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1.
J Neuromuscul Dis ; 8(4): 657-668, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33646171

RESUMO

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: p < 0.001; lower leg: p = 0.003) and the six-minute walk test (6MWT) distance (upper leg: p < 0.001; lower leg: p = 0.010). There was no significant difference in mean IMFI between participants with mild versus severe clinical phenotypes (p = 0.257). 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.

2.
Neurology ; 96(10): e1413-e1424, 2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33441455

RESUMO

OBJECTIVE: To accurately categorize the phenotypes of individuals with collagen VI-related dystrophies (COL6-RDs) during the first years of life to predict long-term motor function and pulmonary function, to provide phenotype-specific anticipatory care, and to improve clinical trial readiness. METHODS: This retrospective, multicenter, international study analyzed the relationship of long-term motor and pulmonary function with the initial maximal motor ability achieved in individuals with COL6-RD. RESULTS: We studied 119 patients with COL6-RD from Spain (n = 54) and the United States (n = 65). The early maximal motor milestones of ability to rise from the floor unassisted and ability to climb 4 steps without holding onto a railing demonstrated reliability in distinguishing between 3 COL6-RD phenotypic subgroups: (1) Ullrich congenital muscular dystrophy, (2) intermediate COL6-RD, and (3) Bethlem myopathy. Long-term motor function and pulmonary function are strongly correlated with the maximal motor ability achieved during the first years of life. Maximal motor capacity can predict other disease-relevant events such as the age at loss of ambulation and the need for the initiation of nocturnal noninvasive ventilation. CONCLUSION: This work proposes a prospective phenotypic classification for COL6-RDs that will enable an accurate prediction of a patient's COL6-RD phenotype during the first years of life. The ability to establish a patient's COL6-RD phenotypic classification early will enable a more accurate prognosis of future motor and pulmonary function, thus improving anticipatory clinical care, and it will be instrumental in aiding the design of future clinical trials by allowing early stratification of trial cohorts.


Assuntos
Colágeno Tipo VI/genética , Distrofias Musculares/genética , Distrofias Musculares/psicologia , Desempenho Psicomotor , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Progressão da Doença , Feminino , Genótipo , Humanos , Estimativa de Kaplan-Meier , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Distrofias Musculares/fisiopatologia , Testes de Função Respiratória , Estudos Retrospectivos , Espanha , Resultado do Tratamento , Estados Unidos , Caminhada , Adulto Jovem
3.
Arch Phys Med Rehabil ; 102(4): 604-610, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33166523

RESUMO

OBJECTIVES: To investigate the responsiveness of the motor function measure (MFM) and determine the minimal clinically important difference (MCID) in individuals with 2 common types of congenital muscular dystrophy (CMD). DESIGN: Observational, prospective, single center, cohort study. SETTING: National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH). PARTICIPANTS: Individuals (N=44) with collagen VI-related dystrophies (COL6-RD, n=23) and 21 individuals laminin alpha2-related muscular dystrophy (LAMA2-RD, n=21) enrolled in a 4-year longitudinal natural history study. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Responsiveness of the MFM-32 and the Rasch-scaled MFM-25 and the MCID of the MFM-32 determined from a patient-reported anchor with 2 different methods, within-patient and between-patient. RESULTS: The original MFM-32 and Rasch-scaled MFM-25 performed similarly overall in both the COL6-RD and LAMA2-RD populations, with all subscores (D1, standing and transfers; D2, axial and proximal; D3, distal) showing a significant decrease over time, except MFM D1 and D3 for LAMA2-RD. The MFM D1 subscore was the most sensitive to change for ambulant individuals, whereas the MFM D2 subscore was the most sensitive to change for nonambulant individuals. The MCID for the MFM-32 total score was calculated as 2.5 and 3.9 percentage points according to 2 different methods. CONCLUSIONS: The MFM showed strong responsiveness in individuals with LAMA2-RD and COL6-RD. Because a floor effect was identified more prominently with the Rasch-Scaled MFM-25, the use of the original MFM-32 as a quantitative variable with the assumption of scale linearity appears to be a good compromise. When designing clinical trials in congenital muscular dystrophies, the use of MCID for MFM should be considered to determine if a given intervention effects show not only a statistically significant change but also a clinically meaningful change.


Assuntos
Avaliação da Deficiência , Diferença Mínima Clinicamente Importante , Atividade Motora/fisiologia , Distrofias Musculares/fisiopatologia , Distrofias Musculares/reabilitação , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Estudos Longitudinais , Masculino , Estudos Prospectivos , Adulto Jovem
4.
J Adv Nurs ; 77(3): 1591-1608, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33270262

RESUMO

AIM: To develop a novel proxy-reported scale of motor function in infants and young children with early-onset neuromuscular disorders (NMD), entitled the Proxy Motor Outcome Measure (PMOM). DESIGN: A mixed method design was employed, applying both qualitative and quantitative research. METHODS: A framework technique using sensitivity analyses guided the development of the most appropriate and relevant subset of items, modelled after 30 neuromuscular disease instruments/scales. The PMOM was designed based on semi-structured interviews with 16 proxies; a focus group of 11 experts in neuromuscular diseases and scale development, 10 of whom also gave quantitative data using a two-round Delphi method survey; and cognitive interviews with five proxies. These processes were conducted between January 2014-March 2019. RESULTS: Nine themes and 32 subthemes were derived from the semi-structured interviews. Five domains and three subdomains of potential items were identified by the focus group. An initial version of the PMOM scale was created with 121 items. Using the two-round Delphi method, 43 items met agreement on pre-defined requirements. The second version of the PMOM scale included these 43 and two additional items based on expert feedback. Proxies gave 114 suggestions on cognitive interviews, 99 of which were successfully addressed by the research team. The final version of the PMOM scale included 43 items. CONCLUSION: We developed a preliminary proxy-reported instrument, the PMOM, to evaluate motor function in infants and young children with early-onset NMD. IMPACT: Proxies hold a wealth of knowledge on their child's motor function during early development, which may complement clinic-based motor function testing. However, there is no validated measure of motor function that incorporates the observation of proxies of infants and young children with NMD. Future work will be focused on assessing the reliability, validity and responsiveness of the PMOM scale and implementing this tool in clinical studies.


Assuntos
Avaliação de Resultados em Cuidados de Saúde , Procurador , Criança , Pré-Escolar , Grupos Focais , Humanos , Lactente , Reprodutibilidade dos Testes , Inquéritos e Questionários
5.
Skelet Muscle ; 10(1): 32, 2020 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-33190635

RESUMO

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.


Assuntos
Doenças Neuromusculares/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Animais , Humanos , Doenças Neuromusculares/genética , Doenças Neuromusculares/patologia , Fenótipo , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/normas , Terminologia como Assunto
6.
J Neurosci Nurs ; 52(4): 172-178, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32511172

RESUMO

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.


Assuntos
Acelerometria/estatística & dados numéricos , Atividade Motora , Distrofias Musculares/congênito , Acelerometria/instrumentação , Adolescente , Criança , Feminino , Humanos , Masculino , Reprodutibilidade dos Testes
7.
Ann Neurol ; 88(2): 332-347, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32403198

RESUMO

OBJECTIVE: A hitherto undescribed phenotype of early onset muscular dystrophy associated with sensorineural hearing loss and primary ovarian insufficiency was initially identified in 2 siblings and in subsequent patients with a similar constellation of findings. The goal of this study was to understand the genetic and molecular etiology of this condition. METHODS: We applied whole exome sequencing (WES) superimposed on shared haplotype regions to identify the initial biallelic variants in GGPS1 followed by GGPS1 Sanger sequencing or WES in 5 additional families with the same phenotype. Molecular modeling, biochemical analysis, laser membrane injury assay, and the generation of a Y259C knock-in mouse were done. RESULTS: A total of 11 patients in 6 families carrying 5 different biallelic pathogenic variants in specific domains of GGPS1 were identified. GGPS1 encodes geranylgeranyl diphosphate synthase in the mevalonate/isoprenoid pathway, which catalyzes the synthesis of geranylgeranyl pyrophosphate, the lipid precursor of geranylgeranylated proteins including small guanosine triphosphatases. In addition to proximal weakness, all but one patient presented with congenital sensorineural hearing loss, and all postpubertal females had primary ovarian insufficiency. Muscle histology was dystrophic, with ultrastructural evidence of autophagic material and large mitochondria in the most severe cases. There was delayed membrane healing after laser injury in patient-derived myogenic cells, and a knock-in mouse of one of the mutations (Y259C) resulted in prenatal lethality. INTERPRETATION: The identification of specific GGPS1 mutations defines the cause of a unique form of muscular dystrophy with hearing loss and ovarian insufficiency and points to a novel pathway for this clinical constellation. ANN NEUROL 2020;88:332-347.


Assuntos
Dimetilaliltranstransferase/genética , Farnesiltranstransferase/genética , Geraniltranstransferase/genética , Perda Auditiva/genética , Distrofias Musculares/genética , Mutação/genética , Insuficiência Ovariana Primária/genética , Adolescente , Adulto , Animais , Feminino , Técnicas de Introdução de Genes/métodos , Perda Auditiva/diagnóstico por imagem , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Distrofias Musculares/diagnóstico por imagem , Linhagem , Insuficiência Ovariana Primária/diagnóstico por imagem , Estrutura Secundária de Proteína , Análise de Sequência de DNA/métodos , Sequenciamento Completo do Exoma/métodos , Adulto Jovem
8.
Patient ; 13(4): 423-434, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32329019

RESUMO

BACKGROUND: In rare diseases such as ryanodine receptor 1-related myopathies (RYR1-RM), health-related quality of life (HRQoL) measures are critically important so clinicians and researchers can better understand what symptoms are most important to participants, with the ultimate goal of finding tangible solutions for them. OBJECTIVES: The main objective of this study was to characterize symptoms in individuals with RYR1-RM to inform future research. A secondary objective of this study was to analyze positive and negative sentiments regarding symptoms and treatment effects post N-acetylcysteine (NAC) administration in individuals with RYR1-RM. METHODS: The study used a mixed-methods design applying methodological triangulation. Qualitative data were collected via semi-structured interviews at three visits to characterize symptoms in individuals with RYR1-RM and to analyze treatment effects. Qualitative data were then transformed into quantitative results to measure the frequency with which each symptom was mentioned by participants. RESULTS: A total of 12 symptoms were identified as areas of interest to participants with RYR1-RM, highlighting fatigue and weakness as key symptoms. Data transformation categorized more than 1000 citations, reporting a greater number of positive comments for postintervention interviews than for baseline and preintervention visits and that NAC group participants stated more positive comments regarding treatment effect than did the placebo group. CONCLUSIONS: We present a comprehensive characterization of symptoms in RYR1-RM and how those symptoms influence HRQoL. Furthermore, the introduction of mixed methods may be a valuable way to better understand patient-centered data in rare diseases to support affected individuals in coping with their symptoms.


Assuntos
Acetilcisteína/uso terapêutico , Doenças Musculares/tratamento farmacológico , Doenças Musculares/genética , Doenças Musculares/fisiopatologia , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Acetilcisteína/administração & dosagem , Acetilcisteína/efeitos adversos , Adaptação Psicológica , Adulto , Criança , Método Duplo-Cego , Fadiga/tratamento farmacológico , Fadiga/fisiopatologia , Feminino , Humanos , Entrevistas como Assunto , Masculino , Pessoa de Meia-Idade , Doenças Musculares/psicologia , Dor/tratamento farmacológico , Dor/fisiopatologia , Qualidade de Vida , Fatores Socioeconômicos
9.
Acta Neuropathol ; 139(6): 1089-1104, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32236737

RESUMO

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.


Assuntos
Cálcio/metabolismo , Doenças Musculares/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Animais , Citoplasma/metabolismo , Humanos , Músculo Esquelético/metabolismo , Doenças Musculares/terapia , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Retículo Sarcoplasmático/metabolismo
10.
Qual Life Res ; 29(8): 2183, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32236775

RESUMO

The article Mixed methods analysis of Health-Related Quality of Life in ambulant individuals affected with RYR1-related myopathies pre-post-N-acetylcysteine therapy, written by Carlos Capella-Peris, Mary M. Cosgrove, Irene C. Chrismer, Magalie Emile-Backer, M. Sonia Razaqyar, Jefrey S. Elliott, Anna Kuo, Paul G. Wakim, Katherine G. Meilleur, was originally published electronically on the publisher's internet portal ( https://doi.org/10.1007/s11136-020-02428-2 ) on 10 February 2020 with open access. With the author(s)' decision to step back from Open Choice, the copyright of the article changed on 1 April 2020 to © Springer Nature Switzerland AG, 2020 and the article is forthwith distributed under the terms of copyright.The original article has been corrected.

11.
Qual Life Res ; 29(6): 1641-1653, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32040747

RESUMO

PURPOSE: To characterize Health-Related Quality of Life (HRQoL) in ambulant individuals with RYR1-RM and to determine if a qualitative PRO tool (subjective self-assessment) complements PROMIS and Neuro-QoL scales to detect changes in HRQoL in ambulant individuals with RYR1-RM post N-acetylcysteine (NAC) treatment. METHODS: The study used a mixed methods research (MMR) design applying methodological triangulation. Qualitative data were collected via semi-structured interviews using open-ended questions. Quantitative data were gathered through PROMIS and Neuro-QoL instruments. Additionally, qualitative data were transformed into quantitative data for subjective self-assessment and frequency analyses. RESULTS: Qualitative results identified five domains and 33 subdomains as areas of interest. The most valuable were the importance of social impacts, the development of several coping strategies, both physical and psychological, and the identification of fatigue and weakness as key symptoms. Data transformation then categorized more than 3100 citations on frequency analyses, globally and by domain, visit, and participant. Regarding quantitative results, there was no clear evidence that any of the three PRO tools captured positive changes as a result of NAC treatment. CONCLUSION: Qualitative results showed a comprehensive characterization of HRQoL in this population based on a symptom/patient-centered approach. These findings will inform future studies. Furthermore, given the similar findings across our multiple methods and endpoints, the introduction of MMR may be a valuable, complementary approach to clinical trials. MMR may be especially useful to incorporate in order to address and follow the FDA's guidance and prioritization on the inclusion of affected individuals' perspectives in clinical trials.


Assuntos
Acetilcisteína/uso terapêutico , Doenças Musculares/psicologia , Qualidade de Vida/psicologia , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Adaptação Psicológica , Adulto , Fadiga/diagnóstico , Feminino , Nível de Saúde , Humanos
12.
Neurology ; 94(13): e1434-e1444, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-31941795

RESUMO

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.


Assuntos
Acetilcisteína/uso terapêutico , Sequestradores de Radicais Livres/uso terapêutico , Doenças Musculares/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Adolescente , Adulto , Criança , Dinoprosta/análogos & derivados , Dinoprosta/urina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Musculares/genética , Doenças Musculares/urina , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Resultado do Tratamento , Teste de Caminhada , Adulto Jovem
13.
Muscle Nerve ; 60(1): 80-87, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31004442

RESUMO

INTRODUCTION: The objective of this study was to obtain a 6-month natural history of motor function performance in individuals with RYR1- related myopathy (RYR1-RM) by using the Motor Function Measure-32 (MFM-32) and graded functional tests (GFT) while facilitating preparation for interventional trials. METHODS: In total, 34 participants completed the MFM-32 and GFTs at baseline and 6-month visits. RESULTS: Motor deficits according to MFM-32 were primarily observed in the standing and transfers domain (D1; mean 71%). Among the GFTs, participants required the most time to ascend/descend stairs (>7.5 s). Functional movement, determined by GFT grades, was strongly correlated with MFM-32 (D1; r ≥ 0.770, P < 0.001). Motor Function Measure-32 and GFT scores did not reflect any change in performance between baseline and 6-month visits. DISCUSSION: The MFM-32 and GFTs detected motor impairment in RYR1-RM, which remained stable over 6 months. Thus, these measures may be suitable for assessing change in motor function in response to therapeutic intervention. Muscle Nerve 60: 80-87, 2019.


Assuntos
Movimento/fisiologia , Miopatias Congênitas Estruturais/fisiopatologia , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Adolescente , Adulto , Criança , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miopatias Congênitas Estruturais/genética , Miopatia da Parte Central/genética , Miopatia da Parte Central/fisiopatologia , Oftalmoplegia/genética , Oftalmoplegia/fisiopatologia , Canal de Liberação de Cálcio do Receptor de Rianodina/deficiência , Adulto Jovem
14.
J Neuromuscul Dis ; 6(1): 133-141, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30714968

RESUMO

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 (n = 37) 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 (n = 18, ICC > 0.80). MFI-20 (n = 37), and FACIT-F (n = 28) also showed good internal consistency (Cronbach's α> 0.80). All MFI-20 subscales, except mental fatigue, and FACIT-F demonstrated evidence of criterion validity when correlated against percent predicted 6MWT distance (MFI-20 n = 37; r = -0.34 to -0.47, all p < 0.05, mental fatigue, r = -0.16, p = 0.35; FACIT-F n = 28, r = 0.41, p = 0.03). This was not the case for percent predicted VO2 peak (all p > 0.05). FBI correlated with MFI-20 general fatigue dimension only (r = -0.35, p = 0.03). 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.


Assuntos
Fadiga/diagnóstico , Doenças Neuromusculares/diagnóstico , Doenças Neuromusculares/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Autorrelato , Acetilcisteína/uso terapêutico , Adolescente , Adulto , Biomarcadores/metabolismo , Criança , Teste de Esforço , Fadiga/tratamento farmacológico , Fadiga/genética , Fadiga/fisiopatologia , Feminino , Seguimentos , Humanos , Masculino , Fármacos Neuromusculares/uso terapêutico , Doenças Neuromusculares/tratamento farmacológico , Doenças Neuromusculares/fisiopatologia , Reprodutibilidade dos Testes , Saliva/metabolismo
15.
Front Neurol ; 10: 1234, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31920904

RESUMO

Introduction: Individuals affected with ryanodine receptor isoform-1-related myopathies (RYR1-RM) commonly experience fatigability in the quadriceps, which may limit physical function and potentially diminish quality of life. Fatigability, in RYR1-RM, results from skeletal muscle injury secondary to dysfunction of the major skeletal muscle Ca++ channel. However, during fatigability testing, affected individuals did not always reach the point of local muscle fatigue as defined by a fatigue index (FATI) at 50% of peak torque. Surakka et al. compared three versions of FATI equations, which vary by the area under the force curve (AUC). By performing this comparison, they were able to determine the optimal equation in individuals with Multiple Sclerosis. Purpose: Using a similar comparison, we sought to identify the optimal FATI equation in the RYR1-RM population. Secondly, because local muscle fatigability might have an impact on independent living, this study also assessed change in local muscle fatigability over a 6-month time frame. Methods: Thirty participants were analyzed from the RYR1-RM natural history study and double-blind, placebo-controlled N-acetylcysteine (NAC) trial, NCT02362425. Twenty-seven had fatigability data, from isometric knee extension and flexion fatigability tests, available for the purpose of establishing a method for predicting FATI at 50% peak torque. For the natural history study, 30 participants were used to assess disease progression of local muscle fatigability achieved during the knee extension fatigability test, and 29 participants for the knee flexion fatigability test. Results: Surakka's equation 1, using the prediction approach, led to the smallest median error, the smallest square-root of uncorrected sum of squares, and the smallest average of the absolute value of the differences. No difference was observed in FATI at 50% peak torque between month 0 and month 6 for extension (p = 0.606) and flexion (p = 0.740). Conclusion: Surakka's equation 1, with the prediction approach, was found to be the most accurate for imputing values when fatigue was not reached during a sustained knee isometric fatigability test in RYR1-RM. Furthermore, when used to assess fatigability-based disease stability, local muscle fatigability, in this RYR1-RM population remained stable.

16.
Neurotherapeutics ; 15(4): 885-899, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30406384

RESUMO

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.


Assuntos
Doenças Musculares , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Animais , Humanos , Doenças Musculares/diagnóstico , Doenças Musculares/genética , Doenças Musculares/terapia , Canal de Liberação de Cálcio do Receptor de Rianodina/genética
17.
J Neurol ; 265(11): 2506-2524, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30155738

RESUMO

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.


Assuntos
Doenças Neuromusculares/genética , Doenças Neuromusculares/fisiopatologia , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Acetilcisteína/uso terapêutico , Adolescente , Adulto , Estudos Transversais , Método Duplo-Cego , Feminino , Estudos de Associação Genética , Variação Genética , Humanos , Masculino , Fármacos Neuromusculares/uso terapêutico , Doenças Neuromusculares/tratamento farmacológico , Doenças Neuromusculares/patologia , Estudos Prospectivos , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Relação Estrutura-Atividade , Adulto Jovem
18.
Orphanet J Rare Dis ; 13(1): 105, 2018 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-29970108

RESUMO

BACKGROUND: RYR1-related Myopathies (RYR1-RM) comprise a group of rare neuromuscular diseases (NMDs) occurring in approximately 1/90000 people in the US pediatric population. RYR1-RM result from pathogenic mutations in the ryanodine receptor isoform-1 (RYR1) gene where consequent RyR1 protein calcium dysregulation leads to impaired excitation-contraction coupling, oxidative and nitrosative stress, and mitochondrial depletion. These physiological deficits perpetuate RyR1 dysfunction causing further muscle injury, muscle weakness, and muscle fatigue. Muscle weakness and fatigue are two primary complaints in patients with RYR1-RM and are major symptoms that limit the ability of individuals to perform activities of daily living. The six-minute walk test (6MWT) is an endurance test with high reliability and validity used to measure walking capacity, disease progression, and more recently, fatigability in NMDs with limited results in RYR1-RM. Therefore, the purpose of our study is to objectively assess disease progression and fatigability in RYR1-RM affected individuals using the 6MWT. We hypothesized that 6MWT distance and fatigability would not change significantly between 0 and 6-month visits in RYR1-RM patients, given the clinically reported stable or slowly progressive nature of the disease. We also hypothesized participants would show fatigability during the 6MWT, given muscle weakness and fatigue are the two primary complaints of affected individuals. RESULTS: As expected, paired t-test analyses revealed no significant difference between total distance traveled (p = .608) or percent change in speed (p = .141) at 0-months compared with the 6-month visit. Fatigability was observed given the decline in speed between the first and last minute of the 6MWT at the 6-month time point (p ≤ .0005,). Although this decline was not significant at baseline, a significant decline in speed from the 1st minute did occur at minutes 2, 3, and 4 during the baseline visit. CONCLUSION: In this RYR1-RM cohort, the 6MWT showed disease stability over a 6-month period but revealed fatigability during the test. Given these results, the 6MWT may be a promising endpoint for evaluating fatigability and therapeutic efficacy in the 6-month treatment phase of our current n-acetylcysteine trial in this population. Improvement post intervention could be attributed to the intervention rather than variability in disease progression. TRIAL REGISTRATION: Clinical Trials.gov, NCT02362425 , Registered 13 February 2015-Prospectively registered.


Assuntos
Doenças Musculares/diagnóstico , Doenças Musculares/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Teste de Caminhada/métodos , Atividades Cotidianas , Adolescente , Adulto , Criança , Progressão da Doença , Fadiga/diagnóstico , Fadiga/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/metabolismo , Adulto Jovem
19.
Front Neurol ; 9: 118, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29556213

RESUMO

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.

20.
Muscle Nerve ; 57(1): 54-60, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28224647

RESUMO

INTRODUCTION: Electrical impedance myography (EIM) is a noninvasive electrophysiological technique that characterizes muscle properties through bioimpedance. We compared EIM measurements to function, strength, and disease severity in a population with congenital muscular dystrophy (CMD). METHODS: Forty-one patients with CMD, either collagen 6 related disorders (COL6-RD; n = 21) or laminin α-2-related disorders (LAMA2-RD; n = 20), and 21 healthy pediatric controls underwent 2 yearly EIM exams. In the CMD cohorts, EIM was compared with functional and strength measurements. RESULTS: Both CMD cohorts exhibited change over time and had correlation with disease severity. The 50-kHZ phase correlated well with function and strength in the COL6-RD cohort but not in the LAMA2-RD cohort. DISCUSSION: EIM is a potentially useful measure in clinical studies with CMD because of its sensitivity to change over a 1-year period and correlation with disease severity. For COL6-RD, there were also functional and strength correlations. Muscle Nerve 57: 54-60, 2018.


Assuntos
Colágeno Tipo VI/genética , Impedância Elétrica , Laminina/genética , Distrofias Musculares/congênito , Distrofias Musculares/genética , Miografia/métodos , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Masculino , Força Muscular , Exame Neurológico/métodos , Corrida , Sensibilidade e Especificidade , Índice de Gravidade de Doença
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