Journal of Neuromuscular Diseases - Volume 9, issue 6

Authors: Landfeldt, Erik

Article Type: Review Article

Abstract: Highly efficacious, potentially curative gene therapies holds immense clinical promise, but also present complex challenges. At the time of regulatory approval and health technology assessment (HTA), evidence of efficacy and safety of gene therapies is often uncertain. In addition, research, development, and manufacturing costs, small pools of eligible patients, and the fact that many gene therapies are administered only once means that they frequently are associated with very high “one-off” price points. Although only a limited number of products have been brought to market globally, hundreds of clinical trials of gene therapies, including several of monogenetic neuromuscular diseases, are currently …ongoing. Over time, as more and more conditions become amendable to gene therapy, the number of transformative, high-cost treatments is likely to increase considerably. For these reasons, concerns have been raised regarding the suitability of current health policy systems, including HTA frameworks, in ensuring appropriate access to these therapeutic innovations while simultaneously safeguarding value for taxpayers’ money, as well as affordability and sustainability. This review provides a summary overview of current challenges and future perspectives of gene therapies for neuromuscular diseases from a health economic point of view. Show more

Keywords: Genetic therapy, neuromuscular diseases, technology assessment, biomedical, muscular atrophy, spinal; muscular dystrophy, duchenne

DOI: 10.3233/JND-221540

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 6, pp. 675-688, 2022

Authors: Szabo, Shelagh M. | Klimchak, Alexa C. | Qian, Christina | Iannaccone, Susan | Popoff, Evan | Gooch, Katherine L.

Article Type: Research Article

Abstract: Background: Data on the clinical course of Duchenne muscular dystrophy (DMD) exist from well-characterized clinical cohorts but estimates from real-world populations are fewer. Objective: The objective was to estimate the prevalence of key clinical milestones by age, among real-world commercially-insured DMD patients in the United States. Methods: MarketScan claims (2013–2018) were used to identify males with DMD. The percentages with wheelchair use or experiencing scoliosis, neurologic/neuropsychiatric involvement, cardiomyopathy, and respiratory involvement were tabulated; as were the median (interquartile range [IQR]) ages at first observed occurrence within the claims data. Results: Among DMD patients (n … = 1,964), the median (IQR) baseline age was 15 (9–21) years, and median follow-up was 1.7 years. Wheelchair use was observed in 55% of those aged 8 to 13 years at cohort entry; scoliosis, among 38% of those 8 to 10 and 52% of those 11 to 13 years; neurologic/neuropsychiatric involvement, among 41–43% of those 8 to 13 years; respiratory involvement, among 45% of those 14 to 19 years; and cardiomyopathy, among 68% of those 14 to 16 and 58% of those 17 to 19 years. Conclusions: The prevalence of key clinical milestones across ages was broadly consistent with published findings. Variability in estimates reflect clinical heterogeneity; these contemporary estimates from real-world data help characterize clinical outcomes in DMD. Show more

Keywords: DMD, claims, real-world, clinical outcomes

DOI: 10.3233/JND-220816

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 6, pp. 689-699, 2022

Authors: Dietvorst, Carmen A.W. | Bot, Daphne | van der Holst, Menno | Niks, Erik H.

Article Type: Research Article

Abstract: Background: Overweight is a common problem in Duchenne muscular dystrophy (DMD) and is associated with reduced mobility and quality of life. The influence of nutritional intake on (over)weight is unclear. Objective: To investigate weight and energy and macronutrients intake compared to age-specific requirements in DMD patients (4–18 years). Methods: We assessed weight and body mass index (BMI) and the amount of energy (kcal/day) and macronutrients based on self-reported nutrition diaries. Nutritional intake was compared to requirements for 3 age-groups according to the Dutch Healthy Diet Guideline (4–8/9–13/14–18 years) using a student’s t -test, and relations with …age and BMI were investigated by means of Pearson’s correlations. Results: Forty-eight patients participated, 22 ambulatory, median age 10.8 years. The majority used corticosteroids (N = 41). Overweight (BMI z-score > 2.07) was present in 19 patients; 6% (4–8 years), 73% (9–13 years) and 47% (14–18 years). Overweight was more common in non-ambulatory (61.6%) than ambulatory patients (13.6%). Patients aged 4–8 received 290 kcal/day more than required (p  < 0.001). Patients aged 9–13 received 349 kcal/day (p  = 0.005) less than required. Overall, intake of fibre, nuts, meat/fish/eggs/legumes and dairy was lower than recommended (p  < 0.05). The difference between energy intake versus requirement correlated moderately to age (r  = –0.549, p  < 0.001) and BMI (r  = –0.562, p  < 0.001). Conclusions: Overweight was found especially in patients aged 9–18 even though they received less energy than required. Younger patients (4–8) had good weight but consumed more energy than required. All patients did not consume enough fibre, nuts, meat/fish/eggs/legumes and dairy. Limiting energy and increasing fibre/protein intake at an early age may prevent overweight at a later age. Show more

Keywords: Duchenne muscular dystrophy, dietary intake, nutritional intake, body mass index, body weight

DOI: 10.3233/JND-220796

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 6, pp. 701-711, 2022

Authors: Duong, Tina | Kishnani, Priya S. | An Haack, Kristina | Foster, Meredith C. | Gibson, James B. | Wilson, Catherine | Hahn, Si Houn | Hillman, Richard | Kronn, David | Leslie, Nancy D. | Peña, Loren D.M. | Sparks, Susan E. | Stockton, David W. | Tanpaiboon, Pranoot | Day, John W.

Article Type: Research Article

Abstract: Background: ADVANCE (NCT01526785) presented an opportunity to obtain a more nuanced understanding of motor function changes in treatment-experienced children with Pompe disease receiving 4000L-production-scale alglucosidase alfa for 52 weeks. Objective: To estimate minimal detectable change (MDC) and effect size on Gross Motor Function Measure-88 (GMFM-88) after 52 weeks of 4000L alglucosidase alfa (complete data N  =  90). Methods: The GMFM-88 mean total % score changes, MDC, and effect size were analyzed post hoc by Pompe Motor Function Level at enrollment, age groups at enrollment, and fraction of life on pre-study 160L-production-scale alglucosidase alfa. …Results: Overall, participants aged < 2 years surpassed MDC at Week 52 (change [mean±standard deviation] 21.1±14.1, MDC range 5.7–13.3, effect size 1.1), whereas participants aged≥2 years did not attain this (change –0.9±15.3, MDC range 10.8–25.2, effect size –0.03). In participants aged < 2 years, improvements surpassed the MDC for walkers (change 17.1±13.3, MDC range 3.0–6.9, effect size 1.7), supported standers (change 35.2±18.0, MDC range 5.9–13.7, effect size 1.8) and sitters (change 24.1±12.1, MDC range 2.6–6.2, effect size 2.7). Age-independent MDC ranges were only attained by walkers (change 7.7±12.3, MDC range 6.4–15.0, effect size 0.4) and sitters (change 9.9±17.2, MDC range 3.3–7.7, effect size 0.9). Conclusions: These first GMFM-88 minimal-detectable-change estimates for alglucosidase alfa-treated Pompe disease offer utility for monitoring motor skills. Trial registration: ClinicalTrials.gov; NCT01526785; Registered 6 February 2012; https://clinicaltrials.gov/ct2/show/NCT01526785 Show more

Keywords: Alglucosidase alfa, infantile-onset Pompe disease, late-onset Pompe disease, Gross Motor Function Measure-88, minimal detectable change, Gross Motor Function Classification System, Pompe Motor Function History

DOI: 10.3233/JND-210784

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 6, pp. 713-730, 2022

Authors: Raymond, Kateri | Gagnon, Cynthia | Levasseur, Mélanie

Article Type: Research Article

Abstract: Background: Myotonic dystrophy type 1 (DM1) is the most prevalent adult form of neuromuscular disorders, for which a decrease of participation with age is known. However, little is known about facilitators and barriers to participation, especially from the perspective of both patients and caregivers. Objective: This study explored and explained changes in participation post-diagnosis with myotonic dystrophy type 1 from the perspective of six adults, their relatives and nurse case managers. Methods: A multiple case study was carried out with these triads (n  =  6) using semi-structured individual interviews, medical charts, and a participation patient-reported outcome …measure. The six cases were built around three women and three men (age: 40–56 years; disease duration: 19–39 years). Their “relatives” were mainly family members. Nurse case managers had done annual follow-ups with all the adults for approximately ten years. Changes in participation were characterized generally by: 1) heterogeneity, 2) insidious increase in restrictions, and more specifically by: 3) redesigning accomplishment, 4) progressive social isolation, 5) restrictions in life-space mobility, and 6) increasingly sedentary activities. Results: Important facilitators of participation were the adult’s resilience, highly meaningful activities, social support, living arrangement, and willingness to use technical aids. Barriers were mostly related to symptoms and a precarious social network, and were affected by misfit and potential syndemic interactions between personal (e.g., comorbidities) and environmental (e.g., stigma) factors. Conclusion: This study identified key facilitators and barriers and their underlying processes, which should be integrated into the evaluation and intervention framework to optimize participation over time. Show more

Keywords: Activities of daily living, environment, neuromuscular diseases, qualitative research, rehabilitation, social participation, myotonic dystrophy, social isolation

DOI: 10.3233/JND-210780

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 6, pp. 731-755, 2022

Authors: Counterman, Kevin J. | Fatovic, Kathy | Good, Daniel C. | Martin, Ann S. | Dasgupta, Sonali | Anziska, Yaacov

Article Type: Research Article

Abstract: Background: Duchenne muscular dystrophy (DMD) is an X-linked recessive neuromuscular disorder resulting from loss of dystrophin. In addition to its role in muscle, isoforms of dystrophin are expressed in different cell types of the brain, and DMD has been linked to language delays, behavioral abnormalities and learning disabilities. Objective: To determine whether disruption of specific DMD isoforms, age, corticosteroid use, ambulation status, or country are associated with behavioral and/or learning concerns in DMD. Methods: De-identified data were collected from the Duchenne Registry from 2007–2019. Females, patients with BMD, and those without genetic testing reports were …excluded from the cohort. For the genetic analysis, patients were divided into four subgroups based on the location of their mutation and the predicted isoforms affected. Bivariate analysis was conducted using chi-square for categorical variables. Two multivariate logistic regressions were used to assess independent associations with behavioral and learning concerns, respectively, and to estimate the effect size of each variable. Results: DMD mutations disrupting expression of Dp140 and Dp71 were associated with a higher likelihood of reported behavioral and learning concerns. Corticosteroid use, categorical age, and country were other factors associated with behavior and learning concerns. Conclusion: This data adds to our current understanding of DMD isoforms, their mutational consequence and impact on behavior and learning. Show more

Keywords: Duchenne muscular dystrophy, genetics, behavior, mutation, epidemiology

DOI: 10.3233/JND-220821

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 6, pp. 757-764, 2022

Authors: van den Bersselaar, L.R. | Gubbels, M.H.M. | Jungbluth, H. | Schouten, M.I. | van der Kooi, A.J. | Quinlivan, R. | Scheffer, G.J. | Riazi, S. | Snoeck, M.M.J. | Voermans, N.C.

Article Type: Research Article

Abstract: Background: Patients with neuromuscular disorders are at increased risk of suffering perioperative complications. Current knowledge concerning this topic is based on small retrospective studies and expert opinion. Therefore, an individualized multidisciplinary approach to perioperative anaesthesia planning is invaluable to anticipate difficulties and to optimize outcomes. Objective: To evaluate current practice regarding preoperative counselling and perioperative care of neuromuscular patients, with the aim to facilitate standardization and improvement of perioperative care for neuromuscular patients. Methods: A questionnaire-based cross-sectional, observational study was conducted between July, 1st 2020 and December, 31st , 2020 in Dutch anaesthesia, neurology and …clinical genetics departments. Main outcome measures were 1.) frequency of consultation requests for neuromuscular patients prior to surgery, 2.) current practice, educational activities and departmental approach to this topic and 3.) preoperative counselling of neuromuscular patients. Results: A total of 83 departments participated. Consultations for a neuromuscular patient scheduled for anaesthesia were requested from anaesthesia and neurology department only infrequently. Local guidelines concerning perioperative care of neuromuscular patients were available in 36.4% of the participating departments. Quality of specific training for residents and staff anaesthetists/neurologists covering perioperative care of neuromuscular patients was rated as ‘very good’ or ‘good’ by 42.9%. Neuromuscular patients scheduled for surgery were ‘always’ or ‘often’ discussed in multidisciplinary meetings involving anaesthesiologists and neurologists in 20.8% of the participating departments. Conclusion: Perioperative care for neuromuscular patients in the Netherlands is highly variable and might benefit from guidelines, education of health care professionals and multidisciplinary meetings between anaesthesiologists and neurologists on a regular basis. Show more

Keywords: Anaesthesia, genetics, malignant hyperthermia, myopathy, perioperative care, preoperative counselling, RYR1

DOI: 10.3233/JND-221512

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 6, pp. 765-775, 2022

Authors: Matteson, Jamie | Wu, Cindy H. | Mathur, Deepika | Tang, Hao | Sciortino, Stanley | Feuchtbaum, Lisa | Bishop, Tracey | Sharma, Sudhir C. | Neogi, Partha | Fitzgibbon, Ina | Olney, Richard S.

Article Type: Research Article

Abstract: Background: Universal spinal muscular atrophy (SMA) newborn screening was implemented in California on June 24, 2020. Objective: We describe California’s experience with the first 18 months of SMA newborn screening, including our assay methodology, timeliness of screening and follow-up milestones, and clinical and epidemiological outcomes observed. Methods: Dried blood spots are screened for SMA using multiplex real time polymerase chain reaction (RT-PCR) to detect deletions of exon 7 in the survival of motor neuron 1 (SMN1 ) gene. Short-term follow-up data is collected from clinical staff via an online data collection tool. Results: In …the first 18 months, 628,791 newborns from California’s diverse population were tested for SMA. Thirty-four screened positive and were confirmed to have the disorder. Infants were referred, diagnosed, and treated at a median of 8, 12, and 33 days of life, respectively. Nearly all infants received the desired treatment modality, and 62% received treatment while still asymptomatic. Conclusions: SMA newborn screening is a highly sensitive and specific test which identifies infants with SMA early when treatment is most effective. Even with newborn screening’s success in facilitating early intervention, there is still work to be done to expedite treatment, especially for infants with the most severe form of the disease. Show more

Keywords: Spinal muscular atrophy, newborn screening, SMN1, SMN2, dried blood spot

DOI: 10.3233/JND-221561

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 6, pp. 777-785, 2022

Authors: Elbashir, Haitham | Fathalla, Waseem | Mundada, Vivek | Iqbal, Mehtab | Al Tawari, Asmaa A | Chandratre, Saleel | Bastaki, Laila | Romany, Ingy | Ismayl, Omar | Abou Tayoun, Ahmad

Article Type: Research Article

Abstract: Background: Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder which leads to progressive muscle degeneration and weakness. Most patients die from cardiac or respiratory failure. Gene transfer therapy offers a promising approach to treating this disorder. Objective: Given the genetic disease burden, family size, and the high consanguinity rates in the Middle East, our objective is to address current practices and challenges of DMD patient care within two countries in this region, namely the United Arab Emirates and Kuwait, and to outline readiness for gene therapy. Methods: An expert panel meeting was held to discuss …the DMD patient journey, disease awareness, current management of DMD, challenges faced and recommendations for improvement. Opportunities and challenges for gene therapy in both countries were also deliberated. A pre-meeting survey was conducted, and the results were used to guide the discussion during the meeting. Results: DMD awareness is poor resulting in a delay in referral and diagnosis of patients. Awareness and education initiatives, along with an interconnected referral system could improve early diagnosis. Genetic testing is available in both countries although coverage varies. Corticosteroid therapy is the standard of care however there is often a delay in treatment initiation. Patients with DMD should be diagnosed and managed by a multi-disciplinary team in centers of excellence for neuromuscular disorders. Key success factors to support the introduction of gene therapy include education and training, timely and accessible genetic testing and resolution of reimbursement and cost issues. Conclusion: There are many challenges facing the management of DMD patients in the United Arab Emirates and Kuwait and most likely other countries within the Middle East. Successful introduction of gene therapy to treat DMD will require careful planning, education, capacity building and prioritization of core initiatives. Show more

Keywords: Duchenne muscular dystrophy, genetic disorders, multidisciplinary care, muscle degeneration, gene therapy

DOI: 10.3233/JND-221528

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 6, pp. 787-801, 2022

Authors: Oliwa, Agata | Joseph, Shuko | Millar, Eoghan | Horrocks, Iain | Penman, Dawn | Baptista, Julia | Cullup, Thomas | Constantinou, Panayiotis | Heuchan, Anne-Marie | Hamilton, Ruth | Longman, Cheryl

Article Type: Case Report

Abstract: This case report describes a girl who presented antenatal arthrogryposis and postnatal hypotonia, generalized and respiratory weakness, joint deformities particularly affecting the lower limbs and poor swallow. By 5 months, cataracts, abnormal electroretinograms, visual evoked potentials (VEPs) and global developmental impairments were recognized. No causative variants were identified on targeted gene panels. After her unexpected death at 11 months, gene-agnostic trio whole exome sequencing revealed a likely pathogenic de novo BICD2 missense variant, NM_001003800.1, c.593T>C, p.(Leu198Pro), confirming the diagnosis of spinal muscular atrophy lower extremity predominant type 2 (SMA-LED2). We propose that cataract, abnormal electroretinograms and VEPs are novel …features of SMA-LED2. Show more

Keywords: Arthrogryposis, cataract, BICD2, SMA-LED2, spinal muscular atrophy lower extremity predominant

DOI: 10.3233/JND-220818

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 6, pp. 803-808, 2022