Aquatic Therapy for Persons with Neuromuscular Diseases – A Scoping Review

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 aquatic therapy. 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.

Static Postural Control Deficits in Adults with Myotonic Dystrophy Type 1, Steinert Disease

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.

Stride Velocity 95th Centile: Insights into Gaining Regulatory Qualification of the First Wearable-Derived Digital Endpoint for use in Duchenne Muscular Dystrophy Trials

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.

Clinical Tests for Predicting Fallers Among Ambulatory Patients with Amyotrophic Lateral Sclerosis: A Preliminary Cohort Study

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.

A Longitudinal Study of Quantitative Muscle Strength and Functional Motor Ability in Ambulatory Boys with Duchenne Muscular Dystrophy

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.

[CASE REPORT] Homozygous N-terminal missense variant in PLEKHG5 associated with intermediate CMT: a case report

Mutations in PLEKHG5, a pleckstrin homology domain containing member of the GEF family, are associated with distal spinal muscular atrophy and intermediate Charcot-Marie-Tooth disease. Here, we describe an isolated case with distal intermediate neuropathy with scapular winging. By whole exome sequencing, we identified the homozygous PLEKHG5 Arg97Gln missense mutation, located in the N-terminal region of the protein. This mutation resides between a zinc-finger motif and a RBD domain, involved in binding rnd3, a RhoA effector protein. We conclude that based on the characteristic phenotype presented by the patient and the supportive genetic findings, the PLEKHG5 mutation is the causative variant.

Impact of SARS-CoV-2 Infection Among Non-Invasive Ventilated ALS Patients

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.

Late Onset Pompe Disease with Novel Mutations and Atypical Phenotypes

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).

Biomarkers for C9orf7-ALS in Symptomatic and Pre-symptomatic Patients: State-of-the-art in the New Era of Clinical Trials

The development of new possible treatments for C9orf72-related ALS and the possibility of early identification of subjects genetically at risk of developing the disease is creating a critical need for biomarkers to track neurodegeneration that could be used as outcome measures in clinical trials. Current candidate biomarkers in C9orf72-ALS include neuropsychology tests, imaging, electrophysiology as well as different circulating biomarkers. Neuropsychology tests show early executive and verbal function involvement both in symptomatic and asymptomatic mutation carriers. At brain MRI, C9orf72-ALS patients present diffuse white and grey matter degeneration, which are already identified up to 20 years before symptom onset and that seem to be slowly progressive over time, while regions of altered connectivity at fMRI and of hypometabolism at [18F]FDG PET have been described as well. At the same time, spinal cord MRI has also shown progressive decrease of FA in the cortico-spinal tract over time. On the side of wet biomarkers, neurofilament proteins are increased both in the CSF and serum just before symptom onset and tend to slowly increase over time, while poly(GP) protein can be detected in the CSF and probably used as target engagement marker in clinical trials.