Journal of Neuromuscular Diseases - Volume 7, issue 1

Authors: Schorling, David C. | Pechmann, Astrid | Kirschner, Janbernd

Article Type: Review Article

Abstract: Spinal Muscular Atrophy (SMA) is caused by autosomal recessive mutations in SMN1 and results in the loss of motor neurons and progressive muscle weakness. The spectrum of disease severity ranges from early onset with respiratory failure during the first months of life to a mild, adult-onset type with slow rate of progression. Over the past decade, new treatment options such as splicing modulation of SMN2 and SMN1 gene replacement by gene therapy have been developed. First drugs have been approved for treatment of patients with SMA and if initiated early they can significantly modify the natural course …of the disease. As a consequence, newborn screening for SMA is explored and implemented in an increasing number of countries. However, available evidence for these new treatments is often limited to a small spectrum of patients concerning age and disease stage. In this review we provide an overview of available and emerging therapies for spinal muscular atrophy and we discuss new phenotypes and associated challenges in clinical care. Collection of real-world data with standardized outcome measures will be essential to improve both the understanding of treatment effects in patients of all SMA subtypes and the basis for clinical decision-making in SMA. Show more

Keywords: Spinal muscular atrophy, antisense oligonucleotides, gene therapy, outcome assessment, neonatal screening, registries

DOI: 10.3233/JND-190424

Citation: Journal of Neuromuscular Diseases, vol. 7, no. 1, pp. 1-13, 2020

Authors: Salabarria, S.M. | Nair, J. | Clement, N. | Smith, B.K. | Raben, N. | Fuller, D.D. | Byrne, B.J. | Corti, M.

Article Type: Review Article

Abstract: Pompe disease (glycogen storage disease type II) is caused by mutations in acid α -glucosidase (GAA ) resulting in lysosomal pathology and impairment of the muscular and cardio-pulmonary systems. Enzyme replacement therapy (ERT), the only approved therapy for Pompe disease, improves muscle function by reducing glycogen accumulation but this approach entails several limitations including a short drug half-life and an antibody response that results in reduced efficacy. To address these limitations, new treatments such as gene therapy are under development to increase the intrinsic ability of the affected cells to produce GAA. Key components to gene therapy strategies include the …choice of vector, promoter, and the route of administration. The efficacy of gene therapy depends on the ability of the vector to drive gene expression in the target tissue and also on the recipient’s immune tolerance to the transgene protein. In this review, we discuss the preclinical and clinical studies that are paving the way for the development of a gene therapy strategy for patients with early and late onset Pompe disease as well as some of the challenges for advancing gene therapy. Show more

Keywords: Pompe disease, adeno-associated virus (AAV), lysosomes, autophagy, promoter, intravenous, intrathecal, intramuscular, immune-response, manufacturing

DOI: 10.3233/JND-190426

Citation: Journal of Neuromuscular Diseases, vol. 7, no. 1, pp. 15-31, 2020

Authors: Jones, Cynthia C. | Cook, Suzanne F. | Jarecki, Jill | Belter, Lisa | Reyna, Sandra P. | Staropoli, John | Farwell, Wildon | Hobby, Kenneth

Article Type: Research Article

Abstract: Background: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by homozygous survival of motor neuron 1 (SMN1 ) gene disruption. Despite a genetic etiology, little is known about subtype concordance among siblings. Objective: To investigate subtype concordance among siblings with SMA. Methods: Cure SMA maintains a database of newly diagnosed patients with SMA, which was utilized for this research. Results: Among 303 sibships identified between 1996 and 2016, 84.8% were subtype concordant. Of concordant sibships, subtype distribution was as follows: Type I, 54.5%; Type II, 31.9%; Type III, 13.2%; Type IV, …0.4%. Subtype and concordance/discordance association was significant (Fisher’s exact test; p  < 0.0001). Among discordant sibships (chi-square test, p  < 0.0001), Types II/III (52.2%) and Types I/II (28.3%) were the most common pairs. No association was found between sibling sex and concordance. Our findings show that most siblings with SMA shared the same subtype concordance (most commonly Type I). Conclusions: These data are valuable for understanding familial occurrence of SMA subtypes, enabling better individual treatment and management planning in view of new treatment options and newborn screening initiatives. Show more

Keywords: Child, growth & development, epidemiology, genetics, infant, mutation, neuromuscular disease

DOI: 10.3233/JND-190399

Citation: Journal of Neuromuscular Diseases, vol. 7, no. 1, pp. 33-40, 2020

Authors: Pechmann, Astrid | Baumann, Matthias | Bernert, Günther | Flotats-Bastardas, Marina | Gruber-Sedlmayr, Ursula | von der Hagen, Maja | Hasselmann, Oswald | Hobbiebrunken, Elke | Horber, Veronka | Johannsen, Jessika | Kellersmann, Anna | Köhler, Cornelia | von Moers, Arpad | Müller-Felber, Wolfgang | Plecko, Barbara | Reihle, Christof | Schlachter, Kurt | Schreiber, Gudrun | Schwartz, Oliver | Smitka, Martin | Steiner, Elisabeth | Stoltenburg, Corinna | Stüve, Burkhard | Theophil, Manuela | Weiß, Claudia | Wiegand, Gert | Wilichowski, Ekkehard | Winter, Benedikt | Wittmann, Wolfgang | Schara, Ulrike | Kirschner, Janbernd

Article Type: Research Article

Abstract: The natural history of patients with spinal muscular atrophy (SMA) has changed due to advances in standard care and development of targeted treatments. Nusinersen was the first drug approved for the treatment of all SMA patients. The transfer of clinical trial data into a real-life environment is challenging, especially regarding the advice of patients and families to what extent they can expect a benefit from the novel treatment. We report the results of a modified Delphi consensus process among child neurologists from Germany, Austria and Switzerland about the indication or continuation of nusinersen treatment in children with SMA type 1 …based on different clinical case scenarios. Show more

DOI: 10.3233/JND-190441

Citation: Journal of Neuromuscular Diseases, vol. 7, no. 1, pp. 41-46, 2020

Authors: Bekooij, T.J.S. | Gilhuis, H.J. | Dawson, L. | Niks, E.H.

Article Type: Research Article

Abstract: In an minority of Myasthenia Gravis (MG) patients, the autoantibodies bind to muscle-specific kinase (MUSK). These MuSK antibody-mediated MG (MuSK MG) patients are not only immunologically distinct, but also have different characteristic clinical features. Dysautonomia in MG is rarely reported. We present a MuSK MG patient who suffered from life-threatening autonomic dysfunction. MuSK MG should be considered in the differential diagnosis in cases of unclarified dysautonomia, given the potential for treatment in those cases.

Keywords: Myasthenia gravis (MG), muscle-specific kinase (MuSK), anti-MuSK antibody myasthenia gravis (MuSK MG), dysautonomia, autonomic dysfunction

DOI: 10.3233/JND-190411

Citation: Journal of Neuromuscular Diseases, vol. 7, no. 1, pp. 47-50, 2020

Authors: Schiemann, Anja H. | Roesl, Cornelia | Pollock, Neil | Langton, Elaine | Bulger, Terasa | Stowell, Kathryn M.

Article Type: Research Article

Abstract: Background: The ryanodine receptor 1 (RyR1) is a major skeletal muscle calcium release channel located in the sarcoplasmic reticulum and involved in excitation-contraction coupling. Variants in the gene encoding RyR1 have been linked to a range of neuromuscular disorders including myopathies and malignant hyperthermia (MH). Objective: We have identified three RYR1 variants (c.1983 G>A, p.Trp661*; c.7025A>G, p.Asn2342Ser and c.2447 C>T, p.Pro816Leu) in a family with a suspected myopathy and associated malignant hyperthermia susceptibility. We used calcium release assays to functionally characterise these variants in a recombinant system. Methods: Site-directed mutagenesis was used to introduce each variant separately …into the human RYR1 cDNA. HEK293-T cells were transfected with the recombinant constructs and calcium release assays were carried out using 4-chloro-m -cresol (4-CmC ) as the RyR1 agonist to investigate the functional consequences of each variant. Results: RYR1 c.1983 G>A, p.Trp661* resulted in a non-functional channel, c.7025A>G, p.Asn2342Ser in a hypersensitive channel and c.2447 C>T, p.Pro816Leu in a hypersensitive channel at higher concentrations of 4-CmC . Conclusions: The p.Trp661* RYR1 variant should be considered as a risk factor for myopathies. The p.Asn2342Ser RYR1 variant, when expressed as a compound heterozygote with a nonsense mutation on the second allele, is likely to result in MH-susceptibility. The role of the p.Pro816Leu variant in MH remains unclear. Show more

Keywords: Malignant hyperthermia, ryanodine receptor, anaesthesia, myopathy, calcium homeostasis

DOI: 10.3233/JND-190430

Citation: Journal of Neuromuscular Diseases, vol. 7, no. 1, pp. 51-60, 2020

Authors: Mavrogeni, Sophie | Giannakopoulou, Aikaterini | Katsalouli, Marina | Pons, Roser Maria | Papavasiliou, Antigoni | Kolovou, Genovefa | Noutsias, Michel | Papadopoulos, George | Karanasios, Evangelos | Chrousos, George P.

Article Type: Research Article

Abstract: Background Friedreich’s ataxia (FA) is an autosomal-recessive neurodegenerative disease characterised by neurologic, cardiac and endocrine abnormalities. Currently, Friedreich cardiomyopathy (FA-CM) staging is based on early ECG findings, high sensitivity troponin (hsTNT) ≥14 ng/ml and echocardiographic left ventricular (LV) morphologic and functional evaluation. However, further parameters, accessible only by cardiovascular magnetic resonance (CMR), such as myocardial oedema, perfusion defects, replacement and/or diffuse myocardial fibrosis, may have a place in the staging of FA-CA. Our aim was to elucidate the additive value of CMR in FA-CM. Methods Three FA cases were assessed using ECG, 24 h Holter recording, hsTNT, routine ECHO including …wall dimension, valvular and ventricular function evaluation and CMR using 1.5T Ingenia system. Ventricular volumes-function, wall dimensions and fibrosis imaging using late gadolinium enhancement (LGE) was performed. Results All FA patients had non-specific ECG changes, almost normal 24 h Holter recording, mild hypertrophy with normal function assessed by echocardiography and increased hsTNT. However, the CMR evaluation revealed the presence of LGE >5% of LV mass, indicative of severe fibrosis. Therefore, the FA patients were re-categorized as having severe FA-CA, although their LVEF remained normal. Conclusion The combination of classical diagnostic indices and CMR may reveal early asymptomatic FA-CM and motivate the early initiation of cardiac treatment. Furthermore, these indices can be also used to validate specific treatment targets in FA, potentially useful in the prevention of FA-CM. Show more

Keywords: Cardiovascular magnetic resonance imaging, Friedreich’s ataxia, diagnosis

DOI: 10.3233/JND-180373

Citation: Journal of Neuromuscular Diseases, vol. 7, no. 1, pp. 61-67, 2020

Authors: Villar-Quiles, Rocío N. | Gomez-Garcia de la Banda, Marta | Barois, Annie | Bouchet-Séraphin, Celine | Romero, Norma B. | Rio, Marlène | Quijano-Roy, Susana | Ferreiro, Ana

Article Type: Case Report

Abstract: Muscular weakness and hypotonia may be associated with multisystem involvement giving rise to complex phenotypes, many of which are uncharacterized. We report a patient presenting with congenital hypotonia and severe ocular and brain abnormalities, evoking a Muscle Eye Brain disease (MEB). She had global muscular weakness, hypotonia and amyotrophy, joint hyperlaxity, kyphoscoliosis, respiratory insufficiency, dysmorphic features and severe intellectual disability. Brain MRI showed cortical atrophy and hypoplasia of the corpus callosum. Normal CK levels, non-progressive course and absence of dystrophic features or α -dystroglycan abnormalities on the muscle biopsy were not typical of MEB. CGH array identified a large de …novo duplication in chromosome 11, including regions partially duplicated in three other patients with common clinical features. This report adds to the differential diagnosis of complex phenotypes characterized by muscular, ocular and CNS involvement and highlights the potential contribution of still unrecognized chromosomal abnormalities to these phenotypes. Show more

Keywords: Myopathy, ocular involvement, congenital muscular dystrophy, muscle-eye-brain, dystroglycanopathy;, CNV

DOI: 10.3233/JND-190413

Citation: Journal of Neuromuscular Diseases, vol. 7, no. 1, pp. 69-76, 2020