Journal of Neuromuscular Diseases - Volume 9, issue 2

Authors: Berardo, Andres | Domínguez-González, Cristina | Engelstad, Kristin | Hirano, Michio

Article Type: Review Article

Abstract: Defects in the replication, maintenance, and repair of mitochondrial DNA (mtDNA) constitute a growing and genetically heterogeneous group of mitochondrial disorders. Multiple genes participate in these processes, including thymidine kinase 2 (TK2 ) encoding the mitochondrial matrix protein TK2, a critical component of the mitochondrial nucleotide salvage pathway. TK2 deficiency (TK2d) causes mtDNA depletion, multiple deletions, or both, which manifest predominantly as mitochondrial myopathy. A wide clinical spectrum phenotype includes a severe, rapidly progressive, early onset form (median survival: < 2 years); a less severe childhood-onset form; and a late-onset form with a variably slower rate of progression. Clinical presentation typically …includes progressive weakness of limb, neck, facial, oropharyngeal, and respiratory muscle, whereas limb myopathy with ptosis, ophthalmoparesis, and respiratory involvement is more common in the late-onset form. Deoxynucleoside monophosphates and deoxynucleosides that can bypass the TK2 enzyme defect have been assessed in a mouse model, as well as under open-label compassionate use (expanded access) in TK2d patients, indicating clinical efficacy with a favorable side-effect profile. This treatment is currently undergoing testing in clinical trials intended to support approval in the US and European Union (EU). In the early expanded access program, growth differentiation factor 15 (GDF-15) appears to be a useful biomarker that correlates with therapeutic response. With the advent of a specific treatment and given the high morbidity and mortality associated with TK2d, clinicians need to know how to recognize and diagnose this disorder. Here, we summarize translational research about this rare condition emphasizing clinical aspects. Show more

Keywords: Mitochondrial myopathies, deoxycytidine, thymidine, DNA, mitochondrial, mitochondrial diseases

DOI: 10.3233/JND-210786

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 2, pp. 225-235, 2022

Authors: Ogonowska-Slodownik, Anna | de Lima, Ana Angélica R. | Cordeiro, Luciana | Morgulec-Adamowicz, Natalia | Alonso-Fraile, María | Güeita-Rodríguez, Javier

Article Type: Review Article

Abstract: Background: Aquatic exercise is among the most common physical activity modalities performed by people with disabilities. Objective: The present paper reviews currently-available research on aquatic therapy (AT) for persons with neuromuscular diseases (NMD). Methods: A scoping review of the existing literature was conducted on PubMed, Embase, Medline, Scopus, Web of Science, SPORTdiscus, CINAHL and Lilacs from the earliest date available until October 2020. It follows the methodological framework for conducting a scoping review proposed by the Joanna Briggs Institute. Results: A total of 28 articles were analyzed and the study parameters grouped by the …topography of NMD; most of the studies (n  = 16) addressed myopathies. A considerable increase in the number of studies was found over time, and heterogeneity was identified across and within AT interventions for persons with NMD; hence, to allow more effective interpretation of study results, there is a need to standardize the fundamental parameters and procedures for AT. Conclusions: This scoping review provides a comprehensive outline of available literature; the findings could serve as a starting point for clinical studies on the effects of AT on persons with NMD, and encourage a more coherent approach to their design. Show more

Keywords: Hydrotherapy, muscular dystrophy, myopathy, scoping review, neuromuscular diseases

DOI: 10.3233/JND-210749

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 2, pp. 237-256, 2022

Authors: Oliveira Santos, Miguel | Domingues, Sara | Gromicho, Marta | Pinto, Susana | de Carvalho, Mamede

Article Type: Research Article

Abstract: Background: The impact of SARS-CoV-2 infection among neuromuscular diseases with respiratory involvement, including amyotrophic lateral sclerosis (ALS), is still to be elucidated. Objectives: We aim to characterize the clinical outcome of ALS patients non-invasive ventilated (NIV), following SARS-CoV-2 infection. Methods: We analyzed retrospectively our patients followed regularly at our ALS clinic, from the beginning of the COVID-19 pandemic (middle March 2020) to March 2021. We included patients on NIV with a documented SARS-CoV-2 infection. We recorded demographic and clinical data, including from the acute infectious illness. Results: Three men with spinal-onset ALS are described, …mean age of onset was 55±9.1 years (45–61), and mean disease duration was 17.5±15.9 months (6.1–41). All of them were wheelchair-bounded, with a mean ALSFRS-R of 15.3±0.6 (15–16). One patient used NIV 15 hours/day, 2 between 4 to 7 hours/day, and all used assisted coughing twice daily. None had coexistent comorbidities. They were managed for SARS-CoV-2 infection as outpatients with fluticasone, bronchodilators, azithromycin and increasing frequency of assisted coughing. Supplemental oxygen (mean of 2 liters per minute) was needed in two patients, and one required NIV also during the daytime. Total recovery from SARS-CoV-2 infection was observed in all, despite being in an advanced stage of their disease, with severe respiratory involvement. Conclusions: Prompt medical treatment is recommended for ALS patients with severe disease infected by SARS-CoV-2. Show more

Keywords: Amyotrophic lateral sclerosis, SARS-CoV-2, COVID-19, non-invasive ventilation, respiratory complications

DOI: 10.3233/JND-210733

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 2, pp. 257-259, 2022

Authors: Chawla, Tanushree | Preethish-Kumar, Veeramani | Polavarapu, Kiran | Vengalil, Seena | Bardhan, Mainak | Puri, RatnaDua | Verma, Jyotsna | Christopher, Rita | Supriya, Manjunath | Nashi, Saraswati | Prasad, Chandrajit | Nadeesh, Bevinahalli | Nalini, Atchayaram

Article Type: Research Article

Abstract: Background: Late onset Pompe disease (LOPD) is rare and generally manifests predominantly as progressive limb girdle muscle weakness. It is linked to the pathogenic mutations in GAA gene, which leads to glycogen accumulation in various tissues. Materials and methods: We describe the unusual clinical, biochemical, histopathological and genetic characteristics of 5 cases of LOPD. Results: The first case had progressive anterior horn cell like disease (AHCD) that evolved later to classical limb girdle syndrome and respiratory failure, the second patient had rigid spine syndrome with gastrointestinal manifestations, the third had limb girdle weakness superimposed with episodic …prolonged worsening and respiratory failure, the fourth had large fibre sensory neuropathy without primary muscle involvement and the fifth presented with classical limb girdle muscle weakness. Two homozygous missense mutations c.1461C > A (p.Phe487Leu) and c.1082C > T (p.Pro361Leu) in the GAA gene were identified in case 1 and 2 respectively. Case 3 was compound heterozygous with inframe c.1935_1940del (p.Val646_Cys647del) and an intronic splice effecting variant c.-32-13T > G. Compound heterozygous missense variants c.971C > T (p.Pro324Leu) and c.794G > A (p.Ser265Asn) were identified in case 4. Case 5 had a frameshift insertion c.1396dupG (p.Val466GlyfsTer40) and a synonymous splice affecting variant c.546G > T(p.Thr182=). Conclusion: We are describing for the first time from India on LOPD with unusual phenotypes identified. A high degree of clinical suspicion and diagnosing rare phenotypes of Pompe disease is imperative to consider early initiation of Enzyme Replacement Therapy (ERT). Show more

Keywords: Pompe disease, late-onset Pompe disease, LOPD, Rigid spine, peripheral neuropathy, anterior horn cell

DOI: 10.3233/JND-210728

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 2, pp. 261-273, 2022

Authors: Zelikovich, Aaron S. | Joslin, Benjamin C. | Casey, Patricia | McNally, Elizabeth M. | Ajroud-Driss, Senda

Article Type: Research Article

Abstract: Background: Glucocorticoid steroids are standard of care in Duchenne Muscular Dystrophy (DMD) to slow disease course. Use of glucocorticoids in other muscular dystrophies, including Becker (BMD) and Limb Girdle (LGMD), has been less explored. Recently, preclinical studies conducted in DMD and LGMD mouse models showed once-weekly prednisone was associated with improved muscle performance without activation of muscle atrophy genes. Objective: To determine safety and tolerability of once-weekly prednisone in patients with LGMD and BMD. Methods: We conducted an open label, exploratory single center study of of once-weekly prednisone at 0.75–1 mg/Kg in LGMD (n  = 19) and BMD …(n  = 1) (mean age 35, range 18–60). The LGMD participants represented multiple different LGMD subtypes, and the study included ambulatory and non-ambulatory participants. Participants were assessed at baseline and 24 weeks for vital signs, blood biomarkers, and for patient-reported side effects. As secondary endpoints, functional muscle testing and body composition were measured. Results: Over the 24-week study, there were no significant changes in blood pressure, HgbA1C, or lipid profiles. We observed a reduction in serum creatine kinase over the study interval. Whole body DEXA scanning suggested a possible increase in lean mass and a reduction in adiposity. Functional measures suggested trends in improved muscle performance. Conclusions: In this single center, open label pilot study, once-weekly prednisone was safe and well tolerated. Additional investigation of once-weekly prednisone in a larger cohort and for a longer period of time is warranted. Show more

Keywords: Muscular dystrophy, prednisone, Limb-Girdle Muscular Dystrophy, Becker Muscular Dystrophy, creatine kinase, neuromuscular diseases

DOI: 10.3233/JND-210741

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 2, pp. 275-287, 2022

Authors: Willcocks, Rebecca J. | Barnard, Alison M. | Wortman, Ryan J. | Senesac, Claudia R. | Lott, Donovan J. | Harrington, Ann T. | Zilke, Kirsten L. | Forbes, Sean C. | Rooney, William D. | Wang, Dah-Jyuu | Finanger, Erika L. | Tennekoon, Gihan I. | Daniels, Michael J. | Triplett, William T. | Walter, Glenn A. | Vandenborne, Krista

Article Type: Research Article

Abstract: Background: Joint contractures are common in boys and men with Duchenne muscular dystrophy (DMD), and management of contractures is an important part of care. The optimal methods to prevent and treat contractures are controversial, and the natural history of contracture development is understudied in glucocorticoid treated individuals at joints beyond the ankle. Objective: To describe the development of contractures over time in a large cohort of individuals with DMD in relation to ambulatory ability, functional performance, and muscle quality measured using magnetic resonance imaging (MRI) and spectroscopy (MRS). Methods: In this longitudinal study, …range of motion (ROM) was measured annually at the hip, knee, and ankle, and at the elbow, forearm, and wrist at a subset of visits. Ambulatory function (10 meter walk/run and 6 minute walk test) and MR-determined muscle quality (transverse relaxation time (T2 ) and fat fraction) were measured at each visit. Results: In 178 boys with DMD, contracture prevalence and severity increased with age. Among ambulatory participants, more severe contractures (defined as greater loss of ROM) were significantly associated with worse ambulatory function, and across all participants, more severe contractures significantly associated with higher MRI T2 or MRS FF (ρ: 0.40–0.61 in the lower extremity; 0.20–0.47 in the upper extremity). Agonist/antagonist differences in MRI T2 were not strong predictors of ROM. Conclusions: Contracture severity increases with disease progression (increasing age and muscle involvement and decreasing functional ability), but is only moderately predicted by muscle fatty infiltration and MRI T2 , suggesting that other changes in the muscle, tendon, or joint contribute meaningfully to contracture formation in DMD. Show more

Keywords: Range of motion, transverse relaxation time, heel cord, 10 m walk/run, 6 minute walk test, magnetic resonance imaging

DOI: 10.3233/JND-210731

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 2, pp. 289-302, 2022

Authors: Haruyama, Koshiro | Kawakami, Michiyuki

Article Type: Research Article

Abstract: Background: Few studies have examined falls and their predictors in patients with amyotrophic lateral sclerosis (ALS). Objective: The aim of this study was to survey fall incidence and to identify variables predicting the presence or absence of falls occurring within 3 months after discharge of patients with ALS from hospital. Methods: The following variables were evaluated in 14 patients with ALS: timed up and go test (TUG), functional reach test, 10-m comfortable gait speed, single-leg stance time, manual muscle test (MMT) scores for the lower limb, total modified Ashworth scale score for the lower limbs, fear …of falling, and pull test score. The primary outcome variable was the occurrence of a fall within 3 months after discharge. The fall rate was calculated based on fall record forms. The specific circumstances of each fall were also recorded. Univariate and multiple regression analyses were used to identify fall predictors. Results: Seven of the 14 ALS patients (50%) experienced a fall within 3 months. Five fallers reported experiencing a fall that had caused injury, and three reported experiencing a fall that had required a hospital visit. Univariate logistic regression analysis identified TUG time, gait speed and MMT of the ankle dorsiflexors as factors associated with falls (p  = 0.02–0.04). Multiple linear regression analysis of fall numbers identified age and TUG time as predictor models (p  = 0.03). Conclusion: TUG time and MMT of ankle dorsiflexors may help predict falls in ALS patients. Validation studies in larger cohorts are needed. Show more

Keywords: Falls, amyotrophic lateral sclerosis, timed up and go test, ankle dorsiflexion, assessment

DOI: 10.3233/JND-210730

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 2, pp. 303-310, 2022

Authors: Parent, Audrey | Ballaz, Laurent | Samadi, Bahare | Vocos, Maria | Comtois, Alain Steve | Pouliot-Laforte, Annie

Article Type: Research Article

Abstract: Background: Myotonic dystrophy type 1 (DM1) is characterized by progressive and predominantly distal muscle atrophy and myotonia. Gait and balance impairments, resulting in falls, are frequently reported in this population. However, the extent to which individuals with DM1 rely more on a specific sensory system for balance than asymptomatic individuals (AI) is unknown. Objective: Evaluate postural control performance in individuals with DM1 and its dependence on vision compared to AI. Methods: 20 participants with DM1, divided into two groups based on their diagnosis, i.e. adult and congenital phenotype, and 12 AI participants were recruited. Quiet standing …postural control was assessed in two visual conditions: eyes-open and eyes-closed. The outcomes measures were: center of pressure (CoP), mean velocity, CoP range of displacement in anteroposterior and mediolateral axis, and the 95% confidence ellipse’s surface. Friedman and Kruskal-Wallis analysis of variance were used to compare outcomes between conditions and groups, respectively. Results: Significant group effect and condition effect were observed on postural control performance. No significant difference was observed between the two DM1 groups. The significant differences observed between the AI group and the two DM1 groups in the eyes-open condition were also observed in the eyes-closed condition. Conclusions: The result revealed poorer postural control performance in people with DM1 compared to AI. The DM1 group also showed similar decrease in performance than AI in eyes-closed condition, suggesting no excessive visual dependency. Show more

Keywords: Myotonic dystrophy, steinert disease, balance, postural control, standing position

DOI: 10.3233/JND-210639

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 2, pp. 311-320, 2022

Authors: Buckon, Cathleen E. | Sienko, Susan E. | Fowler, Eileen G. | Bagley, Anita M. | Staudt, Loretta A. | Sison-Williamson, Mitell | Heberer, Kent R. | McDonald, Craig M. | Sussman, Michael D.

Article Type: Research Article

Abstract: Background: Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder, that is characterized by progressive muscle degeneration and loss of ambulation between 7–13 years of age. Novel pharmacological agents targeting the genetic defects and disease mechanisms are becoming available; however, corticosteroid (CS) therapy remains the standard of care. Objective: The purpose of this longitudinal study was to elucidate the effect of CS therapy on the rate of muscle strength and gross motor skill decline in boys with DMD and assess the sensitivity of selected outcome measures. Methods: Eighty-four ambulatory boys with DMD …(49–180 months), 70 on CS, 14 corticosteroid naïve (NCS), participated in this 8-year multi-site study. Outcomes included; isokinetic dynamometry, the Standing (STD) and Walking/Running/jumping (WRJ) dimensions of the Gross Motor Function Measure (GMFM), and Timed Function Tests (TFTs). Nonlinear mixed modeling procedures determined the rate of change with age and the influence of steroids. Results: Despite CS therapy the rate of decline in strength with age was significant in all muscle groups assessed. CS therapy significantly slowed decline in knee extensor strength, as the NCS group declined at 3x the rate of the CS group. Concurrently, WRJ skills declined in the NCS group at twice the rate of the CS group. 4-stair climb and 10 meter walk/run performance was superior in the boys on CS therapy. Conclusion: CS therapy slowed the rate of muscle strength decline and afforded longer retention of select gross motor skills in boys on CS compared to boys who were NCS. Isokinetic dynamometry, Walk/Run/Jump skills, and select TFTs may prove informative in assessing the efficacy of new therapeutics in ambulatory boys with DMD. Show more

Keywords: Muscle strength, motor function, Duchenne muscular dystrophy, lower extremity, corticosteroids

DOI: 10.3233/JND-210704

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 2, pp. 321-334, 2022

Authors: Servais, Laurent | Yen, Karl | Guridi, Maitea | Lukawy, Jacek | Vissière, David | Strijbos, Paul

Article Type: Article Commentary

Abstract: In 2019, stride velocity 95th centile (SV95C) became the first wearable-derived digital clinical outcome assessment (COA) qualified by the European Medicines Agency (EMA) for use as a secondary endpoint in trials for Duchenne muscular dystrophy. SV95C was approved via the EMA’s qualification pathway for novel methodologies for medicine development, which is a voluntary procedure for assessing the regulatory acceptability of innovative methods used in pharmaceutical research and development. SV95C is an objective, real-world digital ambulation measure of peak performance, representing the speed of the fastest strides taken by the wearer over a recording period of 180 hours. SV95C is correlated …with traditional clinic-based assessments of motor function and has greater sensitivity to clinical change over 6 months than other wearable-derived stride variables, for example, median stride length or velocity. SV95C overcomes many limitations of episodic, clinic-based motor function testing, allowing the assessment of ambulation ability between clinic visits and under free-living conditions. Here we highlight considerations and challenges in developing SV95C using evidence generated by a high-performance wearable sensor. We also provide a commentary of the device’s technical capabilities, which were a determining factor in the regulatory approval of SV95C. This article aims to provide insights into the methods employed, and the challenges faced, during the regulatory approval process for researchers developing new digital tools for patients with diseases that affect motor function. Show more

Keywords: Biomarkers, clinical trial, drug approval, drug development, gait, gait analysis, movement, motor activity, neuromuscular diseases, wearable electronic devices, walking

DOI: 10.3233/JND-210743

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 2, pp. 335-346, 2022