Journal of Neuromuscular Diseases - Volume 9, issue 4

Authors: Biggar, W. Douglas | Skalsky, Andrew | McDonald, Craig M.

Article Type: Review Article

Abstract: Deflazacort and prednisone/prednisolone are the current standard of care for patients with Duchenne muscular dystrophy (DMD) based on evidence that they improve muscle strength, improve timed motor function, delay loss of ambulation, improve pulmonary function, reduce the need for scoliosis surgery, delay onset of cardiomyopathy, and increase survival. Both have been used off-label for many years (choice dependent on patient preference, cost, and geographic location) before FDA approval of deflazacort for DMD in 2017. In this review, we compare deflazacort and prednisone/prednisolone in terms of their key pharmacological features, relative efficacy, and safety profiles in patients with DMD. Differentiating features …include lipid solubility, pharmacokinetics, changes in gene expression profiles, affinity for the mineralocorticoid receptor, and impact on glucose metabolism. Evidence from randomized clinical trials, prospective studies, meta-analyses, and post-hoc analyses suggests that patients receiving deflazacort experience similar or slower rates of functional decline compared with those receiving prednisone/prednisolone. Regarding side effects, weight gain and behavior side effects appear to be greater with prednisone/prednisolone than with deflazacort, whereas bone health, growth parameters, and cataracts appear worse with deflazacort. Show more

Keywords: Deflazacort, duchenne muscular dystrophy, glucocorticoids, prednisone, prednisolone

DOI: 10.3233/JND-210776

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 4, pp. 463-476, 2022

Authors: Audhya, Ivana F. | Cheung, Antoinette | Szabo, Shelagh M. | Flint, Emma | Weihl, Conrad C. | Gooch, Katherine L.

Article Type: Systematic Review

Abstract: Background The impact of age at autosomal recessive limb girdle muscular dystrophy (LGMDR) onset on progression to loss of ambulation (LOA) has not been well established, particularly by subtype. Objectives: To describe the characteristics of patients with adult-, late childhood-, and early childhood-onset LGMDR by subtype and characterize the frequency and timing of LOA. Methods: A systematic review was conducted in MEDLINE, Embase and the Cochrane library. Frequency and timing of LOA in patients with LGMDR1, LGMDR2/Miyoshi myopathy (MM), LGMDR3-6, LGMDR9, and LGMDR12 were synthesized from published data. Results: In 195 studies, 695 (43.4%) …patients had adult-, 532 (33.2%) had late childhood-, and 376 (23.5%) had early childhood-onset of disease across subtypes among those with a reported age at onset (n  = 1,603); distribution of age at onset varied between subtypes. Among patients with LOA (n  = 228), adult-onset disease was uncommon in LGMDR3-6 (14%) and frequent in LGMDR2/MM (42%); LGMDR3-6 cases with LOA primarily had early childhood-onset (74%). Mean (standard deviation [SD]) time to LOA varied between subtypes and was shortest for patients with early childhood-onset LGMDR9 (12.0 [4.9] years, n  = 19) and LGMDR3-6 (12.3 [10.7], n  = 56) and longest for those with late childhood-onset LGMDR2/MM (21.4 [11.5], n  = 36). Conclusions: This review illustrated that patients with early childhood-onset disease tend to have faster progression to LOA than those with late childhood- or adult-onset disease, particularly in LGMDR9. These findings provide a greater understanding of progression to LOA by LGMDR subtype, which may help inform clinical trial design and provide a basis for natural history studies. Show more

Keywords: Muscular dystrophies, limb-girdle, age of onset, disease progression, walking, systematic review

DOI: 10.3233/JND-210771

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 4, pp. 477-492, 2022

Authors: Clemens, Paula R. | Rao, Vamshi K. | Connolly, Anne M. | Harper, Amy D. | Mah, Jean K. | McDonald, Craig M. | Smith, Edward C. | Zaidman, Craig M. | Nakagawa, Tomoyuki | the CINRG DNHS Investigators | Hoffman, Eric P.

Article Type: Research Article

Abstract: Background: Duchenne muscular dystrophy (DMD) is a rare, genetic disease caused by mutations in the DMD gene resulting in an absence of functional dystrophin protein. Viltolarsen, an exon 53 skipping therapy, has been shown to increase endogenous dystrophin levels. Herein, long-term (>2 years) functional outcomes in viltolarsen treated patients were compared to a matched historical control group. Objective: To evaluate long-term efficacy and safety of the anti-sense oligonucleotide viltolarsen in the treatment of patients with DMD amenable to exon 53 skipping therapy. Methods: This trial (NCT03167255) is the extension of a previously published 24-week trial in …North America (NCT02740972) that examined dystrophin levels, timed function tests compared to a matched historical control group (Cooperative International Neuromuscular Research Group Duchenne Natural History Study, CINRG DNHS), and safety in boys 4 to < 10 years (N  = 16) with DMD amenable to exon 53 skipping who were treated with viltolarsen. Both groups were treated with glucocorticoids. All 16 participants elected to enroll in this long-term trial (up to 192 weeks) to continue evaluation of motor function and safety. Results: Time to stand from supine and time to run/walk 10 meters showed stabilization from baseline through week 109 for viltolarsen-treated participants whereas the historical control group showed decline (statistically significant differences for multiple timepoints). Safety was similar to that observed in the previous 24-week trial, which was predominantly mild. There have been no treatment-related serious adverse events and no discontinuations. Conclusions: Based on these results at over 2 years, viltolarsen can be a new treatment option for patients with DMD amenable to exon 53 skipping. Show more

Keywords: Duchenne muscular dystrophy, dystrophin, viltepso, viltolarsen, exon skipping, clinical efficacy

DOI: 10.3233/JND-220811

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 4, pp. 493-501, 2022

Authors: Dowling, James J. | Müller-Felber, Wolfgang | Smith, Barbara K. | Bönnemann, Carsten G. | Kuntz, Nancy L. | Muntoni, Francesco | Servais, Laurent | Alfano, Lindsay N. | Beggs, Alan H. | Bilder, Deborah A. | Blaschek, Astrid | Duong, Tina | Graham, Robert J. | Jain, Minal | Lawlor, Michael W. | Lee, Jun | Coats, Julie | Lilien, Charlotte | Lowes, Linda P. | MacBean, Victoria | Neuhaus, Sarah | Noursalehi, Mojtaba | Pitts, Teresa | Finlay, Caroline | Christensen, Sarah | Rafferty, Gerrard | Seferian, Andreea M. | Tsuchiya, Etsuko | James, Emma S. | Miller, Weston | Sepulveda, Bryan | Vila, Maria Candida | Prasad, Suyash | Rico, Salvador | Shieh, Perry B. | for the INCEPTUS investigators

Article Type: Research Article

Abstract: Background: X-linked myotubular myopathy (XLMTM) is a life-threatening congenital myopathy that, in most cases, is characterized by profound muscle weakness, respiratory failure, need for mechanical ventilation and gastrostomy feeding, and early death. Objective: We aimed to characterize the neuromuscular, respiratory, and extramuscular burden of XLMTM in a prospective, longitudinal study. Methods: Thirty-four participants < 4 years old with XLMTM and receiving ventilator support enrolled in INCEPTUS, a prospective, multicenter, non-interventional study. Disease-related adverse events, respiratory and motor function, feeding, secretions, and quality of life were assessed. Results: During median (range) follow-up of 13.0 (0.5, 32.9) months, …there were 3 deaths (aspiration pneumonia; cardiopulmonary failure; hepatic hemorrhage with peliosis) and 61 serious disease-related events in 20 (59%) participants, mostly respiratory (52 events, 18 participants). Most participants (80%) required permanent invasive ventilation (>16 hours/day); 20% required non-invasive support (6–16 hours/day). Median age at tracheostomy was 3.5 months (95% CI: 2.5, 9.0). Thirty-three participants (97%) required gastrostomy. Thirty-one (91%) participants had histories of hepatic disease and/or prospectively experienced related adverse events or laboratory or imaging abnormalities. CHOP INTEND scores ranged from 19–52 (mean: 35.1). Seven participants (21%) could sit unsupported for≥30 seconds (one later lost this ability); none could pull to stand or walk with or without support. These parameters remained static over time across the INCEPTUS cohort. Conclusions: INCEPTUS confirmed high medical impact, static respiratory, motor and feeding difficulties, and early death in boys with XLMTM. Hepatobiliary disease was identified as an under-recognized comorbidity. There are currently no approved disease-modifying treatments. Show more

Keywords: X-linked myotubular myopathy, centronuclear myopathy, neuromuscular diseases, respiratory failure, ventilators, mechanical, motor disorders

DOI: 10.3233/JND-210781

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 4, pp. 503-516, 2022

Authors: Lewis, Leann | Eichinger, Katy | Dilek, Nuran | Higgs, Kiley | Walker, Michaela | Palmer, David | Cooley, John M. | Johnson, Nicholas | Tawil, Rabi | Statland, Jeffrey

Article Type: Research Article

Abstract: Introduction: In this study, we examined the long-term social and health impacts of the coronavirus disease 2019 (COVID-19) pandemic on people with muscular dystrophy. Methods: We modified our prior COVID-19 Impact Survey to assess impacts from the continuing pandemic using feedback from muscular dystrophy experts, patients, and advocacy group/registry representatives. The survey assessed COVID-19 medical history, and the effects of the pandemic on social aspects, muscle disease, and medical care. We also used the validated 10-item Perceived Stress Scale. The de-identified, electronic survey was distributed to adults with muscular dystrophy via international patient registries and advocacy group websites …from February 8, 2021 to March 22, 2021. Results: Respondents (n = 1243 : 49% Facioscapulohumeral Muscular Dystrophy (FSHD); 43% Myotonic Dystrophy (DM), and 8% Limb-Girdle Muscular Dystrophy (LGMD)) were mostly women and middle-aged (range 18–90 years). Rates of COVID-19 infections were low at 8% with zero deaths. Reported recovery times were also short with only 9% reporting a recovery period greater than eight weeks, and 7% requiring hospitalization with one individual requiring a ventilator. Major challenges reported during the pandemic included stress management, particularly for those with LGMD (27%), and wearing a mask (24%). The majority reported a slight worsening of their disease state. Respondents reported moderate stress levels (stress score = 16.4; range = 0–39), with higher stress levels reported by women and those under age 30 years. Seventy-percent of participants who had telemedicine visits were satisfied with the encounters; however, most reported a preference for in-person visits. Conclusions: People with muscular dystrophy found ways to manage their stress and overcome obstacles during the COVID-19 pandemic. COVID-19 infection rates and medical complications were similar to a general population. Telemedicine visits may have a more permanent role in care. Show more

Keywords: Muscular dystrophy, COVID-19, pandemic, Perceived Stress Scale, telemedicine

DOI: 10.3233/JND-220794

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 4, pp. 517-523, 2022

Authors: Boon, Helena T.M. | Jacobs, Bram | Wouter, van Rheenen | Kamsteeg, Erik-Jan | Kuks, Jan B.M. | Vincent, Angela | Eymard, Bruno | Voermans, Nicol C.

Article Type: Research Article

Abstract: Background: The slow channel syndrome is a rare hereditary disorder caused by a dominant gain-of-function variant in one of the subunits of the acetylcholine receptor at the neuromuscular junction. Patients typically experience axial, limb and particularly extensor finger muscle weakness. Objective: Age at diagnosis is variable and although the long-term prognosis is important for newly diagnosed patients, extensive follow-up studies are rare. We aim to provide answers and perspective for this patient group by presenting an elaborate description of the lifetime follow-up of two slow channel syndrome patients. Methods: We describe 40 years follow-up in two, …genetically confirmed cases (CHRNA1 ; c.866G > T p.(Ser289Ile)(legacy Ser269Ile) and CHRNE ; c.721C > T p.(Leu241Phe)(legacy Leu221Phe) variants). Results: We find that the disease course has a fluctuating pattern and is only mildly progressive. However, hormonal imbalances, (psychological) stress or excessive hot or cold environments are often aggravating factors. Quinidine and fluoxetine are helpful, but ephedrine and salbutamol may also improve symptoms. Conclusion: Slow channel syndrome is mildly progressive with a fluctuating pattern. The observations reported here provide a lifespan perspective and answers to the most pressing questions about prognosis and treatment options for newly diagnosed patients. Show more

Keywords: Slow channel syndrome, myasthenic syndromes, congenital, neuromuscular diseases, retrospective study, follow-up study

DOI: 10.3233/JND-220798

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 4, pp. 525-532, 2022

Authors: Mensch, Alexander | Cordts, Isabell | Scholle, Leila | Joshi, Pushpa Raj | Kleeberg, Kathleen | Emmer, Alexander | Beck-Woedl, Stefanie | Park, Joohyun | Haack, Tobias B. | Stoltenburg-Didinger, Gisela | Zierz, Stephan | Deschauer, Marcus

Article Type: Research Article

Abstract: GFPT1-related congenital myasthenic syndrome (CMS) is characterized by progressive limb girdle weakness, and less prominent involvement of facial, bulbar, or respiratory muscles. While tubular aggregates in muscle biopsy are considered highly indicative in GFPT1-associated CMS, excessive glycogen storage has not been described. Here, we report on three affected siblings with limb-girdle myasthenia due to biallelic pathogenic variants in GFPT1 : the previously reported missense variant c.41G > A (p.Arg14Gln) and the novel truncating variant c.1265_1268del (p.Phe422TrpfsTer26). Patients showed progressive proximal atrophic muscular weakness with respiratory involvement, and a lethal disease course in adulthood. In the diagnostic workup at that time, muscle biopsy …suggested a glycogen storage disease. Initially, Pompe disease was suspected. However, enzymatic activity of acid alpha-glucosidase was normal, and gene panel analysis including 38 genes associated with limb-girdle weakness (GAA included) remained unevocative. Hence, a non-specified glycogen storage myopathy was diagnosed. A decade later, the diagnosis of GFPT1-related CMS was established by genome sequencing. Myopathological reexamination showed pronounced glycogen accumulations, that were exclusively found in denervated muscle fibers. Only single fibers showed very small tubular aggregates, identified in evaluation of serial sections. This family demonstrates how diagnostic pitfalls can be addressed by an integrative approach including broad genetic analysis and re-evaluation of clinical as well as myopathological findings. Show more

Keywords: CMS, LGMD, glycogen storage disease, autophagy, vacuoles

DOI: 10.3233/JND-220822

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 4, pp. 533-541, 2022

Authors: Koeks, Zaıda | Hellebrekers, Danique M.J. | van de Velde, Nienke M. | Alleman, Iris | Spitali, Pietro | van Duyvenvoorde, Hermine A. | Verschuuren, Jan J.G.M. | Hendriksen, Jos G.M. | Niks, Erik H.

Article Type: Research Article

Abstract: Background: In Becker muscular dystrophy evidence for neurocognitive and behavioral comorbidity is evolving. More insight into the extend of these problems is of great importance for early detection and remediation in clinical practice. Objective: In this study we aimed to describe the neurocognitive and behavioral features of a Dutch adult cohort of BMD patients, and to evaluate correlations to motor function outcomes. Methods: 28 adult BMD patients were included. Intelligence, executive functioning, verbal memory and reaction times were assessed cross-sectionally. Additionally, patients completed questionnaires on behavioral and emotional symptoms, psychosocial and executive functions. Results were compared …to normative data and correlated with disease severity as measured by the 10-meter run/walk test and Performance of the Upper Limb version 1.2. Results: 15 patients (53.6%) had a high educational level despite frequent grade repeating (48.3%) during primary or secondary school. Neuropsychological testing revealed that intellectual abilities, verbal memory, processing speed and executive functioning were statistically significant below average, but still within normal range. Regarding outcomes of the behavioral questionnaires, no significant differences were reported compared to the norm population. No relevant correlations with disease severity were found. Conclusions: This cohort of adult BMD patients exhibits minor cognitive impairments and no significant behavioral problems. The lower outcomes on processing speed and verbal memory, combined with the relatively high prevalence of grade repeating during primary and secondary school, implies that these minor impairments played a role in childhood. However, the on average high educational levels suggests that they grow out of their cognitive impairments with ageing. Show more

Keywords: dystrophin, cognition, cognitive dysfunction, intellectual disability, behavior

DOI: 10.3233/JND-210770

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 4, pp. 543-553, 2022

Authors: Naarding, Karin J. | Janssen, Mariska M.H.P. | Boon, Ruben D. | Bank, Paulina J.M. | Matthew, Robert P. | Kurillo, Gregorij | Han, Jay J. | Verschuuren, Jan J.G.M. | de Groot, Imelda J.M. | van der Holst, Menno | Kan, Hermien E. | Niks, Erik H.

Article Type: Research Article

Abstract: Background: Outcome measures for non-ambulant Duchenne muscular dystrophy (DMD) patients are limited, with only the Performance of the Upper Limb (PUL) approved as endpoint for clinical trials. Objective: We assessed four outcome measures based on devices developed for the gaming industry, aiming to overcome disadvantages of observer-dependency and motivation. Methods: Twenty-two non-ambulant DMD patients (range 8.6–24.1 years) and 14 healthy controls (HC; range 9.5–25.4 years) were studied at baseline and 16 patients at 12 months using Leap Motion to quantify wrist/hand active range of motion (aROM) and a Kinect sensor for reached volume with Ability Captured …Through Interactive Video Evaluation (ACTIVE), Functional Workspace (FWS) summed distance to seven upper extremity body points, and trunk compensation (KinectTC). PUL 2.0 was performed in patients only. A stepwise approach assessed quality control, construct validity, reliability, concurrent validity, longitudinal change and patient perception. Results: Leap Motion aROM distinguished patients and HCs for supination, radial deviation and wrist flexion (range p  = 0.006 to <0.001). Reliability was low and the manufacturer’s hand model did not match the sensor’s depth images. ACTIVE differed between patients and HCs (p  < 0.001), correlated with PUL (rho = 0.76), and decreased over time (p  = 0.030) with a standardized response mean (SRM) of –0.61. It was appraised as fun on a 10-point numeric rating scale (median 9/10). PUL decreased over time (p < 0.001) with an SRM of –1.28, and was appraised as fun (median 7/10). FWS summed distance distinguished patients and HCs (p  < 0.001), but reliability in patients was insufficient. KinectTC differed between patients and HCs (p < 0.01), but correlated insufficiently with PUL (rho = –0.69). Conclusions: Only ACTIVE qualified as potential outcome measure in non-ambulant DMD patients, although the SRM was below the commonly used threshold of 0.8. Lack of insight in technological constraints due to intellectual property and software updates made the technology behind these outcome measures a kind of black box that could jeopardize long-term use in clinical development. Show more

Keywords: Muscular dystrophy, duchenne, biomarkers, leap motion, kinect

DOI: 10.3233/JND-210767

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 4, pp. 555-569, 2022

Authors: Khadilkar, Satish Vasant | Halani, Hiral Amrut | Dastur, Rashna | Gaitonde, Pradnya Satish | Oza, Harsh | Hegde, Madhuri

Article Type: Research Article

Abstract: Background: Hereditary muscle disorders are clinically and genetically heterogeneous. Limited information is available on their genetic makeup and their prevalence in India. Objective: To study the genetic basis of prevalent hereditary myopathies. Material and methods: This is a retrospective study conducted at a tertiary care center. The study was approved by the institutional ethics board. The point of the collection was the genetic database. The genetic data of myopathy patients for the period of two and half years (2019 to mid-2021) was evaluated. Those with genetic diagnoses of DMD, FSHD, myotonic dystrophies, mitochondriopathies, and acquired myopathies …were excluded. The main outcome measures were diagnostic yield and the subtype prevalence with their gene variant spectrum. Results: The definitive diagnostic yield of the study was 39% (cases with two pathogenic variants in the disease-causing gene). The major contributing genes were GNE (15%), DYSF (13%), and CAPN3 (7%). Founder genes were documented in Calpainopathy and GNE myopathy. The uncommon myopathies identified were Laminopathy (0.9%), desminopathy (0.9%), and GMPPB-related myopathy (1.9%). Interestingly, a small number of patients showed pathogenic variants in more than one myopathy gene, the multigenic myopathies. Conclusion: This cohort study gives hospital-based information on the prevalent genotypes of myopathies (GNE, Dysferlinopathy, and calpainopathy), founder mutations, and also newly documents the curious occurrence of multigenicity in a small number of myopathies. Show more

Keywords: Hereditary muscle diseases, NGS (Next-generation sequencing), VUS (variant of uncertain significance), founder mutation

DOI: 10.3233/JND-220801

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 4, pp. 571-580, 2022