissions, and several reported more ROP blind infants once restrictions lifted. Themes associated with services continuing included limited lockdown, autonomy and flexibility, commitment, advocacy and technology. Themes associated with a negative impact include fear and panic, closure of facilities, COVID infection or quarantining of health workers and parents, lack of transport and exacerbation of poverty. CONCLUSIONS: The COVID pandemic had a very variable impact on the provision of ROP services. In some countries where the impact was great, more infants may have become blind from ROP. Lessons can be learnt for planning pandemic preparedness.
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BACKGROUND: Ryanodine receptor 1-related myopathy (RYR1-RM) can present with a selective pattern and gradient of intramuscular fatty infiltration (IMFI) on magnetic resonance imaging (MRI). OBJECTIVE: To demonstrate an automated protocol for quantification of IMFI in the lower extremity muscles of individuals with RYR1-RM using T1-weighted MRI and to examine the relationships of IMFI with motor function and clinical severity. METHODS: Axial images of the lower extremity muscles were acquired by T1-weighted fast spin-echo and short tau inversion recovery (STIR) sequences. A modified ImageJ-based program was used for quantification. IMFI data was analyzed by mode of inheritance, motor function, and clinical severity. RESULTS: Upper and lower leg IMFI from 36 genetically confirmed and ambulatory RYR1-RM affected individuals (26 dominant and 10 recessive) were analyzed using Grey-scale quantification. There was no statistically significant difference in IMFI between dominant and recessive cases in upper or lower legs. IMFI in both upper and lower legs was inversely correlated with participant performance on the motor function measure (MFM-32) total score (upper leg: pâ<â0.001; lower leg: pâ=â0.003) and the six-minute walk test (6MWT) distance (upper leg: pâ<â0.001; lower leg: pâ=â0.010). There was no significant difference in mean IMFI between participants with mild versus severe clinical phenotypes (pâ=â0.257). CONCLUSION: A modified ImageJ-based algorithm was able to select and quantify fatty infiltration in a cohort of heterogeneously affected individuals with RYR1-RM. IMFI was not predictive of mode of inheritance but showed strong correlation with motor function and capacity tests including MFM-32 and 6MWT, respectively.
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Músculo Esquelético/diagnóstico por imagen , Enfermedades Musculares/diagnóstico por imagen , Canal Liberador de Calcio Receptor de Rianodina , Adolescente , Adulto , Niño , Femenino , Humanos , Pierna/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
The RYR1 gene, which encodes the sarcoplasmic reticulum calcium release channel or type 1 ryanodine receptor (RyR1) of skeletal muscle, was sequenced in 1988 and RYR1 variations that impair calcium homeostasis and increase susceptibility to malignant hyperthermia were first identified in 1991. Since then, RYR1-related myopathies (RYR1-RM) have been described as rare, histopathologically and clinically heterogeneous, and slowly progressive neuromuscular disorders. RYR1 variants can lead to dysfunctional RyR1-mediated calcium release, malignant hyperthermia susceptibility, elevated oxidative stress, deleterious post-translational modifications, and decreased RyR1 expression. RYR1-RM-affected individuals can present with delayed motor milestones, contractures, scoliosis, ophthalmoplegia, and respiratory insufficiency.Historically, RYR1-RM-affected individuals were diagnosed based on morphologic features observed in muscle biopsies including central cores, cores and rods, central nuclei, fiber type disproportion, and multi-minicores. However, these histopathologic features are not always specific to RYR1-RM and often change over time. As additional phenotypes were associated with RYR1 variations (including King-Denborough syndrome, exercise-induced rhabdomyolysis, lethal multiple pterygium syndrome, adult-onset distal myopathy, atypical periodic paralysis with or without myalgia, mild calf-predominant myopathy, and dusty core disease) the overlap among diagnostic categories is ever increasing. With the continuing emergence of new clinical subtypes along the RYR1 disease spectrum and reports of adult-onset phenotypes, nuanced nomenclatures have been reported (RYR1- [related, related congenital, congenital] myopathies). In this narrative review, we provide historical highlights of RYR1 research, accounts of the main diagnostic disease subtypes and propose RYR1-related disorders (RYR1-RD) as a unified nomenclature to describe this complex and evolving disease spectrum.
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Enfermedades Neuromusculares/metabolismo , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Animales , Humanos , Enfermedades Neuromusculares/genética , Enfermedades Neuromusculares/patología , Fenotipo , Canal Liberador de Calcio Receptor de Rianodina/genética , Canal Liberador de Calcio Receptor de Rianodina/normas , Terminología como AsuntoRESUMEN
BACKGROUND: When tested in a controlled clinic environment, individuals with neuromuscular-related symptoms may complete motor tasks within normal predicted ranges. However, measuring activity at home may better reflect typical motor performance. The accuracy of accelerometry measurements in individuals with congenital muscular dystrophy (CMD) is unknown. We aimed to compare accelerometry and manual step counts and assess free-living physical activity intensity in individuals with CMD using accelerometry. METHODS: Ambulatory pediatric CMD participants (n = 9) performed the 6-minute walk test in clinic while wearing ActiGraph GT3X accelerometer devices. During the test, manual step counting was conducted to assess concurrent validity of the ActiGraph step count in this population using Bland-Altman analysis. In addition, activity intensity of 6 pediatric CMD participants was monitored at home with accelerometer devices for an average of 7 days. Cut-point values previously validated for neuromuscular disorders were used for data analysis. RESULTS: Bland-Altman and intraclass correlation analyses showed no concurrent validity between manual and ActiGraph-recorded step counts. Fewer steps were recorded by ActiGraph step counts compared with manual step counts (411 ± 74 vs 699 ± 43, respectively; P = .004). Although improved, results were in the same direction with the application of low-frequency extension filters (587 ± 40 vs 699 ± 43, P = .03). ActiGraph step-count data did not correlate with manual step count (Spearman ρ = 0.32, P = .41; with low-frequency extension: Spearman ρ = 0.45, P = .22). Seven-day physical activity monitoring showed that participants spent more than 80% of their time in the sedentary activity level. CONCLUSIONS: In a controlled clinic setting, step count was significantly lower by ActiGraph GT3X than by manual step counting, possibly because of the abnormal gait in this population. Additional studies using triaxial assessment are needed to validate accelerometry measurement of activity intensity in individuals with CMD. Accelerometry outcomes may provide valuable measures and complement the 6-minute walk test in the assessment of treatment efficacy in CMD.
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Acelerometría/estadística & datos numéricos , Actividad Motora , Distrofias Musculares/congénito , Acelerometría/instrumentación , Adolescente , Niño , Femenino , Humanos , Masculino , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: Pathogenic variations in the gene encoding the skeletal muscle ryanodine receptor (RyR1) are associated with malignant hyperthermia (MH) susceptibility, a life-threatening hypermetabolic condition and RYR1-related myopathies (RYR1-RM), a spectrum of rare neuromuscular disorders. In RYR1-RM, intracellular calcium dysregulation, post-translational modifications, and decreased protein expression lead to a heterogenous clinical presentation including proximal muscle weakness, contractures, scoliosis, respiratory insufficiency, and ophthalmoplegia. Preclinical model systems of RYR1-RM and MH have been developed to better understand underlying pathomechanisms and test potential therapeutics. METHODS: We conducted a comprehensive scoping review of scientific literature pertaining to RYR1-RM and MH preclinical model systems in accordance with the PRISMA Scoping Reviews Checklist and the framework proposed by Arksey and O'Malley. Two major electronic databases (PubMed and EMBASE) were searched without language restriction for articles and abstracts published between January 1, 1990 and July 3, 2019. RESULTS: Our search yielded 5049 publications from which 262 were included in this review. A majority of variants tested in RYR1 preclinical models were localized to established MH/central core disease (MH/CCD) hot spots. A total of 250 unique RYR1 variations were reported in human/rodent/porcine models with 95% being missense substitutions. The most frequently reported RYR1 variant was R614C/R615C (human/porcine total n = 39), followed by Y523S/Y524S (rabbit/mouse total n = 30), I4898T/I4897T/I4895T (human/rabbit/mouse total n = 20), and R163C/R165C (human/mouse total n = 18). The dyspedic mouse was utilized by 47% of publications in the rodent category and its RyR1-null (1B5) myotubes were transfected in 23% of publications in the cellular model category. In studies of transfected HEK-293 cells, 57% of RYR1 variations affected the RyR1 channel and activation core domain. A total of 15 RYR1 mutant mouse strains were identified of which ten were heterozygous, three were compound heterozygous, and a further two were knockout. Porcine, avian, zebrafish, C. elegans, canine, equine, and drosophila model systems were also reported. CONCLUSIONS: Over the past 30 years, there were 262 publications on MH and RYR1-RM preclinical model systems featuring more than 200 unique RYR1 variations tested in a broad range of species. Findings from these studies have set the foundation for therapeutic development for MH and RYR1-RM.
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Hipertermia Maligna , Enfermedades Musculares , Animales , Caenorhabditis elegans , Perros , Células HEK293 , Caballos , Humanos , Hipertermia , Hipertermia Maligna/genética , Ratones , Enfermedades Musculares/genética , Mutación , Conejos , Canal Liberador de Calcio Receptor de Rianodina/genética , Porcinos , Pez CebraRESUMEN
RYR1 encodes the type 1 ryanodine receptor, an intracellular calcium release channel (RyR1) on the skeletal muscle sarcoplasmic reticulum (SR). Pathogenic RYR1 variations can destabilize RyR1 leading to calcium leak causing oxidative overload and myopathy. However, the effect of RyR1 leak has not been established in individuals with RYR1-related myopathies (RYR1-RM), a broad spectrum of rare neuromuscular disorders. We sought to determine whether RYR1-RM affected individuals exhibit pathologic, leaky RyR1 and whether variant location in the channel structure can predict pathogenicity. Skeletal muscle biopsies were obtained from 17 individuals with RYR1-RM. Mutant RyR1 from these individuals exhibited pathologic SR calcium leak and increased activity of calcium-activated proteases. The increased calcium leak and protease activity were normalized by ex-vivo treatment with S107, a RyR stabilizing Rycal molecule. Using the cryo-EM structure of RyR1 and a new dataset of > 2200 suspected RYR1-RM affected individuals we developed a method for assigning pathogenicity probabilities to RYR1 variants based on 3D co-localization of known pathogenic variants. This study provides the rationale for a clinical trial testing Rycals in RYR1-RM affected individuals and introduces a predictive tool for investigating the pathogenicity of RYR1 variants of uncertain significance.
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Calcio/metabolismo , Enfermedades Musculares/metabolismo , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Animales , Citoplasma/metabolismo , Humanos , Músculo Esquelético/metabolismo , Enfermedades Musculares/terapia , Canal Liberador de Calcio Receptor de Rianodina/genética , Retículo Sarcoplasmático/metabolismoRESUMEN
OBJECTIVE: To investigate the efficacy of N-acetylcysteine (NAC) for decreasing elevated oxidative stress and increasing physical endurance in individuals with ryanodine receptor 1-related myopathies (RYR1-RM). METHODS: In this 6-month natural history assessment (n = 37) followed by a randomized, double-blinded, placebo-controlled trial, 33 eligible participants were block-randomized (1:1) to receive NAC (n = 16) or placebo (n = 17), orally for 6 months (adult dose 2,700 mg/d; pediatric dose 30 mg/kg/d). The primary endpoint was urine 15-F2t isoprostane concentration and the clinically meaningful co-primary endpoint was 6-minute walk test (6MWT) distance. RESULTS: When compared to the general population, participants had elevated baseline 15-F2t isoprostane concentrations and most had a decreased 6MWT distance (mean ± SD 3.2 ± 1.5 vs 1.1 ± 1.7 ng/mg creatinine and 468 ± 134 vs 600 ± 58 m, respectively, both p < 0.001). 15-F2t isoprostane concentration and 6MWT distance did not change over the 6-month natural history assessment (p = 0.98 and p = 0.61, respectively). NAC treatment did not improve 15-F2t isoprostane concentration (least squares means difference 0.1 [95% confidence interval [CI] -1.4 to 1.6] ng/mg creatinine, p = 0.88) or 6MWT distance (least squares means difference 24 [95% CI -5.5 to 53.4] m, p = 0.11). NAC was safe and well-tolerated at the doses administered in this study. CONCLUSION: In ambulatory RYR1-RM-affected individuals, we observed stable disease course, and corroborated preclinical reports of elevated oxidative stress and decreased physical endurance. NAC treatment did not decrease elevated oxidative stress, as measured by 15-F2t isoprostane. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that, for people with RYR1-RM, treatment with oral NAC does not decrease oxidative stress as measured by 15-F2t isoprostane. CLINICALTRIALSGOV IDENTIFIER: NCT02362425.
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Acetilcisteína/uso terapéutico , Depuradores de Radicales Libres/uso terapéutico , Enfermedades Musculares/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Adolescente , Adulto , Niño , Dinoprost/análogos & derivados , Dinoprost/orina , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Musculares/genética , Enfermedades Musculares/orina , Canal Liberador de Calcio Receptor de Rianodina/genética , Resultado del Tratamiento , Prueba de Paso , Adulto JovenRESUMEN
BACKGROUND: RYR1-related disorders (RYR1-RD), are a spectrum of genetic neuromuscular disorders. Affected individuals frequently experience fatigue yet appropriate tools to assess RYR1-RD-associated fatigue remain underdeveloped. OBJECTIVE: This study assessed the reliability and validity of two self-report questionnaires, the multidimensional fatigue inventory (MFI-20) and adult/pediatric functional assessment of chronic illness-fatigue (FACIT-F/Peds-FACIT-F) as potential fatigue measures in RYR1-RD affected individuals. METHODS: Participants (nâ=â37) were enrolled in an RYR1-RD combined natural history study and clinical trial. At baseline, participants completed fatigue questionnaires, six-minute walk test (6MWT), cardiopulmonary exercise test (CPET) and saliva collection for fatigue biomarker index (FBI) quantification. RESULTS: All questionnaires exhibited good test-retest reliability (nâ=â18, ICCâ>â0.80). MFI-20 (nâ=â37), and FACIT-F (nâ=â28) also showed good internal consistency (Cronbach's α>â0.80). All MFI-20 subscales, except mental fatigue, and FACIT-F demonstrated evidence of criterion validity when correlated against percent predicted 6MWT distance (MFI-20 nâ=â37; râ=â-0.34 to -0.47, all pâ<â0.05, mental fatigue, râ=â-0.16, pâ=â0.35; FACIT-F nâ=â28, râ=â0.41, pâ=â0.03). This was not the case for percent predicted VO2 peak (all pâ>â0.05). FBI correlated with MFI-20 general fatigue dimension only (râ=â-0.35, pâ=â0.03). Comparison of standardized questionnaire scores revealed that RYR1-RD affected individuals experience significantly greater fatigue than the general population. CONCLUSIONS: MFI-20 and FACIT-F are valid and reliable tools for assessing RYR1-RD-associated fatigue, a symptom centrally implicated in this rare disorder.
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Fatiga/diagnóstico , Enfermedades Neuromusculares/diagnóstico , Enfermedades Neuromusculares/genética , Canal Liberador de Calcio Receptor de Rianodina/genética , Autoinforme , Acetilcisteína/uso terapéutico , Adolescente , Adulto , Biomarcadores/metabolismo , Niño , Prueba de Esfuerzo , Fatiga/tratamiento farmacológico , Fatiga/genética , Fatiga/fisiopatología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Fármacos Neuromusculares/uso terapéutico , Enfermedades Neuromusculares/tratamiento farmacológico , Enfermedades Neuromusculares/fisiopatología , Reproducibilidad de los Resultados , Saliva/metabolismoRESUMEN
Ryanodine receptor type 1-related myopathies (RYR1-RM) are the most common class of congenital myopathies. Historically, RYR1-RM classification and diagnosis have been guided by histopathologic findings on muscle biopsy. Main histological subtypes of RYR1-RM include central core disease, multiminicore disease, core-rod myopathy, centronuclear myopathy, and congenital fiber-type disproportion. A range of RYR1-RM clinical phenotypes has also emerged more recently and includes King Denborough syndrome, RYR1 rhabdomyolysis-myalgia syndrome, atypical periodic paralysis, congenital neuromuscular disease with uniform type 1 fibers, and late-onset axial myopathy. This expansion of the RYR1-RM disease spectrum is due, in part, to implementation of next-generation sequencing methods, which include the entire RYR1 coding sequence rather than being restricted to hotspot regions. These methods enhance diagnostic capabilities, especially given historic limitations of histopathologic and clinical overlap across RYR1-RM. Both dominant and recessive modes of inheritance have been documented, with the latter typically associated with a more severe clinical phenotype. As with all congenital myopathies, no FDA-approved treatments exist to date. Here, we review histopathologic, clinical, imaging, and genetic diagnostic features of the main RYR1-RM subtypes. We also discuss the current state of treatments and focus on disease-modulating (nongenetic) therapeutic strategies under development for RYR1-RM. Finally, perspectives for future approaches to treatment development are broached.
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Enfermedades Musculares , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Animales , Humanos , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/genética , Enfermedades Musculares/terapia , Canal Liberador de Calcio Receptor de Rianodina/genéticaRESUMEN
Variants in the skeletal muscle ryanodine receptor 1 gene (RYR1) result in a spectrum of RYR1-related disorders. Presentation during infancy is typical and ranges from delayed motor milestones and proximal muscle weakness to severe respiratory impairment and ophthalmoplegia. We aimed to elucidate correlations between genotype, protein structure and clinical phenotype in this rare disease population. Genetic and clinical data from 47 affected individuals were analyzed and variants mapped to the cryo-EM RyR1 structure. Comparisons of clinical severity, motor and respiratory function and symptomatology were made according to the mode of inheritance and affected RyR1 structural domain(s). Overall, 49 RYR1 variants were identified in 47 cases (dominant/de novo, n = 35; recessive, n = 12). Three variants were previously unreported. In recessive cases, facial weakness, neonatal hypotonia, ophthalmoplegia/paresis, ptosis, and scapular winging were more frequently observed than in dominant/de novo cases (all, p < 0.05). Both dominant/de novo and recessive cases exhibited core myopathy histopathology. Clinically severe cases were typically recessive or had variants localized to the RyR1 cytosolic shell domain. Motor deficits were most apparent in the MFM-32 standing and transfers dimension, [median (IQR) 85.4 (18.8)% of maximum score] and recessive cases exhibited significantly greater overall motor function impairment compared to dominant/de novo cases [79.7 (18.8)% vs. 87.5 (17.7)% of maximum score, p = 0.03]. Variant mapping revealed patterns of clinical severity across RyR1 domains, including a structural plane of interest within the RyR1 cytosolic shell, in which 84% of variants affected the bridging solenoid. We have corroborated genotype-phenotype correlations and identified RyR1 regions that may be especially sensitive to structural modification.
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Enfermedades Neuromusculares/genética , Enfermedades Neuromusculares/fisiopatología , Canal Liberador de Calcio Receptor de Rianodina/genética , Acetilcisteína/uso terapéutico , Adolescente , Adulto , Estudios Transversales , Método Doble Ciego , Femenino , Estudios de Asociación Genética , Variación Genética , Humanos , Masculino , Fármacos Neuromusculares/uso terapéutico , Enfermedades Neuromusculares/tratamiento farmacológico , Enfermedades Neuromusculares/patología , Estudios Prospectivos , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Relación Estructura-Actividad , Adulto JovenRESUMEN
Methylmercury (MeHg) is a proposed environmental stimulus in systemic lupus erythematosus (SLE). Humans are primarily exposed to MeHg through fish consumption. Fish are also important sources of n-3 long chain polyunsaturated fatty acids (n-3 LCPUFA). This in vitro study investigated the inflammatory response of isolated peripheral blood mononuclear cells (PBMCs), when exposed to either MeHg alone or with added n-3 LCPUFA, from SLE patients (Nâ¯=â¯12) compared to healthy sex matched controls (Nâ¯=â¯12). The PBMCs were isolated and exposed to 200â¯nM of MeHg for 24â¯h with or without pre-exposure to eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) at a concentration of 100⯵M each. Supernatants were analyzed for the inflammatory markers. Following exposure to MeHg, mean TNF-α concentrations were significantly higher in SLE patients (2226.01⯱â¯348.98pg/ml) compared to controls (701.40⯱â¯680.65â¯pg/ml) (Pâ¯=â¯.008). Pre-exposure of cells with MeHg and EPA resulted in a significantly higher concentration of IL-8 in supernatants from SLE patients (2137.83⯱â¯1559.01â¯pg/ml) compared to that of the controls (879.26⯱â¯979.49â¯pg/ml) (Pâ¯=â¯.030). EPA and DHA attenuated the pro-inflammatory inducing effects of MeHg in SLE and control cells. In summary, exposure to MeHg stimulated a higher TNF-α response in SLE patients compared with healthy controls; nevertheless the presence of n-3 LCPUFA reduced the overall inflammatory response, albeit to a lesser degree in SLE patients.
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Antiinflamatorios/farmacología , Ácidos Docosahexaenoicos/farmacología , Ácido Eicosapentaenoico/farmacología , Contaminantes Ambientales/toxicidad , Leucocitos Mononucleares/efectos de los fármacos , Lupus Eritematoso Sistémico/inmunología , Compuestos de Metilmercurio/toxicidad , Adulto , Células Cultivadas , Citocinas/metabolismo , Femenino , Humanos , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana EdadRESUMEN
The ryanodine receptor 1-related congenital myopathies (RYR1-RM) comprise a spectrum of slow, rare neuromuscular diseases. Affected individuals present with a mild-to-severe symptomatology ranging from proximal muscle weakness, hypotonia and joint contractures to scoliosis, ophthalmoplegia, and respiratory involvement. Although there is currently no FDA-approved treatment for RYR1-RM, our group recently conducted the first clinical trial in this patient population (NCT02362425). This study aimed to characterize novel RYR1 variants with regard to genetic, laboratory, muscle magnetic resonance imaging (MRI), and clinical findings. Genetic and histopathology reports were obtained from participant's medical records. Alamut Visual Software was used to determine if participant's variants had been previously reported and to assess predicted pathogenicity. Physical exams, pulmonary function tests, T1-weighted muscle MRI scans, and blood measures were completed during the abovementioned clinical trial. Six novel variants (two de novo, three dominant, and one recessive) were identified in individuals with RYR1-RM. Consistent with established RYR1-RM histopathology, cores were observed in all biopsies, except Case 6 who exhibited fiber-type disproportion. Muscle atrophy and impaired mobility with Trendelenburg gait were the most common clinical symptoms and were identified in all cases. Muscle MRI revealed substantial inter-individual variation in fatty infiltration corroborating the heterogeneity of the disease. Two individuals with dominant RYR1 variants exhibited respiratory insufficiency: a clinical symptom more commonly associated with recessive RYR1-RM cases. This study demonstrates that a genetics-led approach is suitable for the diagnosis of suspected RYR1-RM which can be corroborated through histopathology, muscle MRI and clinical examination.
RESUMEN
PURPOSE: Vitamin D inadequacy is a global health concern in athletes as well as the general population. Whilst the role of vitamin D in skeletal health is well defined, there remains uncertainty over whether vitamin D supplementation has an added benefit beyond bone health. METHODS: This randomised placebo-controlled trial in healthy male and female Gaelic footballers (n = 42) investigated the effect of vitamin D3 supplementation [3000 IU (75 µg) daily for 12 weeks, via an oral spray solution] on VO2 max which was the primary outcome measure. Secondary outcomes included skeletal muscle and lung function. RESULTS: Supplementation significantly increased total 25-hydroxyvitamin D concentrations compared to the placebo group (mean ± SD change from baseline, 36.31 ± 32.34 vs. 6.11 ± 23.93 nmol/L, respectively; P = 0.006). At baseline, 50 and 22 % of footballers presented with vitamin D insufficiency (31-49 nmol/L) and deficiency (<30 nmol/L), respectively. Total 25-hydroxyvitamin D concentration did not significantly correlate with any measure of physical performance. Analysis of covariance (ANCOVA) models demonstrated that vitamin D supplementation over 12 weeks had no significant effect on VO2 max (P = 0.375), vertical jump height (P = 0.797), left and right handgrip strength (P = 0.146 and P = 0.266, respectively), forced vital capacity (P = 0.573) or forced expiratory volume at 1 s (P = 0.665), after adjusting for confounders. The high prevalence of vitamin D inadequacy observed in this cohort of collegiate Gaelic footballers supports the need for vitamin D supplementation during wintertime to avoid being at risk of poor bone health. CONCLUSIONS: Twelve-week daily supplementation with 3000 IU (75 µg) vitamin D3 successfully resolved deficiency but did not have any significant effect on VO2 max, skeletal muscle or lung function.
Asunto(s)
Colecalciferol/administración & dosificación , Suplementos Dietéticos , Fútbol Americano , Consumo de Oxígeno , Fenómenos Fisiológicos en la Nutrición Deportiva , Deficiencia de Vitamina D/tratamiento farmacológico , Administración Oral , Adolescente , Atletas , Composición Corporal , Calcio/sangre , Colecalciferol/sangre , Creatinina/sangre , Método Doble Ciego , Ejercicio Físico , Femenino , Fuerza de la Mano , Humanos , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Masculino , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Evaluación Nutricional , Vaporizadores Orales , Cooperación del Paciente , Resultado del Tratamiento , Deficiencia de Vitamina D/sangre , Adulto JovenRESUMEN
Vitamin D is typically supplied in capsule form, both in trials and in clinical practice. However, little is known regarding the efficacy of vitamin D administered via oral sprays - a method that primarily bypasses the gastrointestinal absorption route. This study aimed to compare the efficacy of vitamin D3 liquid capsules and oral spray solution in increasing wintertime total 25-hydroxyvitamin D (25(OH)D) concentrations. In this randomised, open-label, cross-over trial, healthy adults (n 22) received 3000 IU (75 µg) vitamin D3 daily for 4 weeks in either capsule or oral spray form. Following a 10-week washout phase, participants received the opposite treatment for a final 4 weeks. Anthropometrics and fasted blood samples were obtained before and after supplementation, with samples analysed for total 25(OH)D, creatinine, intact parathyroid hormone and adjusted Ca concentrations. At baseline, vitamin D sufficiency (total 25(OH)D>50 nmol/l), insufficiency (31-49 nmol/l) and clinical deficiency (<30 nmol/l) were evident in 59, 23 and 18 % of the participants, respectively. Overall, baseline total mean 25(OH)D concentration averaged 59·76 (sd 29·88) nmol/l, representing clinical sufficiency. ANCOVA revealed no significant difference in the mean and standard deviation change from baseline in total 25(OH)D concentrations between oral spray and capsule supplementation methods (26·15 (sd 17·85) v. 30·38 (sd 17·91) nmol/l, respectively; F=1·044, adjusted r 2 0·493, P=0·313). Oral spray vitamin D3 is an equally effective alternative to capsule supplementation in healthy adults.
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Colecalciferol/administración & dosificación , Suplementos Dietéticos , Deficiencia de Vitamina D/prevención & control , 25-Hidroxivitamina D 2/sangre , Adulto , Biomarcadores/sangre , Calcifediol/sangre , Calcio/sangre , Cápsulas , Colecalciferol/efectos adversos , Colecalciferol/uso terapéutico , Estudios Cruzados , Suplementos Dietéticos/efectos adversos , Femenino , Humanos , Análisis de Intención de Tratar , Perdida de Seguimiento , Masculino , Irlanda del Norte , Vaporizadores Orales , Hormona Paratiroidea/sangre , Cooperación del Paciente , Estaciones del Año , Índice de Severidad de la Enfermedad , Deficiencia de Vitamina D/sangre , Deficiencia de Vitamina D/dietoterapia , Deficiencia de Vitamina D/fisiopatología , Adulto JovenRESUMEN
Vitamin D deficiency is a global health concern that is prevalent in Ireland. The vitamin D status of elite Irish athletes following implementation of a revised supplementation policy in 2010/2011 has not been explored to date. This study aimed to assess the vitamin D status of elite Irish athletes participating in high-profile sports and establish if equatorial travel, supplementation and/or sunbed use predict vitamin D status. Across Ireland, blood samples (n = 92) were obtained from cricketers (n = 28), boxers (n = 21) and women's rugby sevens players (n = 43) between November 2013 and April 2015. Total 25-hydroxyvitamin D (25(OH)D) concentrations were quantified using LC-MS/MS. Parathyroid hormone and adjusted calcium concentrations were measured by clinical biochemistry. Athletes completed a questionnaire that queried equatorial travel, supplementation and sunbed use. Vitamin D sufficiency (25(OH)D >50 nmol/L) was evident in 86% of athletes. Insufficiency (31-49 nmol/L) and deficiency (<30 nmol/L) was present in only 12% and 2% of athletes respectively. On average, athletes from all sport disciplines were vitamin D sufficient and 25% reported vitamin D supplementation which was a significant positive predictor of vitamin D status, (OR 4.31; 95% CI 1.18-15.75; p = 0.027). Equatorial travel and sun bed use were reported in 47% and 16% of athletes respectively however these factors did not predict vitamin D status (both p > 0.05). Although different cohorts were assessed, the overall prevalence of vitamin D insufficiency/deficiency was 55% in 2010/2011 compared with only 14% in 2013/2015. Targeted supplementation is highly effective in optimising vitamin D status, negating the need for blanket-supplementation in elite cohorts.
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Atletas , Suplementos Dietéticos , Política Nutricional , Cooperación del Paciente , Fenómenos Fisiológicos en la Nutrición Deportiva , Deficiencia de Vitamina D/prevención & control , Vitamina D/uso terapéutico , 25-Hidroxivitamina D 2/sangre , Calcifediol/sangre , Estudios de Cohortes , Femenino , Humanos , Irlanda/epidemiología , Masculino , Política Nutricional/tendencias , Estado Nutricional , Esfuerzo Físico , Prevalencia , Estaciones del Año , Autoinforme , Instalaciones Deportivas y Recreativas , Deficiencia de Vitamina D/sangre , Deficiencia de Vitamina D/dietoterapia , Deficiencia de Vitamina D/epidemiologíaRESUMEN
Athletes may be predisposed to low vitamin D concentrations, with studies reporting a high prevalence of athletes with a vitamin D concentration below 50 nmol/L across a range of sports and geographical locations, particularly over the winter months. It is well documented that vitamin D is important for osseous health by enhancing calcium absorption at the small intestine; however, emerging research suggests that vitamin D may also benefit a plethora of extra-skeletal target tissues and systems. There is strong evidence that vitamin D is capable of regulating both innate and adaptive immune processes via binding of active vitamin D to its complementary receptor. Supplementation with vitamin D may also enhance skeletal muscle function through morphological adaptations and enhanced calcium availability during cross-bridge cycling; however, an exact mechanism of action is yet to be elucidated. Such findings have prompted research into the importance of maintaining vitamin D concentrations over wintertime and the possible physiological and immunological benefits of vitamin D supplementation in athletes. The following review critically evaluates existing literature and presents novel perspectives on how vitamin D may enhance athletic performance.