Journal of Neuromuscular Diseases - Volume 8, issue 6

Authors: Aoki, Yoshitsugu | Wood, Matthew J.A.

Article Type: Review Article

Abstract: Research and drug development concerning rare diseases are at the cutting edge of scientific technology. To date, over 7,000 rare diseases have been identified. Despite their individual rarity, 1 in 10 individuals worldwide is affected by a rare condition. For the majority of these diseases, there is no treatment, much less cure; therefore, there is an urgent need for new therapies to extend and improve quality of life for persons who suffer from them. Here we focus specifically on rare neuromuscular diseases. Currently, genetic medicines using short antisense oligonucleotides (ASO) or small interfering ribonucleic acids that target RNA transcripts are …achieving spectacular success in treating these diseases. For Duchenne muscular dystrophy (DMD), the state-of-the-art is an exon skipping therapy using an antisense oligonucleotide, which is prototypical of advanced precision medicines. Very recently, golodirsen and viltolarsen, for treatment of DMD patients amenable to skipping exon 53, have been approved by regulatory agencies in the USA and Japan, respectively. Here, we review scientific and clinical progress in developing new oligonucleotide therapeutics for selected rare neuromuscular diseases, discussing their efficacy and limitations. Show more

Keywords: Rare disease, ultra-rare disease, neuromuscular disease, duchenne muscular dystrophy, antisense oligonucleotides, ASO, orphan drug, RNase H1-dependent, steric-blocking, splice switching, siRNA, genetic medicine and precision medicine

DOI: 10.3233/JND-200560

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 6, pp. 869-884, 2021

Authors: Tiet, May Yung | Lin, Zhiyuan | Gao, Fei | Jennings, Matthew James | Horvath, Rita

Article Type: Research Article

Abstract: Background: Leigh syndrome (LS) is the most frequent paediatric clinical presentation of mitochondrial disease. The clinical phenotype of LS is highly heterogeneous. Though historically the treatment for LS is largely supportive, new treatments are on the horizon. Due to the rarity of LS, large-scale interventional studies are scarce, limiting dissemination of information of therapeutic options to the wider scientific and clinical community. Objective: We conducted a systematic review of pharmacological therapies of LS following the guidelines for FAIR-compliant datasets. Methods: We searched for interventional studies within Clincialtrials.gov and European Clinical trials databases. Randomised controlled trials, observational …studies, case reports and case series formed part of a wider MEDLINE search. Results: Of the 1,193 studies initially identified, 157 met our inclusion criteria, of which 104 were carried over into our final analysis. Treatments for LS included very few interventional trials using EPI-743 and cysteamine bitartrate. Wider literature searches identified case series and reports of treatments repleting glutathione stores, reduction of oxidative stress and restoration of oxidative phosphorylation. Conclusions: Though interventional randomised controlled trials have begun for LS, the majority of evidence remains in case reports and case series for a number of treatable genes, encoding cofactors or transporter proteins of the mitochondria. Our findings will form part of the international expert-led Solve-RD efforts to assist clinicians initiating treatments in patients with treatable variants of LS. Show more

DOI: 10.3233/JND-210715

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 6, pp. 885-897, 2021

Authors: Quinlivan, R. | Messer, B. | Murphy, P. | Astin, R. | Mukherjee, R. | Khan, J. | Emmanuel, A. | Wong, S.C. | Kulshresha, R. | Willis, T. | Pattni, J. | Willis, D. | Morgan, A. | Savvatis, K. | Keen, R. | Bourke, J. | Marini Bettolo, C. | Hewamadduma, C. | on behalf of the ANSN

Article Type: Research Article

Abstract: There are growing numbers of adults with Duchenne Muscular Dystrophy living well into their fourth decade. These patients have complex medical needs that to date have not been addressed in the International standards of care. We sought to create a consensus based standard of care through a series of multi-disciplinary workshops with specialists from a wide range of clinical areas: Neurology, Cardiology, Respiratory Medicine, Gastroenterology, Endocrinology, Palliative Care Medicine, Rehabilitation, Renal, Anaesthetics and Clinical Psychology. Detailed reports of evidence reviewed and the consensus building process were produced following each workshop and condensed into this final document which was approved by …all members of the Adult North Star Network including service users. The aim of this document is to provide a framework to improve clinical services and multi-disciplinary care for adults living with Duchenne Muscular Dystrophy. Show more

Keywords: Duchenne Muscular Dystrophy, non-invasive ventilation, multi-disciplinary care

DOI: 10.3233/JND-200609

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 6, pp. 899-926, 2021

Authors: Heutinck, Lotte | Houwen-van Opstal, Saskia L.S. | Krom, Yvonne D. | Niks, Erik H. | Verschuuren, Jan J.G.M. | Jansen, Merel | de Groot, Imelda J.M.

Article Type: Research Article

Abstract: Background and objective: To optimize care for patients with DMD, it is essential to know to what extent current care complies with the recommended monitoring frequencies suggested by the DMD care considerations. The objective of this study was to investigate the current care for patients with DMD in the Netherlands and to what extent the care complies with the international care considerations. Methods: A cross-sectional questionnaire was carried out among the Dutch DMD patients and caregivers about the patients’ functional and health status, visits to healthcare professionals, clinical tests and assessments, therapy, medication use and access to medical …aids and devices. Compliance to guidelines was defined by comparing the frequency of visits to health care providers and clinical tests with the recommended frequencies derived from the care considerations of 2010. Results: Eighty-four participants completed the questionnaire. The majority of participants met the recommended visit frequencies to a neuromuscular specialist and cardiologist. Compliance was suboptimal for respiratory assessments in the non-ambulatory phase, monitoring of side effects of corticosteroid use and neuromuscular assessments. Disease specific information supply was perceived as sufficient and participants were satisfied with the received care. Conclusions: This study identifies areas in which compliance is lacking. Countries, such as the Netherlands, working according to a shared care system require easy and low-threshold communication between health care centers and a clear division of roles and responsibilities to reach optimal compliance. In the Netherlands the Duchenne Center Netherlands has the coordinating role. Show more

Keywords: Duchenne muscular dystrophy, guideline, compliance, shared care

DOI: 10.3233/JND-210670

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 6, pp. 927-938, 2021

Authors: Duong, Tina | Canbek, Jennifer | Birkmeier, Marisa | Nelson, Leslie | Siener, Catherine | Fernandez-Fernandez, Alicia | Henricson, Erik | McDonald, Craig M. | Gordish-Dressman, Heather | CINRG-DNHS Investigators

Article Type: Research Article

Abstract: Background: Duchenne muscular dystrophy (DMD) is a rare x-linked recessive genetic disorder affecting 1 in every 5000–10000 [1, 2 ]. This disease leads to a variable but progressive sequential pattern of muscle weakness that eventually causes loss of important functional milestones such as the ability to walk. With promising drugs in development to ameliorate the effects of muscle weakness, these treatments must be associated with a clinically meaningful functional change. Objective: The objective of this analysis is to determine both distribution, minimal detectable change (MDC), and anchor-based, minimal clinically important difference, (MCID) of 12 month change values in …standardized time function tests (TFT) used to monitor disease progression in DMD. Method: This is a retrospective analysis of prospectively collected data from a multi-center prospective natural history study with the Cooperative International Neuromuscular Research Group (CINRG). This study calculated MDC and MCID values for 3 commonly used timed function tests typically used to monitor disease progression; supine to stand (STS), 10 meter walk/run (10MWT), and 4 stair climb (4SC). MDC used standard error of measurement (SEM) while MCID measurements used the Vignos scale as an anchor to determine clinical change in functional status. Results: All 3 TFT were significantly important clinical endpoints to detect MDC and MCID changes. MDC and MCID 12 month changes were significant in 10MWT (–0.138, –0.212), Supine to Stand (–0.026, –0.023) and 4 stair climb (–0.034, –0.035) with an effect size greater or close to 0.2. Conclusion: The 3 TFT are clinically meaningful endpoints used to establish change in DMD. MCID values were higher than MDC values indicating that an anchor-based approach using Vignos as a clinically meaningful loss of lower extremity abilities is appropriate to assess change in boys with DMD. Show more

Keywords: Duchenne muscular dystrophy, MCID, time function tests

DOI: 10.3233/JND-210646

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 6, pp. 939-948, 2021

Authors: Rehmann, R. | Schneider-Gold, C. | Froeling, M. | Güttsches, A.K. | Rohm, M. | Forsting, J. | Vorgerd, M. | Schlaffke, L.

Article Type: Research Article

Abstract: Background: Myotonic Dystrophies type 1 and type 2 are hereditary myopathies with dystrophic muscle degeneration in varying degrees. Differences in muscle diffusion between both diseases have not been evaluated yet. Objective: To evaluate the ability of muscle diffusion tensor imaging (mDTI) and Dixon fat-quantification to distinguish between Myotonic Dystrophy (DM) type 1 and type 2 and if both diseases show distinct muscle involvement patterns. Methods: We evaluated 6 thigh and 7 calf muscles (both legs) of 10 DM 1, 13 DM 2 and 28 healthy controls (HC) with diffusion tensor imaging, T1w and mDixonquant sequences in …a 3T MRI scanner. The quantitative mDTI-values axial diffusivity (λ 1 ), mean diffusivity (MD), radial diffusivity (RD) and fractional anisotropy (FA) as well as fat-fraction were analysed. CTG-triplet repeat-length of DM 1 patients was correlated with diffusion metrics and fat-fraction. Results: mDTI showed significant differences between DM 1 and DM 2 vs. healthy controls in diffusion parameters of the thigh (all p  < 0.001) except for FA (p  = 0.0521 / 0.8337). In calf muscles mDTI showed significant differences between DM 1 and DM 2 patients (all p  < 0.0001) as well as between DM 1 patients and controls (all p  = 0.0001). Thigh muscles had a significant higher fat-fraction in both groups vs. controls (p  < 0.05). There was no correlation of CTG triplet length with mDTI values and fat-fraction. Discussion: mDTI reveals specific changes of the diffusion parameters and fat-fraction in muscles of DM 1 and DM 2 patients. Thus, the quantitative MRI methods presented in this study provide a powerful tool in differential diagnosis and follow-up of DM 1 and DM 2, however, the data must be validated in larger studies. Show more

Keywords: Myotonic Dystrophy type 1, Myotonic Dystrophy type 2, diffusion tensor imaging, muscle, skeletal, magnetic resonance imaging

DOI: 10.3233/JND-210660

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 6, pp. 949-962, 2021

Authors: Greene, Ericka | Thonhoff, Jason | John, Blessy S. | Rosenfield, David B. | Helekar, Santosh A.

Article Type: Research Article

Abstract: Background: Repeated neuromuscular electrical stimulation in type 1 Myotonic Dystrophy (DM1) has previously been shown to cause an increase in strength and a decrease in hyperexcitability of the tibialis anterior muscle. Objective: In this proof-of-principle study our objective was to test the hypothesis that noninvasive repetitive transcranial magnetic stimulation of the primary motor cortex (M1) with a new portable wearable multifocal stimulator causes improvement in muscle function in DM1 patients. Methods: We performed repetitive stimulation of M1, localized by magnetic resonance imaging, with a newly developed Transcranial Rotating Permanent Magnet Stimulator (TRPMS). Using a randomized within-patient …placebo-controlled double-blind TRPMS protocol, we performed unilateral active stimulation along with contralateral sham stimulation every weekday for two weeks in 6 adults. Methods for evaluation of muscle function involved electromyography (EMG), hand dynamometry and clinical assessment using the Medical Research Council scale. Results: All participants tolerated the treatment well. While there were no significant changes clinically, EMG showed significant improvement in nerve stimulus-evoked compound muscle action potential amplitude of the first dorsal interosseous muscle and a similar but non-significant trend in the trapezius muscle, after a short exercise test, with active but not sham stimulation. Conclusions: We conclude that two-week repeated multifocal cortical stimulation with a new wearable transcranial magnetic stimulator can be safely conducted in DM1 patients to investigate potential improvement of muscle strength and activity. The results obtained, if confirmed and extended by future safety and efficacy trials with larger patient samples, could offer a potential supportive TRPMS treatment in DM1. Show more

Keywords: Motor cortex stimulation, transcranial magnetic stimulation, functional restoration, muscle strengthening, rehabilitation

DOI: 10.3233/JND-210690

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 6, pp. 963-972, 2021

Authors: Francis, Olivia L. | Joshi, Avni | Prince, Ty | Krishnaswamy, Guha | Patel, Niraj C.

Article Type: Research Article

Abstract: Stiff Person Syndrome (SPS), a rare autoimmune neurologic disorder characterized by fluctuating muscle spasms and rigidity, is mediated by autoantibodies to glutamic acid decarboxylase (GAD) antibodies. Symptoms of SPS have been shown to improve after administration of intravenous immunoglobulin (IVIG) however, there is a paucity of information regarding use of SCIg in SPS. Four patients with Stiff Person Syndrome were treated with SCIgPro20 for a period between 31 to 101 months. Most reactions were local and mild. All patients reported improvement in spasticity, and 2 patients reported improvement in seizure frequency. SCIgPro20 was well tolerated in patients with SPS and …was associated with improvement in symptoms. Show more

Keywords: Stiff Person Syndrome, immunodeficiency, immunoglobulin, subcutaneous

DOI: 10.3233/JND-200616

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 6, pp. 973-977, 2021

Authors: De Blasiis, Paolo | Fullin, Allegra | Sansone, Mario | Del Viscovo, Luca | Napolitano, Filomena | Terracciano, Chiara | Lus, Giacomo | Melone, Mariarosa Anna Beatrice | Sampaolo, Simone

Article Type: Research Article

Abstract: Background: Late Onset Pompe Disease (LOPD) is a rare myopathy characterized by prevailing weakness of trunk and pelvic girdle muscles that causes motor disabilities. Spinal deformities have been reported unclearly on clinical examination. No study quantitatively assessed upright posture defining specific alterations of LOPD various phenotype. Objective: Identify postural abnormalities in a homogeneous group of LOPD patients using 3D Stereophotogrammetry (St) and x-Ray (xR). Methods: Seven LOPD siblings were recruited. They were assessed by clinical scales and, in upright posture, using xR and 3D-St with a new marker set protocol. Fourteen healthy individuals, age and sex-matched, …were used as controls for St-parameters; normative xR-values were found in literature. Results: LOPD patients showed a significant weakness of trunk and tibialis anterior muscles. Statistical analysis of St-parameters showed a larger ankle, knee, elbow, dorsal, S2-C7, heel-S2-C7, heel-S2-nasion angles and a lower sagittal vertical axis (SVA) than controls. xR-analysis highlighted an absence of scoliosis and a lower occipito-cervical, C2-C7 cervical and Cobb dorsal angles, and a trend to lower lumbar lordosis and SVA compared to normal values. Significant correlation was found in dorsal and lumbar angles calculated using xR-markers placed on spiny apophysis, xR-centre of vertebral bodies, Cobb-method and St-markers. Conclusion: This is the first quantitative study of postural abnormalities in LOPD patients using 3D-St and xR, highlighting sagittal standing alignment changes, difficult to assess to direct exam.Our new St-protocol showed a high reliability compared to xR. Further studies on larger population of LOPD might confirm the usefulness of these instrumental methods for monitoring disease course. Show more

Keywords: 3D Stereophotogrammetry, marker set protocol, posture, standing alignment, x-Ray, Late Onset Pompe Disease

DOI: 10.3233/JND-210663

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 6, pp. 979-988, 2021

Authors: McDonald, Craig M. | Shieh, Perry B. | Abdel-Hamid, Hoda Z. | Connolly, Anne M. | Ciafaloni, Emma | Wagner, Kathryn R. | Goemans, Nathalie | Mercuri, Eugenio | Khan, Navid | Koenig, Erica | Malhotra, Jyoti | Zhang, Wenfei | Han, Baoguang | Mendell, Jerry R. | on behalf of the the Italian DMD Telethon Registry Study Group, Leuven NMRC Registry Investigators, CINRG Duchenne Natural History Investigators, and PROMOVI Trial Clinical Investigators

Article Type: Research Article

Abstract: Background Eteplirsen received accelerated FDA approval for treatment of Duchenne muscular dystrophy (DMD) with mutations amenable to exon 51 skipping, based on demonstrated dystrophin production. Objective To report results from PROMOVI, a phase 3, multicenter, open-label study evaluating efficacy and safety of eteplirsen in a larger cohort. Methods Ambulatory patients aged 7–16 years, with confirmed mutations amenable to exon 51 skipping, received eteplirsen 30 mg/kg/week intravenously for 96 weeks. An untreated cohort with DMD not amenable to exon 51 skipping was also enrolled. Results 78/79 eteplirsen-treated patients completed 96 weeks of treatment. 15/30 untreated patients …completed the study; this cohort was considered an inappropriate control group because of genotype-driven differences in clinical trajectory. At Week 96, eteplirsen-treated patients showed increased exon skipping (18.7-fold) and dystrophin protein (7-fold) versus baseline. Post-hoc comparisons with patients from eteplirsen phase 2 studies (4658-201/202) and mutation-matched external natural history controls confirmed previous results, suggesting clinically notable attenuation of decline on the 6-minute walk test over 96 weeks (PROMOVI: –68.9 m; phase 2 studies: –67.3 m; external controls: –133.8 m) and significant attenuation of percent predicted forced vital capacity annual decline (PROMOVI: –3.3%, phase 2 studies: –2.2%, external controls: –6.0%; p  < 0.001). Adverse events were generally mild to moderate and unrelated to eteplirsen. Most frequent treatment-related adverse events were headache and vomiting; none led to treatment discontinuation. Conclusions This large, multicenter study contributes to the growing body of evidence for eteplirsen, confirming a positive treatment effect, favorable safety profile, and slowing of disease progression versus natural history. Show more

Keywords: Muscular dystrophy, duchenne, safety, treatment efficacy, clinical trial, phase 3

DOI: 10.3233/JND-210643

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 6, pp. 989-1001, 2021