Journal of Neuromuscular Diseases - Volume 7, issue 3

Authors: Savarese, Marco | Välipakka, Salla | Johari, Mridul | Hackman, Peter | Udd, Bjarne

Article Type: Review Article

Abstract: Human genes have a variable length. Those having a coding sequence of extraordinary length and a high number of exons were almost impossible to sequence using the traditional Sanger-based gene-by-gene approach. High-throughput sequencing has partly overcome the size-related technical issues, enabling a straightforward, rapid and relatively inexpensive analysis of large genes. Several large genes (e.g. TTN, NEB , RYR1 , DMD ) are recognized as disease-causing in patients with skeletal muscle diseases. However, because of their sheer size, the clinical interpretation of variants in these genes is probably the most challenging aspect of the high-throughput genetic investigation in the …field of skeletal muscle diseases. The main aim of this review is to discuss the technical and interpretative issues related to the diagnostic investigation of large genes and to reflect upon the current state of the art and the future advancements in the field. Show more

Keywords: Large genes, variant interpretation, genetic diagnosis, variants of uncertain significance (VUS), copy number variants (CNV)

DOI: 10.3233/JND-190459

Citation: Journal of Neuromuscular Diseases, vol. 7, no. 3, pp. 203-216, 2020

Authors: Waldrop, Megan A. | Yaou, Rabah Ben | Lucas, Karin K. | Martin, Ann S. | O’Rourke, Erin | FILNEMUS | Ferlini, Alessandra | Muntoni, Francesco | Leturcq, France | Tuffery-Giraud, Sylvie | Weiss, Robert B. | Flanigan, Kevin M.

Article Type: Research Article

Abstract: Background: Eteplirsen, the first FDA-approved RNA-modifying therapy for DMD, is applicable to ∼13% of patients with DMD. Because multiple exonic deletions are amenable to exon 51 skipping, the isoforms resulting from the various exon 51-skipped transcripts may vary in stability, function, and phenotype. Objective/Methods: We conducted a detailed review of dystrophinopathy published literature and unpublished databases to compile phenotypic features of patients with exon 51 “skip-equivalent” deletions. Results: Theoretically, 48 different in-frame transcripts may result from exon 51 skipping. We found sufficient clinical information on 135 patients carrying mutations that would result in production of 11 …(23%) of these transcripts, suggesting the remainder have not been identified in vivo. The majority had mild phenotypes: BMD (n  = 81) or isolated dilated cardiomyopathy (n  = 3). Particularly interesting are the asymptomatic (n  = 10) or isolated hyperCKemia (n  = 20) patients with deletions of exons 45– 51, 48– 51, 49– 51 and 50– 51. Finally, 16 (12%) had more severe phenotypes described as intermediate (n  = 2) or DMD (n  = 14), and 6 reports had no definitive phenotype. Conclusions: This review shows that the majority of exon 51 “skip-equivalent” deletions result in milder (BMD) phenotypes and supports that exon 51 skipping therapy could provide clinical benefit, although we acknowledge that other factors, such as age at treatment initiation or ongoing standard of care, may influence the degree of benefit. Show more

Keywords: DMD, BMD, exon skipping, eteplirsen, systematic review

DOI: 10.3233/JND-200483

Citation: Journal of Neuromuscular Diseases, vol. 7, no. 3, pp. 217-229, 2020

Authors: Strandberg, Kristin | Ayoglu, Burcu | Roos, Andreas | Reza, Mojgan | Niks, Erik | Signorelli, Mirko | Fasterius, Erik | Pontén, Fredrik | Lochmüller, Hanns | Domingos, Joana | Ala, Pierpaolo | Muntoni, Francesco | Aartsma-Rus, Annemieke | Spitali, Pietro | Nilsson, Peter | Szigyarto, Cristina Al-Khalili

Article Type: Research Article

Abstract: Background: Duchenne Muscular Dystrophy is a severe, incurable disorder caused by mutations in the dystrophin gene. The disease is characterized by decreased muscle function, impaired muscle regeneration and increased inflammation. In a clinical context, muscle deterioration, is evaluated using physical tests and analysis of muscle biopsies, which fail to accurately monitor the disease progression. Objectives: This study aims to confirm and asses the value of blood protein biomarkers as disease progression markers using one of the largest longitudinal collection of samples. Methods: A total of 560 samples, both serum and plasma, collected at three clinical sites …are analyzed using a suspension bead array platform to assess 118 proteins targeted by 250 antibodies in microliter amount of samples. Results: Nine proteins are confirmed as disease progression biomarkers in both plasma and serum. Abundance of these biomarkers decreases as the disease progresses but follows different trajectories. While carbonic anhydrase 3, microtubule associated protein 4 and collagen type I alpha 1 chain decline rather constantly over time, myosin light chain 3, electron transfer flavoprotein A, troponin T, malate dehydrogenase 2, lactate dehydrogenase B and nestin plateaus in early teens. Electron transfer flavoprotein A, correlates with the outcome of 6-minutes-walking-test whereas malate dehydrogenase 2 together with myosin light chain 3, carbonic anhydrase 3 and nestin correlate with respiratory capacity. Conclusions: Nine biomarkers have been identified that correlate with disease milestones, functional tests and respiratory capacity. Together these biomarkers recapitulate different stages of the disorder that, if validated can improve disease progression monitoring. Show more

Keywords: Affinity-based proteomics, protein biomarkers, Duchenne muscular dystrophy, disease progression, serum and plasma

DOI: 10.3233/JND-190454

Citation: Journal of Neuromuscular Diseases, vol. 7, no. 3, pp. 231-246, 2020

Authors: Kekou, Kyriaki | Svingou, Maria | Sofocleous, Christalena | Mourtzi, Niki | Nitsa, Evangelia | Konstantinidis, George | Youroukos, Sotiris | Skiadas, Konstantinos | Katsalouli, Marina | Pons, Roser | Papavasiliou, Antigoni | Kotsalis, Charalabos | Pavlou, Evangelos | Evangeliou, Athanasios | Katsarou, Efstathia | Voudris, Konstantinos | Dinopoulos, Argirios | Vorgia, Pelagia | Niotakis, George | Diamantopoulos, Nikolaos | Nakou, Iliada | Koute, Vasiliki | Vartzelis, George | Papadimas, George-Konstantinos | Papadopoulos, Constantinos | Tsivgoulis, Georgios | Traeger-Synodinos, Joanne

Article Type: Research Article

Abstract: Background: Promising genetic treatments targeting the molecular defect of severe early-onset genetic conditions are expected to dramatically improve patients’ quality of life and disease epidemiology. Spinal Muscular Atrophy (SMA), is one of these conditions and approved therapeutic approaches have recently become available to patients. Objective: Analysis of genetic and clinical data from SMA patients referred to the single public-sector provider of genetic services for the disease throughout Greece followed by a retrospective assessment in the context of epidemiology and genotype-phenotype associations. Methods: Molecular genetic analysis and retrospective evaluation of findings for 361 patients tested positive for …SMA- and 862 apparently healthy subjects from the general population. Spearman rank test and generalized linear models were applied to evaluate secondary modifying factors with respect to their impact on clinical severity and age of onset. Results: Causative variations- including 5 novel variants- were detected indicating a minimal incidence of about 1/12,000, and a prevalence of at least 1.5/100,000. For prognosis a minimal model pertaining disease onset before 18 months was proposed to include copy numbers of NAIP (OR = 9.9;95% CI, 4.7 to 21) and SMN2 (OR = 6.2;95% CI, 2.5–15.2) genes as well as gender (OR = 2.2;95% CI, 1.04 to 4.6). Conclusions: This long-term survey shares valuable information on the current status and practices for SMA diagnosis on a population basis and provides an important reference point for the future assessment of strategic advances towards disease prevention and health care planning. Show more

Keywords: Spinal muscular atrophy, incidence, prevalence, gender, epidemiology, mutation, neuromuscular disease

DOI: 10.3233/JND-190466

Citation: Journal of Neuromuscular Diseases, vol. 7, no. 3, pp. 247-256, 2020

Authors: Yeo, Crystal Jing Jing | Simeone, Sarah D. | Townsend, Elise L. | Zhang, Ren Zhe | Swoboda, Kathryn J.

Article Type: Research Article

Abstract: Background: The impact of nusinersen therapy on outcomes in adults with Spinal Muscular Atrophy (SMA) remains uncertain. Objective: To demonstrate whether nusinersen therapy, at currently prescribed doses, can stabilize or improve motor function in adults with SMA using existing outcome measures. Methods: A single-center prospective cohort study of 6 adults with SMA type 3, with inclusion/exclusion criteria intended to optimize the ability to demonstrate change using established outcome measures. Primary outcomes were the Hammersmith Functional Motor Scale-Expanded (HFMSE) and the Revised Upper Limb Measure (RULM). Secondary outcomes were the PedsQL Fatigue scale, the SMA Functional Rating …Scale (SMAFRS), and the 6-minute and 10-meter walk tests (6 MWT and 10 MWT). Estimates of change in HFMSE and RULM mean scores across visits were calculated using a linear mixed effects model. Change from baseline was used for other outcome measures. Results: HFMSE and RULM scores over 12 months were stable or improved in all participants, with a mean increase of 2 points in each. Other measures showed high intra-individual variability. Adverse events related to the primary diagnosis, including injury and infection, significantly impacted the ability to reliably perform walk tests in the four ambulatory participants. Conclusions: HFMSE and RULM show potential as responsive outcome measures of motor function in ambulatory and non-ambulatory adults with SMA type 3. A time-dependent accrual of benefit of nusinersen on motor function was apparent in this cohort. More sensitive alternative measures of quality of life, fatigue, exercise tolerance, stability and ADLs are clearly needed for adults with SMA. Show more

Keywords: Spinal muscular atrophy, adult, antisense oligonucleotides, treatment outcome, exercise tolerance

DOI: 10.3233/JND-190453

Citation: Journal of Neuromuscular Diseases, vol. 7, no. 3, pp. 257-268, 2020

Authors: Datta, Sorabh | Singh, Shivangi | Govindarajan, Raghav

Article Type: Research Article

Abstract: Background: The role of the complement cascade in acetylcholine receptor antibody-negative (AChR–) myasthenia gravis (MG) is unclear. Objective: To assess the efficacy and tolerability of eculizumab (terminal complement inhibitor) in patients with AChR–MG. Methods: Retrospective chart review of data from six patients treated for 12 months with eculizumab for treatment-refractory, AChR–(by radioimmunoassay) generalized MG (gMG). The eculizumab dose was 900 mg/week for 4 weeks then 1200 mg every 2 weeks. Outcome measures were Myasthenia Gravis–Activities of Daily Living (MG-ADL) scores, number of exacerbations, and qualitative physical assessments based on selected items of the Quantitative Myasthenia Gravis evaluation (ptosis, …double vision, eye closure, duration of ability to stretch out limbs). Results: All patients were female (mean age, 50.8 years). In the 12 months before eculizumab initiation, all measures were relatively stable. After its initiation, clinically meaningful reductions (≥2 points) in total MG-ADL scores were observed before or at 5 months and were maintained to Month 12 in all patients; mean (standard deviation [SD]) scores were 11.3 (0.9) and 5.0 (0.9), respectively. There was also a reduction in the mean (SD) number of exacerbations per patient, from 2.8 (1.2) to 0.3 (0.5) in the 12 months before and after eculizumab initiation, respectively. Physical assessment ratings were improved in all patients. Adverse events were reported in four patients, but all were mild and none were treatment-related. Conclusions: This small retrospective analysis provides preliminary evidence for the efficacy of eculizumab in treatment-refractory gMG that was AChR–according to radioimmunoassay. Larger, more robust studies are warranted to evaluate this further. Show more

Keywords: Myasthenia gravis, ACh receptors, neuromuscular junction, complement inactivating agents, activities of daily living, corticosteroids

DOI: 10.3233/JND-190464

Citation: Journal of Neuromuscular Diseases, vol. 7, no. 3, pp. 269-277, 2020

Authors: Horlings, Corinne G.C. | Rath, Jakob | Finsterer, Josef | Wanschitz, Julia V. | Löscher, Wolfgang N.

Article Type: Research Article

Abstract: Objectives: laboratory tests for work-up of hereditary and acquired neuropathies of peripheral nerves are frequently uncritically utilized. This overview focuses on the most common laboratory tests and investigations needed for diagnosing PNPs by the general neurologist. Method: Literature search. Results: laboratory tests recommended for the work-up of hereditary and acquired neuropathies should be chosen according to the individual and family history, clinical presentation, and electrophysiological findings. Laboratory tests should be selected specifically according to the suspected type of neuropathy to avoid unnecessary tests and expenses. Work-up should include as few samples as necessary for uncovering the …etiology and should consider the sensitivity/specificity of the tests applied.. Basic screening tests for neuropathies should include a blood cell count, thyroid, renal and liver function tests, blood glucose levels, HbA1c, vitamin-B12, and immunofixation. Other laboratory investigations should be carried out only if a specific phenotype is present or if unexpected changes of the disease course occur. In these cases referral to a neuromuscular center is recommended. Conclusions: Laboratory tests are helpful for the diagnosis of acquired and hereditary neuropathies but these tests should be ordered according to the history, clinical presentation and findings on electrophysiological investigations. If basic laboratory parameters fail to uncover the etiology, patients should be referred to a center specialized in neuromuscular disorders. Show more

Keywords: Neuropathy, nerve conduction, diagnosis, hereditary, electromyography

DOI: 10.3233/JND-200488

Citation: Journal of Neuromuscular Diseases, vol. 7, no. 3, pp. 279-286, 2020

Authors: Kooi-van Es, Mieke | Erasmus, Corrie E. | de Swart, Bert J.M. | Voet, Nicoline B.M. | van der Wees, Philip J. | de Groot, Imelda J.M. | van den Engel-Hoek, Lenie | studygroup Dutch pediatric rehabilitation centers

Article Type: Research Article

Abstract: Background: Dysphagia and dysarthria are frequently described in pediatric neuromuscular diseases (pNMD). The consequences can be substantial: failure to thrive, malnutrition, aspiration pneumonia, or communication problems. Early detection and identification of risk factors and etiology support preventing complications and morbidity, including impact on quality of life. Information about the prevalence of dysphagia and dysarthria in pNMD is scarce. Objective: To describe the pooled prevalence of dysphagia and dysarthria in pNMD in the Netherlands. In addition, we describe the prevalence of dysphagia and dysarthria each, and the prevalence of chewing (oral) and swallowing problems per diagnostic group, based on …their anatomic origin. Methods: Data were collected from 295 children (mean age 11;0 years, range 2;6–18;0) with pNMD in 12 hospitals and rehabilitation centers in the Netherlands. A speech language therapist established whether dysphagia and dysarthria were present or not. Results: In almost all the 14 diagnostic groups of pNMD, dysphagia and dysarthria were present. Pooled overall prevalence of dysphagia and dysarthria was 47.2% and 31.5%, respectively. Of 114 children with dysphagia, 90.0% had chewing problems, 43.0% showed swallowing problems and 33.3% showed both chewing and swallowing problems. Conclusions: The overall pooled prevalence of dysphagia and dysarthria was high in the population of pNMD. It can be argued that periodic monitoring of dysphagia and dysarthria and early referral to a speech language therapist should be a necessity from the start of the diagnosis in the whole pNMD population. Show more

Keywords: Dysphagia, dysarthria, neuromuscular diseases, children, prevalence

DOI: 10.3233/JND-190436

Citation: Journal of Neuromuscular Diseases, vol. 7, no. 3, pp. 287-295, 2020

Authors: de Meel, Robert H.P. | Barnett, Carolina | Bril, Vera | Tannemaat, Martijn R. | Verschuuren, Jan J.G.M.

Article Type: Research Article

Abstract: Introduction: The recently developed Myasthenia Gravis Impairment Index (MGII) is a promising measure as it has less floor effects and a higher relative efficiency in its responsiveness to treatment effect compared to other MG measures. This study aimed at validating the MGII in a Dutch cohort of MG patients and analyzing the sensitivity of MGII compared to MG-ADL for changes in generalized weakness. Methods: We analyzed (generalized items of; -gen ) MGII, quantitative myasthenia gravis (QMG), Myasthenia Gravis Activities of Daily Living (MG-ADL), EQ-5D visual analog, Myasthenia Gravis Composite (MGC) and ACTIVLIM (an ADL questionnaire focusing on generalized …weakness) scores in a prospective cohort of 99 MG patients. We investigated correlations between MGII and other outcome measures. We used a generalized linear model to assess whether MGIIgen had an additional sensitivity on top of MG-ADLgen for changes (Δ ) in QMGgen in individual patients. Results: MGII had a lower floor effect (4%) compared to QMG (6%), MG-ADL (11%) and MGC (16%). MGII correlated well with QMG (r = 0.68), MG-ADL (r = 0.83) and MGC (r = 0.74). As expected, the correlations with EQ visual analog and ACTIVLIM were lower (r = – 0.57 and – 0.48). Δ MGIIgen had an additional value on top of Δ MG-ADLgen in the prediction of Δ QMGgen (B = 0.54, p  = 0.01). Discussion: The MGII score was cross-culturally validated in a Dutch cohort of MG patients. MGII had a higher sensitivity for generalized weakness than MG-ADL. Show more

Keywords: Myasthenia gravis, MGII, MG-ADL, QMG, generalized weakness

DOI: 10.3233/JND-200484

Citation: Journal of Neuromuscular Diseases, vol. 7, no. 3, pp. 297-300, 2020

Authors: Oktay, Yavuz | Güngör, Serdal | Zeltner, Lena | Wiethoff, Sarah | Schöls, Ludger | Sonmezler, Ece | Yilmaz, Elmasnur | Munro, Benjamin | Bender, Benjamin | Kernstock, Christoph | Kaemereit, Sofie | Liepelt, Inga | Töpf, Ana | Yis, Uluc | Laurie, Steven | Yaramis, Ahmet | Zuchner, Stephan | Hiz, Semra | Lochmüller, Hanns | Schüle, Rebecca | Horvath, Rita

Article Type: Research Article

Abstract: Background: In 2009, we identified TACO1 as a novel mitochondrial disease gene in a single family, however no second family has been described to confirm the role of TACO1 in mitochondrial disease. Objective: In this report, we describe two independent consanguineous families carrying pathogenic variants in TACO1 , confirming the phenotype. Methods: Detailed clinical investigations and whole exome sequencing with haplotype analysis have been performed in several members of the two reported families. Results: Clinical phenotype of the patients confirms the originally reported phenotype of a childhood-onset progressive cerebellar and pyramidal syndrome …with optic atrophy and learning difficulties. Brain MRI showed periventricular white matter lesions with multiple cystic defects, suggesting leukoencephalopathy in both patients. One patient carried the previously described homozygous TACO1 variant (p.His158ProfsTer8) and haplotype analysis suggested that this variant is a rare founder mutation. The second patient from another family carried a homozygous novel frame shift variant (p.Cys85PhefsTer15). Conclusions: The identification of two Turkish families with similar characteristic clinical presentation and an additional homozygous nonsense mutation confirms that TACO1 is a human mitochondrial disease gene. Although most patients with this clinical presentation undergo next generation sequencing analysis, screening for selected founder mutations in the Turkish population based on the precise clinical presentation may reduce time and cost of finding the genetic diagnosis even in the era of massively parallel sequencing. Show more

DOI: 10.3233/JND-200510

Citation: Journal of Neuromuscular Diseases, vol. 7, no. 3, pp. 301-308, 2020