Journal of Neuromuscular Diseases - Volume 10, issue 1

Authors: Bouman, Karlijn | Dittrich, Anne T.M. | Groothuis, Jan T. | van Engelen, Baziel G.M. | Janssen, Mirian C.H. | Voermans, Nicol C. | Draaisma, Jos M.T. | Erasmus, Corrie E.

Article Type: Review Article

Abstract: Background: Congenital myopathies are rare neuromuscular disorders presenting with a wide spectrum of clinical features, including long bone fractures (LBFs) that negatively influence functional prognosis, quality of life and survival. Systematic research on bone quality in these patients is lacking. Objective: This scoping review aims to summarize all evidence on bone quality and to deduce recommendations for bone quality management in congenital myopathies. Methods: Five electronic databases (Pubmed, Embase, Cochrane, Web of Science, CINAHL) were searched. All studies on bone quality in congenital myopathies were included. Decreased bone quality was defined as low bone mineral density …and/or (fragility) LBFs. Study selection and data extraction were performed by three independent reviewers. Results: We included 244 single cases (mean: 4.1±7.6 years; median: 0 years) diagnosed with a congenital myopathy from 35 articles. Bone quality was decreased in 93 patients (37%) (mean: 2.6±6.8 years; median: 0 years). Low bone mineral density was reported in 11 patients (4.5%) (mean: 10.9±9.7; median: 11 years). Congenital LBFs were reported in 64 patients (26%). (Fragility) LBFs later at life were described in 24 patients (9.8%) (mean: 14.9±11.0; median: 14 years). Four cases (1.6%) were reported to receive vitamin D and/or calcium supplementation or diphosphonate administration. Conclusion: LBFs are thus frequently reported in congenital myopathies. We therefore recommend optimal bone quality management through bone mineral density assessment, vitamin D and calcium suppletion, and referral to internal medicine or pediatrics for consideration of additional therapies in order to prevent complications of low bone mineral density. Show more

Keywords: Congenital myopathy, osteoporosis, osteopenia, bone density, bone fracture, Photon absorptiometry (DEXA-scan), vitamin D, calcium, diphosphonates

DOI: 10.3233/JND-221543

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 1, pp. 1-13, 2023

Authors: Farrar, Michelle A. | Kariyawasam, Didu | Grattan, Sarah | Bayley, Klair | Davis, Mark | Holland, Sandra | Waddel, Leigh B. | Jones, Kristi | Lorentzos, Michelle | Ravine, Anja | Wotton, Tiffany | Wiley, Veronica

Article Type: Review Article

Abstract: A pilot newborn screening (NBS) program for Duchenne muscular dystrophy (DMD) study proposes to assess the feasibility of the screening procedure, temporal course of the various steps of screening, and the public acceptability of the program. This is particularly vital to ascertain as DMD is considered a ‘non-treatable’ disease and thus does not fit the traditional criteria for newborn screening. However, modern perspectives of NBS for DMD are changing and point to possible net benefits for children and their families undertaking NBS for DMD. The aim of this workshop was to establish pathways for the successful implementation and evaluation of …a pilot NBS for DMD program in Australia. Consensus was reached as to the rationale for, potential benefits, risks, barriers and facilitators of screening, alongside the establishment of screening protocols and clinical referral pathways. Show more

Keywords: Duchenne muscular dystrophy, newborn screening, presymptomatic, implementation, translation

DOI: 10.3233/JND-221535

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 1, pp. 15-28, 2023

Authors: Pechmann, Astrid | Behrens, Max | Dörnbrack, Katharina | Tassoni, Adrian | Wenzel, Franziska | Stein, Sabine | Vogt, Sibylle | Zöller, Daniela | Bernert, Günther | Hagenacker, Tim | Schara-Schmidt, Ulrike | Walter, Maggie C. | Steinbach, Meike | Blaschek, Astrid | Baumann, Matthias | Baumgartner, Manuela | Becker, Benedikt | Flotats-Bastardas, Marina | Friese, Johannes | Günther, Rene | Hahn, Andreas | Küpper, Hanna | Johannsen, Jessika | Kamm, Christoph | Koch, Jan Christoph | Köhler, Cornelia | Kölbel, Heike | Kolzter, Kirsten | von Moers, Arpad | Naegel, Steffen | Neuwirth, Christoph | Petri, Susanne | Rödiger, Annekathrin | Schimmel, Mareike | Schrank, Bertold | Schreiber, Gudrun | Smitka, Martin | Stadler, Christian | Steiner, Elisabeth | Stögmann, Eva | Trollmann, Regina | Türk, Matthias | Weiler, Markus | Stoltenburg, Corinna | Willichowsky, Ekkehard | Zeller, Daniel | Ziegler, Andreas | Lochmüller, Hanns | Kirschner, Janbernd | Ameshofer, Lisa | Andres, Barbara | Angelova-Toshkina, Daniela | Banholzer, Daniela | Bant, Christina | Baum, Petra | Baumann, Sandra | Baur, Ute | Behring, Bettina | Bellut, Julia | Bertsche, Astrid | Bevot, Andrea | Bischofberger, Jasmin | Bitzan, Lisa | Bjelica, Bogdan | Blankenburg, Markus | Böger, Sandra | Bonetti, Friederike | Bongartz, Anke | Brakemeier, Svenja | Bratka, Lisa | Braun, Nathalie | Braun, Sarah | Brauner, Brigitte | Bretschneider, Christa | Burgenmeister, Nadine | Burke, Bea | Cirak, Sebahattin | Cordts, Isabell | Dall, Andrea | de Vries, Heike | Della Marina, Adela | Denecke, Jonas | Deschauer, Marcus | Dibrani, Zylfie | Diebold, Uta | Dondit, Lutz | Drebes, Jessica | Driemeyer, Joenna | Dukic, Vladimir | Eckenweiler, Matthias | Eisenkölbl, Astrid | Eminger, Mirjam | Fischer, Michal | Fischer, Cornelia | Freigang, Maren | Gaiser, Philippa | Gangfuß, Andrea | Tasch, Gehrke | Geitmann, Stephanie | George, Annette | Gosk-Tomek, Magdalena | Grinzinger, Susanne | Gröning, Kristina | Groß, Martin | Güttsches, Anne-Katrin | Hagenmeyer, Anna | Hartmann, Hans | Haverkamp, Julia | Hiebeler, Miriam | Hoevel, Annegret | Hoffmann, Georg Friedrich | Holtkamp, Britta | Holzwarth, Dorothea | Homma, Annette | Horber, Veronka | Horneff, Viola | Hörnig, Carolin | Hotter, Anna | Hubert, Andrea | Huppke, Peter | Husain, Ralf A. | Illsinger, Sabine | Jansen, Eva | Jung, Lisa | Kaiser, Nadja | Kappel, Stefan | Bolte, Katharina | Koch, Johannes | Kölker, Stefan | Korschinsky, Brigitte | Kostede, Franziska | Krause, Karsten | Lang, Annina | Lange, Irene | Langer, Thorsten | Lechner, Yvonne | Lehmann, Helmar | Leypold, Christine | Lingor, Paul | Lipka, Jaqueline | Löscher, Wolfgang | Luiking, Antje | Machetanz, Gerrit | Malm, Eva | Martakis, Kyriakos | Menzen, Bettina | Metelmann, Moritz | Meyer zu Hörste, Gerd | Montagnese, Federica | Mörtlbauer, Kathrin | Müller, Petra | Müller, Anne | Müller, Anja | Müschen, Lars | Niesert, Moritz | Pauschek, Josefine | Pernegger, Elke | Pilshofer, Veronika | Plecko, Barbara | Pollok, Jürgen | Preisel, Martin | Pühringer, Manuel | Quinten, Anna Lisa | Raffler, Sabine | Ramadan, Barbara | Rappold, Mika | Rauscher, Christian | Reckmann, Kerstin | Reihle, Christof | Reinhardt, Tabea | Röder, Melanie | Roland-Schäfer, Doris | Roth, Erdmute | Ruß, Lena | Saffari, Afshin | Schimmel, Mareike | Schlachter, Kurt | Schlag, Melina | Schlotter-Weigel, Beate | Schneider, Joanna | Schöne-Bake, Jan-Christoph | Schorling, David | Schreiner, Isabella | Schüssler, Stephanie | Schwarzbach, Michaela | Schwerin-Nagel, Anette | Schwippert, Michaela | Semmler, Luisa | Smuda, Karin | Sprenger-Svacina, Alina | Stadler, Theresa | Steffens, Paula | Steuernagel, Daniela | Stolte, Benjamin | Thimm, Andreas | Tiefenthaler, Elke | Topakian, Raffi | van der Stam, Lieske | Vettori, Katia | Vollmann, Peter | Vorgerd, Matthias | Weiß, Claudia | Weiss, Deike | Wenninger, Stephan | Werring, Svea | Wessel, Maria | Weyen, Ute | Wider, Sabine | Wiebe, Nils Ole | Wiegand, Gert | Wiesenhofer, Anna | Wiethoff, Sarah | Wirner, Corinna | Wohnrade, Camilla | Wunderlich, Gilbert | Zemlin, Michael | Zobel, Joachim

Article Type: Research Article

Abstract: Background and objectives: Disease progression in patients with spinal muscular atrophy (SMA) has changed dramatically within the past years due to the approval of three different disease-modifying treatments. Nusinersen was the first drug to be approved for the treatment of SMA patients. Clinical trials provided data from infants with SMA type 1 and children with SMA type 2, but there is still insufficient evidence and only scarcely reported long-term experience for nusinersen treatment in ambulant patients. Here, we report data from the SMArtCARE registry of ambulant patients under nusinersen treatment with a follow-up period of up to 38 months. …Methods: SMArtCARE is a disease-specific registry in Germany, Austria and Switzerland. Data are collected as real-world data during routine patient visits. Our analysis included all patients under treatment with nusinersen able to walk independently before start of treatment with focus on changes in motor function. Results: Data from 231 ambulant patients were included in the analysis. During the observation period, 31 pediatric walkers (27.2%) and 31 adult walkers (26.5%) experienced a clinically meaningful improvement of≥30 m in the 6-Minute-Walk-Test. In contrast, only five adult walkers (7.7%) showed a decline in walking distance≥30 m, and two pediatric walkers (1.8%) lost the ability to walk unassisted under treatment with nusinersen. HFMSE and RULM scores improved in pediatric and remained stable in adult patients. Conclusion: Our data demonstrate a positive effect of nusinersen treatment in most ambulant pediatric and adult SMA patients. We not only observed a stabilization of disease progression or lack of deterioration, but clinically meaningful improvements in walking distance. Show more

Keywords: Spinal muscular atrophy, nusinersen, walker, ambulant, SMArtCARE

DOI: 10.3233/JND-221600

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 1, pp. 29-40, 2023

Authors: Mouchet, Julie | Roumpanis, Spyros | Gaki, Eleni | Lipnick, Scott | Oskoui, Maryam | Scalco, Renata S. | Darras, Basil T.

Article Type: Research Article

Abstract: Background: Spinal muscular atrophy (SMA) is a neuromuscular disease caused by homozygous deletion or loss-of-function mutations of the survival of motor neuron 1 (SMN1 ) gene, resulting in reduced levels of SMN protein throughout the body. Patients with SMA may have multiple tissue defects, which could present prior to neuromuscular symptoms. Objective: To assess the signs, comorbidities and potential extraneural manifestations associated with SMA in treatment-naïve patients. Methods: This observational, retrospective and matched-cohort study used secondary insurance claims data from the US IBM® MarketScan® Commercial, Medicaid and Medicare Supplemental databases between 01/01/2000 and 12/31/2013. …Treatment-naïve individuals aged≤65 years with≥2 International Classification of Diseases, Ninth Revision (ICD-9) SMA codes were stratified into four groups (A–D), according to age at index (date of first SMA code recorded) and type of ICD-9 code used, and matched with non-SMA controls. The occurrence of ICD-9 codes, which were converted to various classifications (phecodes and system classes), were compared between groups in pre- and post-index periods. Results: A total of 1,457 individuals with SMA were included and matched to 13,362 controls. Increasing numbers of SMA-associated phecodes and system classes were generally observed from pre- to post-index across all groups. The strongest associations were observed in the post-index period for the youngest age groups. Endocrine/metabolic disorders were associated with SMA in almost all groups and across time periods. Conclusions: This exploratory study confirmed the considerable disease burden in patients with SMA and identified 305 unique phecodes associated with SMA, providing a rationale for further research into the natural history and progression of SMA, including extraneural manifestations of the disease. Show more

Keywords: Comorbidity, retrospective studies, Survival of Motor Neuron 1 Protein, comparative study

DOI: 10.3233/JND-210764

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 1, pp. 41-53, 2023

Authors: Müller-Felber, Wolfgang | Blaschek, Astrid | Schwartz, Oliver | Gläser, Dieter | Nennstiel, Uta | Brockow, Inken | Wirth, Brunhilde | Burggraf, Siegfried | Röschinger, Wulf | Becker, Marc | Durner, Jürgen | Eggermann, Katja | Kölbel, Heike | Müller, Christine | Hannibal, Iris | Olgemöller, Bernd | Schara, Ulrike | von Moers, Arpad | Trollmann, Regina | Johannssen, Jessika | Ziegler, Andreas | Cirak, Sebahattin | Hahn, Andreas | von der Hagen, Maja | Weiss, Claudia | Schreiber, Gudrun | Flotats-Bastardas, Marina | Hartmann, Hans | Illsinger, Sabine | Pechmann, Astrid | Horber, Veronka | Kirschner, Jan | Köhler, Cornelia | Winter, Benedikt | Friese, Johannes | Vill, Katharina

Article Type: Research Article

Abstract: Now that targeted therapies for spinal muscular atrophy are available, attempts are being made worldwide to include screening for spinal muscular atrophy in general newborn screening. In Germany, after pilot projects from 2018–2021, it was included in the general newborn screening from October 2021. To ensure a smooth transition, criteria for follow-up were developed together with key stakeholders. At the beginning of the transition to nationwide screening, false positive findings were reported in 3 patients. After optimization of the screening method in the laboratories concerned, all findings have been subsequently confirmed. On average, the first presentation to a neuromuscular center …occurred on day 12 of life, and in patients with 2 or 3 SMN2 copies, therapy started on day 26 of life. Compared with the pilot project, there was no significant delay in timing. Show more

Keywords: Spinal muscular atrophy, newborn screening, SMA treatment, 5q-SMA

DOI: 10.3233/JND-221577

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 1, pp. 55-65, 2023

Authors: McDonald, Craig M. | Mayer, Oscar H. | Hor, Kan N. | Miller, Debra | Goemans, Nathalie | Henricson, Erik K. | Marden, Jessica R. | Freimark, Jonathan | Lane, Henry | Zhang, Adina | Frean, Molly | Trifillis, Panayiota | Koladicz, Karyn | Signorovitch, James

Article Type: Research Article

Abstract: Background: Evidence on the long-term efficacy of steroids in Duchenne muscular dystrophy (DMD) after loss of ambulation is limited. Objective: Characterize and compare disease progression by steroid treatment (prednisone, deflazacort, or no steroids) among non-ambulatory boys with DMD. Methods: Disease progression was measured by functional status (Performance of Upper Limb Module for DMD 1.2 [PUL] and Egen Klassifikation Scale Version 2 [EK] scale) and by cardiac and pulmonary function (left ventricular ejection fraction [LVEF], forced vital capacity [FVC] % -predicted, cough peak flow [CPF]). Longitudinal changes in outcomes, progression to key disease milestones, and dosing and …body composition metrics were analyzed descriptively and in multivariate models. Results: This longitudinal cohort study included 86 non-ambulatory patients with DMD (mean age 13.4 years; n  = 40 [deflazacort], n  = 29 [prednisone], n  = 17 [no steroids]). Deflazacort use resulted in slower average declines in FVC % -predicted vs. no steroids (+3.73 percentage points/year, p  < 0.05). Both steroids were associated with significantly slower average declines in LVEF, improvement in CPF, and slower declines in total PUL score and EK total score vs. no steroids; deflazacort was associated with slower declines in total PUL score vs. prednisone (all p  < 0.05). Both steroids also preserved functional abilities considered especially important to quality of life, including the abilities to perform hand-to-mouth function and to turn in bed at night unaided (all p  < 0.05 vs. no steroids). Conclusions: Steroid use after loss of ambulation in DMD was associated with delayed progression of important pulmonary, cardiac, and upper extremity functional deficits, suggesting some benefits of deflazacort over prednisone. Show more

Keywords: Treatment outcome, deflazacort, Duchenne muscular dystrophy, prednisone, ambulation

DOI: 10.3233/JND-221575

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 1, pp. 67-79, 2023

Authors: Chrzanowski, Stephen M. | Nagy, Janice A. | Pandeya, Sarbesh | Rutkove, Seward B.

Article Type: Research Article

Abstract: Background: Sensitive, objective, and longitudinal outcome measures applicable to both pre-clinical and clinical interventions are needed to assess muscle health in Duchenne muscular dystrophy (DMD). Electrical impedance myography (EIM) has the potential to non-invasively measure disease progression in mice and boys with DMD. Objective: We sought to evaluate how electrical impedance values (i.e., phase, reactance, and resistance) correlate to established measures of disease in both D2-mdx and wild type (WT) mice and boys with and without DMD. Methods: Histological, functional, and EIM data collected from previous studies of WT and D2-mdx mice at 6, 13, 21 …and 43 weeks of age were reanalyzed. In parallel, previously collected functional outcome measures and EIM values were reanalyzed from boys with and without DMD at four different age groups from 2 to 14 years old. Results: In mice, disease progression as detected by histological, functional, and EIM measures, was appreciable over this time period and grip strength best correlated to longitudinal phase and reactance impedance values. In boys, disease progression quantified through commonly utilized functional outcome measures was significant and longitudinal phase demonstrated the strongest correlation with functional outcome measures. Conclusion: Similar changes in EIM values, specifically in longitudinal reactance and phase, were found to show significant correlations to functional measures in both mice and boys. Thus, EIM demonstrates applicability in both pre-clinical and clinical settings and can be used as a safe, non-invasive, and longitudinal proxy biomarker to assess muscle health in DMD. Show more

Keywords: Electrical impedance myography, duchenne muscular dystrophy, D2-mdx mice, biomarker, functional outcome measures., Grant Support: NIH/NINDS, R01 NS091159. NIH/NIAMS, R01 AR060850

DOI: 10.3233/JND-210787

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 1, pp. 81-90, 2023

Authors: Chen, Zhiyong | Saini, Monica | Koh, Jasmine S. | Prasad, Kalpana | Koh, Swee Hoon | Tay, Karine S.S. | Lee, Ming | Tan, Yi Jayne | Ng, Adeline S.L. | Tay, Stacey Kiat Hong | Tan, Kong Bing | Tandon, Ankit | Tan, Jeane M.M. | Chai, Josiah Y.H.

Article Type: Research Article

Abstract: Aim: We describe a cohort of five patients with limb-girdle muscular dystrophy (LGMD) 2G/LGMD-R7 in a South-east Asian cohort. Background: LGMD2G/LGMD-R7-telethonin-related is caused by mutations in the TCAP gene that encodes for telethonin. Methods: We identified consecutive patients with LGMD2G/LGMD-R7-telethonin-related, diagnosed at the National Neuroscience Institute (NNI) and National University Hospital (NUH) between January 2000 and June 2021. Results: At onset, three patients presented with proximal lower limb weakness, one patient presented with Achilles tendon contractures, and one patient presented with delayed gross motor milestones. At last follow up, three patients had a …limb girdle pattern of muscle weakness and two had a facioscapular humeral pattern of weakness. Whole body muscle MRI performed for one patient with a facioscapular-humeral pattern of weakness showed a pattern of muscle atrophy similar to facioscapular-humeral dystrophy. One patient had histological features consistent with myofibrillar myopathy; electron microscopy confirmed the disruption of myofibrillar architecture. One patients also had reduced staining to telethonin antibody on immunohistochemistry. Conclusion: We report the unique clinical and histological features of a Southeast Asian cohort of five patients with LGMD2G/LGMD-R7-telethonin-related muscular dystrophy and further expand its clinical and histopathological spectrum. Show more

Keywords: Telethonin deficiency, LGMD2G, TCAP, muscular dystrophy

DOI: 10.3233/JND-221517

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 1, pp. 91-106, 2023

Authors: Murata, Daisuke | Grunseich, Christopher | Iijima, Miho | Chan, David | Corse, Andrea | Hoke, Ahmet | Schindler, Alice | Sesaki, Hiromi | Roda, Ricardo H.

Article Type: Research Article

Abstract: Background: The number of mutations in nuclear encoded genes causing mitochondrial disease is ever increasing. Identification of these mutations is particularly important in the diagnosis of neuromuscular disorders as their presentation may mimic other acquired disorders.We present a novel heterozygous variant in mitochondrial fission factor (MFF) which mimics myasthenia gravis. Objective: To determine if the MFF c.937G>A, p.E313K variant causes a mild mitochondrial phenotype. Methods: We used whole exome sequencing (WES) to identify a novel heterozygous variant in MFF in a patient with ptosis, fatigue and muscle weakness. Using patient derived fibroblasts, we performed assays to …evaluate mitochondrial and peroxisome dynamics. Results: We show that fibroblasts derived from this patient are defective in mitochondrial fission, despite normal recruitment of Drp1 to the mitochondria. Conclusions: The MFF c.937G>A, p.E313K variant leads to a mild mitochondrial phenotype and is associated with defective mitochondrial fission in patient-derived fibroblasts. Show more

Keywords: Mitochondrial myopathies, mitochondrial fission factor, MFF, mitochondrial dynamics

DOI: 10.3233/JND-221532

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 1, pp. 107-118, 2023

Authors: Giannese, Domenico | Montano, Vincenzo | Lopriore, Piervito | Nesti, Claudia | LoGerfo, Annalisa | Caligo, Maria Adelaide | Dal Canto, Flavio | Pasquinelli, Gianandrea | Bonadio, Angelo Giovanni | Moriconi, Diego | Siciliano, Gabriele | Mancuso, Michelangelo

Article Type: Case Report

Abstract: Background: Mitochondrial tRNA (MTT) genes are hotspot for mitochondrial DNA mutation and are responsible of half mitochondrial disease. MTT mutations are associated with a broad spectrum of phenotype often with complex multisystem involvement and complex genotype-phenotype correlations. MT-TL1 mutations, among which the m.3243A>G mutation is the most frequent, are associated with myopathy, maternal inherited diabetes and deafness, MELAS, cardiomyopathy, and focal segmental glomerulosclerosis. Case study: Here we report the case of an Italian 49-years old female presenting with encephalomyopathy, chronic proteinuric kidney disease and a new heteroplasmic m.3274_3275delAC MT-TL1 gene mutation. Conclusions: Our case …demonstrates a systemic mitochondrial disease caused by the heteroplasmic m.3274_3275delAC MT-TL1 gene mutation, not yet described in the literature. A mitochondrial disease should be suspected in case of complex multisystem phenotypes, including steroid-resistant nephrotic syndrome with multisystemic involvement. Show more

Keywords: mtDNA, mitochondrial diseases, mitochondrial myopathies, glomerulosclerosis, kidney disease

DOI: 10.3233/JND-221526

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 1, pp. 119-123, 2023