Journal of Neuromuscular Diseases - Volume 10, issue 4

Authors: Fischer, Ryan | Porter, Katherine | Donovan, Joanne M. | Scavina, Mena T. | Armstrong, Niki | Denger, Brian | Hasham, Shabir | Peay, Holly

Article Type: Research Article

Abstract: Background: Corticosteroids are recommended to all people with Duchenne as standard of care; patient experience data is important to guide corticosteroid decision making and as a comparator for new treatment options. Objective: This study assesses patient and caregiver-reported benefits and side effects from corticosteroids to treat Duchenne muscular dystrophy, their importance, and satisfaction. Methods: Using one-on-one interviews (n  = 28) and an online survey (n  = 236), parents and adults with Duchenne reported corticosteroid benefits and side effects rated as both experienced and important. Results: Benefits to breathing, heart function, arm strength, slowing progression of weakness, …and getting around were rated as particularly important, regardless of ambulatory status. Important side effects included increased fracture risk, unwanted weight gain, and diabetes/prediabetes. Parents rated behavior issues and adults rated delayed puberty as having high importance. Being ambulatory was independently associated with reporting more net benefit (p  = 0.02). For side effects, parent scores were significantly higher than adult score (p  = 0.02). Corticosteroid type was not significant. Participants were, overall, satisfied with corticosteroids (means ranging from 6.2 to 7.7 on a scale of 0–10), with no significant differences based on corticosteroid type. Conclusions: Overall, most participants were satisfied with the use of corticosteroids. While a range of side effects were rated as important and relatively common, individuals using corticosteroids and their caregivers indicate that benefits outweigh the side effects. Qualitative data indicate that high acceptability is influenced by lack of treatment alternatives. Patient experience data on use of corticosteroids in Duchenne may be relevant to drug development, regulatory assessment of new treatments, and to families making decisions about corticosteroid use. Show more

Keywords: Steroids, corticosteroids, Duchenne, satisfaction, standard of care, side effects

DOI: 10.3233/JND-221617

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 4, pp. 593-613, 2023

Authors: Unnikrishnan, Gopikrishnan | Polavarapu, Kiran | Bardhan, Mainak | Nashi, Saraswati | Vengalil, Seena | Preethish-Kumar, Veeramani | Valasani, Ravi Kiran | Huddar, Akshata | Nishadham, Vikas | Nandeesh, Bevinahalli Nanjegowda | Nalini, Atchayaram

Article Type: Research Article

Abstract: Background: The phenotypic spectrum of Fukutin-related protein (FKRP ) mutations is highly variable and comprises of limb girdle muscular dystrophy (LGMD) R9 (previously LGMD 2I) and FKRP related congenital muscular dystrophies. Objective: To identify the distinct genotype phenotype pattern in Indian patients with FKRP gene mutations. Methods: We retrospectively reviewed the case files of patients with muscular dystrophy having a genetically confirmed FKRP mutation. All patients had undergone genetic testing using next-generation sequencing. Results: Our patients included five males and four females presenting between 1.5 years and seven years of age …(median age - 3 years). The initial symptom was a delayed acquisition of gross motor developmental milestones in seven patients and recurrent falls and poor sucking in one patient each. Two patients had a language delay, with both having abnormalities on the brain MRI. Macroglossia, scapular winging, and facial weakness were noted in one, three and four patients respectively. Calf muscle hypertrophy was seen in eight patients and ankle contractures in six. At the last follow-up, three patients had lost ambulation (median age - 7 years; range 6.5–9 years) and three patients had not attained independent ambulation. Creatine kinase levels ranged between 2793 and 32,396 U/L (mean 12,120 U/L). A common mutation - c.1343C>T was noted in 5 patients in our cohort. Additionally, four novel mutations were identified. Overall, six patients had an LGMD R9 phenotype, and three had a congenital muscular dystrophy phenotype. Conclusion: Patients with FKRP mutations can have varied presentations. A Duchenne-like phenotype was the most commonly encountered pattern in our cohort, with c.1343C>T being the most common mutation Show more

Keywords: FKRP, muscular dystrophy, LGMD, congenital muscular dystrophies

DOI: 10.3233/JND-221618

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 4, pp. 615-626, 2023

Authors: Sarasate, Mikel | González, Nuria | Córdoba-Izquierdo, Ana | Prats, Enric | Gonzalez-Moro, Jose Miguel Rodriguez | Martí, Sergi | Lujan, Manel | Calle, Myriam | Antón, Antonio | Povedano, Mónica | Farrero, Eva

Article Type: Research Article

Abstract: Background and objective: Forced vital capacity (FVC) less than 50% of predicted is one of the main parameters used for Non-Invasive Ventilation (NIV) initiation in Amyotrophic Lateral Sclerosis (ALS). Recent studies suggest that higher values of FVC could be considered as a threshold. The aim of this study is to evaluate whether early use of NIV improves the prognosis of ALS patients compared with standard initiation. Methods: This is a randomized, parallel, multicenter, open-label, controlled clinical trial, with recruitment at the ALS outpatient multidisciplinary units of six Spanish hospitals. Patients were included when their FVC reached the 75% …threshold and were randomized by computer, stratifying by center in an allocation ratio of 1:1 to Early NIV (FVC below 75%) or Standard NIV (FVC below 50%) initiation. The primary outcome was time to death or tracheostomy. Trial registration number ClinicalTrials.gov: NCT01641965. Results: Between May 2012 and June 2014, 42 patients were randomized to two groups, 20 to Early NIV and 22 to Standard NIV initiation. We found differences in survival in favor of the intervention group: an incidence of mortality (2.68 [1.87–5.50] vs. 3.33 [1.34–4.80] person-months) and a median survival (25.2 vs. 19.4 months), although without reaching statistical significance (p  = 0.267). Conclusions: This trial did not reach the primary endpoint of survival; nevertheless, it is the first Randomized Controlled Trial (RCT) to demonstrate the benefits of early NIV in slowing the decline of respiratory muscle strength and reducing adverse events. Although not all the results reached statistical significance, all the analyzed data favor early NIV. In addition, this study demonstrates good tolerance and compliance with early NIV without quality of sleep impairment. These data reinforce the early respiratory evaluation of ALS patients and NIV initiation with an FVC of around 75%. Show more

Keywords: ALS, Early NIV, survival, respiratory insufficiency, respiratory complications

DOI: 10.3233/JND-221658

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 4, pp. 627-637, 2023

Authors: Dunaway Young, Sally | McGrattan, Katlyn | Johnson, Emily | van der Heul, Marise | Duong, Tina | Bakke, Merete | Werlauff, Ulla | Pasternak, Amy | Cattaneo, Camilla | Hoffman, Katie | Fanelli, Lavinia | Breaks, Anne | Allison, Kristen | Baranello, Giovanni | Finkel, Richard | Coratti, Giorgia | Lofra, Robert Muni

Article Type: Research Article

Abstract: Background: Progressive weakness can affect bulbar muscles in individuals with moderate to severe forms of spinal muscular atrophy (SMA). The paucity of standardized, valid bulbar assessments capturing clinically significant deficits in SMA impedes the ability to monitor function, facilitate intervention, or detect treatment response. Objective: To fill this void, an international multidisciplinary team gathered to develop an agreed upon consensus-derived assessment of bulbar function in SMA for inter-professional administration to enhance our ability to monitor disease progression, support clinical management, and evaluate treatment effects. Methods: Fifty-six international clinicians experienced in SMA were invited and engaged using …the Delphi method over multiple rounds of web-based surveys to establish consensus. Results: Serial virtual meetings occurred with 42 clinicians (21 speech and language therapists, 11 physical therapists, 5 neurologists, 4 occupational therapists, and 1 dentist). Seventy-two validated assessments of bulbar function were identified for potential relevance to individuals with SMA (32 accessible objective, 11 inaccessible objective, 29 patient-reported outcomes). Delphi survey rounds (n  = 11, 15, 15) achieved consensus on individual items with relevance and wording discussed. Key aspects of bulbar function identified included: oral intake status, oral facial structure and motor strength, swallowing physiology, voice & speech, and fatigability. Conclusions: Multidisciplinary clinicians with expertise in bulbar function and SMA used Delphi methodology to reach consensus on assessments/items considered relevant for SMA across all age groups. Future steps include piloting the new scale moving towards validation/reliability. This work supports the advancement of assessing bulbar function in children and adults with SMA by a variety of professionals. Show more

Keywords: Spinal muscular atrophy, bulbar function, outcome measures, deglutition, voice, speech, swallowing

DOI: 10.3233/JND-221672

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 4, pp. 639-652, 2023

Authors: Trifunov, Selena | Natera-de Benito, Daniel | Carrera-García, Laura | Codina, Anna | Expósito-Escudero, Jesica | Ortez, Carlos | Medina, Julita | Torres Alcala, Soraya | Bernal, Sara | Alias, Laura | Badosa, Carmen | Balsells, Sol | Alcolea, Daniel | Nascimento, Andres | Jimenez-Mallebrera, Cecilia

Article Type: Research Article

Abstract: Background: Three therapeutic strategies have radically changed the therapeutic scenario for spinal muscular atrophy (SMA). However, therapeutic response differs between individuals. There is a need to identify biomarkers to further assess therapeutic response and to better understand which variables determine the extent of response. Methods: We conducted a study using an optimized digital droplet PCR-based method for the ultra-sensitive detection of SMN transcript in serum EVs from SMA 2 individuals treated with nusinersen over 14 months. In parallel, we investigated levels of serum and CSF neurofilament heavy chain (pNF-H) in the same cohort. Results: Expression of …flSMN transcript in EVs of SMA 2 individuals prior to nusinersen was lower than in controls (0.40 vs 2.79 copies/ul; p  < 0.05) and increased after 14 months of nusinersen (0.40 vs 1.11 copies/ul; p  < 0.05). The increase in flSMN with nusinersen was significantly higher in younger individuals (p  < 0.05). Serum pNF-h was higher in non-treated individuals with SMA 2 than in controls (230.72 vs 22.88 pg/ml; p  < 0.05) and decreased with nusinersen (45.72 pg/ml at 6 months, 39.02 pg/ml at 14 months). CSF pNF-h in SMA 2 individuals also decreased with nusinersen (248.04 pg/ml prior to treatment, 197.10 pg/dl at 2 months, 104.43 pg/dl at 6 months, 131.03 pg/dl at 14 months). Conclusions: We identified an increase of flSMN transcript in serum EVs of SMA 2 individuals treated with nusinersen that was more pronounced in the younger individuals. Our results indicate that flSMN transcript expression in serum EVs is a possible biomarker in SMA to predict or monitor the response to treatment. Show more

Keywords: Biomarkers, cerebrospinal fluid, nusinersen, response predictors, serum, spinal muscular atrophy

DOI: 10.3233/JND-230012

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 4, pp. 653-665, 2023

Authors: Chen, Pin-Shiuan | Chao, Chi-Chao | Tsai, Li-Kai | Huang, Hsin-Yi | Chien, Yin-Hsiu | Huang, Pei-Hsin | Hwu, Wuh-Liang | Hsieh, Sung-Tsang | Lee, Ni-Chung | Hsueh, Hsueh-Wen | Yang, Chih-Chao

Article Type: Research Article

Abstract: Background: Whole-exome sequencing (WES) facilitates the diagnosis of hereditary neuromuscular disorders. To achieve an accurate diagnosis, physicians should interpret the genetic report carefully along with clinical information and examinations. We described our experience with (1) clinical validation in patients with variants found using WES and (2) a diagnostic approach for those with negative findings from WES. Methods: WES was performed on patients with the clinical impression of hereditary neuromuscular disorders. Information on clinical manifestations, neurological examination, electrodiagnostic studies, histopathology of muscle and nerve, and laboratory tests were collected. Results: Forty-one patients (Male/Female: 18/23, age of onset: …34.5±15.9) accepted WES and were categorized into four scenarios: (1) patients with a positive WES result, (2) patients with an inconclusive WES result but supporting clinical data, (3) negative findings from WES, but a final diagnosis after further work-up, and (4) undetermined etiology from WES and in further work-ups. The yield rate of the initial WES was 63.4% (26/41). Among these, seventeen patients had positive WES result, while the other nine patients had inconclusive WES result but supporting clinical data. Notably, in the fifteen patients with negative findings from WES, four patients (26.7%) achieved a diagnosis after further workup: tumor-induced osteomalacia, metabolic myopathy with pathogenic variants in mitochondrial DNA, microsatellite expansion disease, and vasculitis-related neuropathy. The etiologies remained undetermined in eleven patients (myopathy: 7, neuropathy: 4) after WES and further workup. Conclusions: It is essential to design genotype-guided molecular studies to correlate the identified variants with their clinical features. For patients who had negative findings from WES, acquired diseases, mitochondrial DNA disorders and microsatellite expansion diseases should be considered. Show more

Keywords: Whole-exome sequencing, neuromuscular disorders, myopathy, neuropathy, motor neuron disease

DOI: 10.3233/JND-230013

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 4, pp. 667-684, 2023

Authors: Connolly, Anne M. | Zaidman, Craig M. | Brandsema, John F. | Phan, Han C. | Tian, Cuixia | Zhang, Xueping | Li, Jack | Eisner, Mark D. | Carrier, Ewa

Article Type: Research Article

Abstract: BACKGROUND: Duchenne muscular dystrophy (DMD) is a neuromuscular disease stemming from dystrophin gene mutations. Lack of dystrophin leads to progressive muscle damage and replacement of muscle with fibrotic and adipose tissue. Pamrevlumab (FG-3019), a fully human monoclonal antibody that binds to connective tissue growth factor (CTGF), is in Phase III development for treatment of DMD and other diseases. METHODS: MISSION (Study 079; NCT02606136) was an open-label, Phase II, single-arm trial of pamrevlumab in 21 non-ambulatory patients with DMD (aged≥12 years, receiving corticosteroids) who received 35-mg/kg intravenous infusions every 2 weeks for 2 years. The primary endpoint was change …from baseline in percent predicted forced vital capacity (ppFVC). Secondary endpoints included other pulmonary function tests, upper limb function and strength assessments, and changes in upper arm fat and fibrosis scores on magnetic resonance imaging. RESULTS: Fifteen patients completed the trial. Annual change from baseline (SE) in ppFVC was –4.2 (0.7) (95% CI –5.5, –2.8). Rate of decline in ppFVC in pamrevlumab-treated patients was slower than observed in historical published trials of non-ambulatory patients. MISSION participants experienced slower-than-anticipated muscle function declines compared with natural history and historical published trials of non-ambulatory patients with DMD. Pamrevlumab was well-tolerated. Treatment-emergent adverse events were mild to moderate, and none led to study discontinuation. CONCLUSIONS: nti-CTGF therapy with pamrevlumab represents a potential treatment for DMD. The lack of internal control group limits the results. Show more

Keywords: Clinical trial, connective tissue growth factor, Duchenne muscular dystrophy, percent predicted forced vital capacity, grip strength, monoclonal antibody, pamrevlumab

DOI: 10.3233/JND-230019

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 4, pp. 685-699, 2023

Authors: Joosten, Isis B.T. | Fuchs, Cas J. | Beelen, Milou | Plasqui, Guy | van Loon, Luc J.C. | Faber, Catharina G.

Article Type: Research Article

Abstract: Background: Myotonic dystrophy type 1 (DM1) patients are at risk for metabolic abnormalities and commonly experience overweight and obesity. Possibly, weight issues result from lowered resting energy expenditure (EE) and impaired muscle oxidative metabolism. Objectives: This study aims to assess EE, body composition, and muscle oxidative capacity in patients with DM1 compared to age-, sex- and BMI-matched controls. Methods: A prospective case control study was conducted including 15 DM1 patients and 15 matched controls. Participants underwent state-of-the-art methodologies including 24 h whole room calorimetry, doubly labeled water and accelerometer analysis under 15-days of free-living conditions, muscle biopsy, …full body magnetic resonance imaging (MRI), dual-energy x-ray absorptiometry (DEXA), computed tomography (CT) upper leg, and cardiopulmonary exercise testing. Results: Fat ratio determined by full body MRI was significantly higher in DM1 patients (56 [49–62] %) compared to healthy controls (44 [37–52] % ; p  = 0.027). Resting EE did not differ between groups (1948 [1742–2146] vs (2001 [1853–2425>] kcal/24 h, respectively; p  = 0.466). In contrast, total EE was 23% lower in DM1 patients (2162 [1794–2494] vs 2814 [2424–3310] kcal/24 h; p  = 0.027). Also, DM1 patients had 63% less steps (3090 [2263–5063] vs 8283 [6855–11485] steps/24 h; p  = 0.003) and a significantly lower VO2 peak (22 [17–24] vs 33 [26–39] mL/min/kg; p  = 0.003) compared to the healthy controls. Muscle biopsy citrate synthase activity did not differ between groups (15.4 [13.3–20.0] vs 20.1 [16.6–25.8] μM/g/min, respectively; p  = 0.449). Conclusions: Resting EE does not differ between DM1 patients and healthy, matched controls when assessed under standardized circumstances. However, under free living conditions, total EE is substantially reduced in DM1 patients due to a lower physical activity level. The sedentary lifestyle of DM1 patients seems responsible for the undesirable changes in body composition and aerobic capacity. Show more

Keywords: Myotonic dystrophy, energy expenditure, body composition, physical activity

DOI: 10.3233/JND-230036

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 4, pp. 701-712, 2023

Authors: Wennberg, Alexandra | Lenzoni, Sabrina | Turcano, Pierpaolo | Casagrande, Elena | Caumo, Luca | Sorarú, Gianni | Pegoraro, Elena | Semenza, Carlo

Article Type: Short Communication

Abstract: Sleep quality and its association with cognition has been widely studied in some neurodegenerative diseases, but less is known about this association in spinal muscular atrophy (SMA). In adult SMA (n  = 21) patients and age-matched controls (n  = 23), we assessed subjectively measured sleep quality and daytime somnolence. Cognition was assessed with a multi-domain neuropsychological battery. Further, we investigated the association between clinical functional scores and sleep questionnaire scores. Among SMA patients, better motor and limb function was associated with better subjective sleep quality (p ’s< 0.05). Clinicians should consider sleep quality in patient care and future studies are needed to better …understand these relationships. Show more

Keywords: Spinal muscular atrophy, neuromuscular disease, sleep quality, cognition

DOI: 10.3233/JND-221627

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 4, pp. 713-717, 2023

Authors: Machetanz, Gerrit | Grziwotz, Marc | Semmler, Luisa | Maier, Mathias | Maegerlein, Christian | Deschauer, Marcus

Article Type: Case Report

Abstract:  In patients with spinal muscular atrophy (SMA) headache after intrathecal administration of nusinersen is usually attributed to post-lumbar puncture syndrome. However, lumbar puncture opening pressure (LOP) has also been reported to be increased in children with SMA, both before and after treatment with nusinersen, although symptoms associated with increased LOP were not observed. We report to our knowledge the first case of symptomatic intracranial hypertension in an adult SMA patient. This 21-year-old man suffered from headache and vomiting followed by visual disturbances after the 12th injection of nusinersen. Bilateral papilledema was recognized ophthalmologically. MRI of the head showed signs of …intracranial hypertension and additionally arachnoid cysts but not hydrocephalus. Symptoms resolved after 8 weeks of treatment with repeated lumbar punctures and acetazolamide. This case raises the possibility of intracranial hypertension as a complication of nusinersen therapy although arachnoid cysts represent another risk factor for intracranial hypertension. We recommend that patients suffering from headache after nusinersen injections should not only be questioned and examined for symptoms suggestive of post-lumbar puncture syndrome, but also intracranial hypertension. Show more

Keywords: Spinal muscular atrophy, nusinersen, antisense oligonucleotides, intracranial hypertension, arachnoid cysts

DOI: 10.3233/JND-230032

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 4, pp. 719-725, 2023