Journal of Neuromuscular Diseases - Volume 7, issue 2

Authors: Keegan, Niall P.

Article Type: Review Article

Abstract: The DMD gene is the largest in the human genome, with a total intron content exceeding 2.2Mb. In the decades since DMD was discovered there have been numerous reported cases of pseudoexons (PEs) arising in the mature DMD transcripts of some individuals, either as the result of mutations or as low-frequency errors of the spliceosome. In this review, I collate from the literature 58 examples of DMD PEs and examine the diversity and commonalities of their features. In particular, I note the high frequency of PEs that arise from deep intronic SNVs and discuss a possible …link between PEs induced by distal mutations and the regulation of recursive splicing. Show more

Keywords: Cryptic Splice Sites, Muscular Dystrophy, Duchenne, DNA Mutational Analysis, RNA Splicing

DOI: 10.3233/JND-190431

Citation: Journal of Neuromuscular Diseases, vol. 7, no. 2, pp. 77-95, 2020

Authors: Glascock, Jacqueline | Sampson, Jacinda | Connolly, Anne M. | Darras, Basil T. | Day, John W. | Finkel, Richard | Howell, R. Rodney | Klinger, Katherine W. | Kuntz, Nancy | Prior, Thomas | Shieh, Perry B. | Crawford, Thomas O. | Kerr, Douglas | Jarecki, Jill

Article Type: Short Communication

DOI: 10.3233/JND-190468

Citation: Journal of Neuromuscular Diseases, vol. 7, no. 2, pp. 97-100, 2020

Authors: Lee, Jang Woo | Oh, Hyun Jun | Choi, Won Ah | Kim, Dong Jin | Kang, Seong-Woong

Article Type: Research Article

Abstract: Background: Duchenne muscular dystrophy (DMD) patients can have various issues that affect their quality of life, including eating and digestive conditions. Objective: We sought to identify the relationship between respiratory function and various eating and digestion related symptoms in patients with advanced Duchenne muscular dystrophy (DMD). Methods: Eating and digestive symptoms, including loss of appetite, nausea, vomiting, diarrhea, constipation, swallowing difficulty, mastication difficulty, early satiety, and aspiration, were evaluated among patients with advanced DMD who were nonambulatory and required noninvasive mechanical ventilatory support. In addition, various respiratory function parameters were measured, including forced vital capacity (FVC), …maximal insufflation capacity (MIC), peak cough flow (PCF), assisted PCF (APCF), maximal inspiratory pressure (MIP), and maximal expiratory pressure (MEP). We then analyzed the relationship between gastrointestinal symptoms and respiratory function parameters. Results: A total of 180 patients (age, 22.3±5.0 years) were included in the analysis. Loss of appetite and early satiety showed no correlation with any of the respiratory function parameters. Constipation was correlated with MEP; swallowing difficulty was correlated with MIC, APCF, MIP and MEP; and mastication difficulty was correlated with FVC, PCF, APCF, MIP, and MEP. Notably, age did not correlate with any gastrointestinal symptoms. Conclusions: Eating and digestive symptoms are more closely correlated with respiratory function than with age in patients with DMD. We think this correlation is mainly caused by the skeletal muscle strength, which is major determinant of both digestive and respiratory function. Show more

Keywords: Duchenne muscular dystrophy, respiratory function, digestive symptoms, deglutition disorders

DOI: 10.3233/JND-190435

Citation: Journal of Neuromuscular Diseases, vol. 7, no. 2, pp. 101-107, 2020

Authors: Müller-Felber, Wolfgang | Vill, Katharina | Schwartz, Oliver | Gläser, Dieter | Nennstiel, Uta | Wirth, Brunhilde | Burggraf, Siegfried | Röschinger, Wulf | Becker, Marc | Durner, Jürgen | Eggermann, Katja | Müller, Christine | Hannibal, Iris | Olgemöller, Bernd | Schara, Ulrike | Blaschek, Astrid | Kölbel, Heike

Article Type: Research Article

Abstract: Although the value of newborn screening (NBS) for early detection and treatment opportunity in SMA patients is generally accepted, there is still an ongoing discussion about the best strategy in children with 4 and more copies of the SMN2 gene. This gene is known to be the most important but not the only disease modifier. In our SMA-NBS pilot project in Germany comprising 278,970 infants screened between January 2018 and November 2019 were 38 positive cases with a homozygous SMN1 deletion. 40% of them had 4 or more SMN2 copies. The incidence for homozygous SMN1 …deletion was 1 : 7350, which is within the known range of SMA incidence in Germany. Of the 15 SMA children with 4 SMN2 copies, one child developed physical signs of SMA by the age of 8 months. Reanalysis of the SMN2 copy number by a different test method revealed 3 copies. Two children had affected siblings with SMA Type III, who were diagnosed only after detection of the index patient in the NBS. One had a positive family history with an affected aunt (onset of disease at the age of 3 years). Three families were lost to medical follow up; two because of socioeconomic reasons and one to avoid the psychological stress associated with the appointments. Decisions on how to handle patients with 4 SMN2 copies are discussed in the light of the experience gathered from our NBS pilot SMA program. Show more

Keywords: Spinal muscular atrophy, newborn screening, survival motor neuron gene, SMN2

DOI: 10.3233/JND-200475

Citation: Journal of Neuromuscular Diseases, vol. 7, no. 2, pp. 109-117, 2020

Authors: Benyamini, Hadar | Kling, Yehuda | Yakovlev, Lena | Becker Cohen, Michal | Nevo, Yuval | Elgavish, Sharona | Harazi, Avi | Argov, Zohar | Sela, Ilan | Mitrani-Rosenbaum, Stella

Article Type: Research Article

Abstract: Background: Mutations in GNE cause a recessive, adult onset myopathy characterized by slowly progressive distal and proximal muscle weakness. Knock-in mice carrying the most frequent mutation in GNE myopathy patients, Gne M743T/M743T , usually die few days after birth from severe renal failure, with no muscle phenotype. However, a spontaneous sub-colony remains healthy throughout a normal lifespan without any kidney or muscle pathology. Objective: We attempted to decipher the molecular mechanisms behind these phenotypic differences and to determine the mechanisms preventing the kidney and muscles from disease. Methods: We analyzed the transcriptome and proteome of …kidneys and muscles of sick and healthy Gne M743T/M743T mice. Results: The sick Gne M743T/M743T kidney was characterized by up-regulation of extra-cellular matrix degradation related processes and by down-regulation of oxidative phosphorylation and respiratory electron chain pathway, that was also observed in the asymptomatic muscles. Surprisingly, the healthy kidneys of the Gne M743T/M743T mice were characterized by up-regulation of hallmark muscle genes. In addition the asymptomatic muscles of the sick Gne M743T/M743T mice showed upregulation of transcription and translation processes. Conclusions: Overexpression of muscle physiology genes in healthy Gne M743T/M743T mice seems to define the protecting mechanism in these mice. Furthermore, the strong involvement of muscle related genes in kidney may bridge the apparent phenotypic gap between GNE myopathy and the knock-in Gne M743T/M743T mouse model and provide new directions in the study of GNE function in health and disease. Show more

Keywords: GNE myopathy, GNE mouse model, HIBM, RNA-Seq, proteomics

DOI: 10.3233/JND-190461

Citation: Journal of Neuromuscular Diseases, vol. 7, no. 2, pp. 119-136, 2020

Authors: Forrester, Natalie | Rattihalli, Rohini | Horvath, Rita | Maggi, Lorenzo | Manzur, Adnan | Fuller, Geraint | Gutowski, Nicholas | Rankin, Julia | Dick, David | Buxton, Christopher | Greenslade, Mark | Majumdar, Anirban

Article Type: Research Article

Abstract: Pathogenic variants in the Glycyl-tRNA synthetase gene cause the allelic disorders Charcot-Marie-Tooth disease type 2D and distal hereditary motor neuropathy type V. We describe clinical features in 8 unrelated patients found to have Glycyl-tRNA synthetase variants by Next Generation Sequencing. In addition to upper limb predominant symptoms, other presentations included failure to thrive, feeding difficulties and lower limb dominant symptoms. Variability in the age at testing ranged from 14 months to 59 years. The youngest being symptomatic from 3 months and ventilator-dependent. Sequence variants were reported as pathogenic, p.(Glu125Lys), p.(His472Arg); likely pathogenic, p.(His216Arg), p.(Gly327Arg), p.(Lys510Gln), p.(Met555Val); and of uncertain significance, …p.(Arg27Pro). Our case series describes novel Glycyl-tRNA synthetase variants and demonstrates the clinical utility of Next Generation Sequencing testing for patients with hereditary neuropathy. Identification of novel variants by Next Generation Sequencing illustrates that there exists a wide spectrum of clinical features and supports the newer simplified classification of neuropathies. Show more

Keywords: Aminoacyl-tRNA synthetases, Charcot-Marie-Tooth disease, distal hereditary motor neuropathy, Glycyl-tRNA synthetase, Next Generation Sequencing, peripheral neuropathies

DOI: 10.3233/JND-200472

Citation: Journal of Neuromuscular Diseases, vol. 7, no. 2, pp. 137-143, 2020

Authors: Finkel, Richard S. | Day, John W. | De Vivo, Darryl C. | Kirschner, Janbernd | Mercuri, Eugenio | Muntoni, Francesco | Shieh, Perry B. | Tizzano, Eduardo | Desguerre, Isabelle | Quijano-Roy, Susana | Saito, Kayoko | Droege, Marcus | Dabbous, Omar | Khan, Farid | Renault, Lydie | Anderson, Frederick A. | Servais, Laurent

Article Type: Research Article

Abstract: Background: Dramatic improvements in spinal muscular atrophy (SMA) treatment have changed the prognosis for patients with this disease, leading to important new questions. Gathering representative, real-world data about the long-term efficacy and safety of emerging SMA interventions is essential to document their impact on patients and caregivers. Objectives: This registry will assess outcomes in patients with genetically confirmed SMA and provide information on the effectiveness and long-term safety of approved and emerging treatments. Design and Methods: RESTORE is a prospective, multicenter, multinational observational registry. Patients will be managed according to usual clinical practice. Both newly recruitedSMAtreatment …centers and sites involved in existing SMA registries, including iSMAC, Treat-NMD, French SMA Assistance Publique- Hôpitaux de Paris (AP-HP), Cure-SMA, SMArtCARE, will be eligible to participate; de novo ; sites already participating in another registry may be included via consortium agreements. Data from patients enrolled in partnering registries will be shared with the RESTORE Registry and data for newly diagnosed patients will be added upon enrollment. Patients will be enrolled over a 5-year period and followed for 15 years or until death. Assessments will include SMA history and treatment, pulmonary, nutritional, and motor milestones, healthcare resource utilization, work productivity, activity impairment, adverse events, quality of life, caregiver burden, and survival. Status: Recruitment started in September 2018. As of January 3, 2020, 64 patients were enrolled at 25 participating sites. Conclusions: The RESTORE Registry has begun recruiting recently diagnosed patients with genetically confirmed SMA, enabling assessment of both short- and long-term patient outcomes. Show more

Keywords: Spinal muscular atrophy, multinational, prospective, registry, outcomes, rare disease, long-term follow-up, NCT04174157

DOI: 10.3233/JND-190451

Citation: Journal of Neuromuscular Diseases, vol. 7, no. 2, pp. 145-152, 2020

Authors: Savarese, Marco | Johari, Mridul | Johnson, Katherine | Arumilli, Meharji | Torella, Annalaura | Töpf, Ana | Rubegni, Anna | Kuhn, Marius | Giugliano, Teresa | Gläser, Dieter | Fattori, Fabiana | Thompson, Rachel | Penttilä, Sini | Lehtinen, Sara | Gibertini, Sara | Ruggieri, Alessandra | Mora, Marina | Maver, Ales | Peterlin, Borut | Mankodi, Ami | Lochmüller, Hanns | Santorelli, Filippo Maria | Schoser, Benedikt | Fajkusová, Lenka | Straub, Volker | Nigro, Vincenzo | Hackman, Peter | Udd, Bjarne

Article Type: Research Article

Abstract: BACKGROUND: Extensive genetic screening results in the identification of thousands of rare variants that are difficult to interpret. Because of its sheer size, rare variants in the titin gene (TTN ) are detected frequently in any individual. Unambiguous interpretation of molecular findings is almost impossible in many patients with myopathies or cardiomyopathies. OBJECTIVE: To refine the current classification framework for TTN -associated skeletal muscle disorders and standardize the interpretation of TTN variants. METHODS: We used the guidelines issued by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) …to re-analyze TTN genetic findings from our patient cohort. RESULTS: We identified in the classification guidelines three rules that are not applicable to titin-related skeletal muscle disorders; six rules that require disease-/gene-specific adjustments and four rules requiring quantitative thresholds for a proper use. In three cases, the rule strength need to be modified. CONCLUSIONS: We suggest adjustments are made to the guidelines. We provide frequency thresholds to facilitate filtering of candidate causative variants and guidance for the use and interpretation of functional data and co-segregation evidence. We expect that the variant classification framework for TTN -related skeletal muscle disorders will be further improved along with a better understanding of these diseases. Show more

Keywords: Titin, cardiomyopathies, skeletal muscle disorders, clinical interpretation, data sharing

DOI: 10.3233/JND-190423

Citation: Journal of Neuromuscular Diseases, vol. 7, no. 2, pp. 153-166, 2020

Authors: Barnard, Alison M. | Riehl, Samuel L. | Willcocks, Rebecca J. | Walter, Glenn A. | Angell, Amber M. | Vandenborne, Krista

Article Type: Research Article

Abstract: Observational research benefits from inclusion of diverse cohorts. To characterize racial and ethnic diversity in observational and natural history research studies of Duchenne muscular dystrophy (DMD), highly cited and influential observational studies were identified. Fourteen United States-based articles were included. All studies cited >70% White participants with the majority having few racial minority participants. Enrollment of Black/African American individuals was particularly limited (<5% in all but one study), and Hispanic/Latino participants ranged from 3.3– 26.5% of cohorts. These results suggest a need for effective strategies to recruit, enroll, and retain racially and ethnically diverse populations into observational research in DMD.

Keywords: Muscular dystrophies, Bibliometrics, Healthcare Disparities, Minority Health, Observational Studies

DOI: 10.3233/JND-190447

Citation: Journal of Neuromuscular Diseases, vol. 7, no. 2, pp. 167-173, 2020

Authors: Lutchmansingh, Khama | Venkatesh, Y. Swamy | Boppana, Leela Krishna Teja | Seemungal, Terence | Rao, Ambika | Sandy, Sherry | Teelucksingh, Surujpal

Article Type: Research Article

Abstract: Background: Neuropathic feet are at very high risk for infection and amputation. The slipping slipper sign (SSS) is elicited by a simple questionnaire test reported to detect the presence of severe diabetic peripheral neuropathy. This test can be administered by non-medical staff. In this study, subjects with and without the SSS were evaluated by nerve conduction studies (NCS) and ultrasound measurements of the right sural nerve diameters as well as with traditional scoring systems for peripheral and autonomic neuropathy. Objective: To demonstrate that the Slipping Slipper Sign can be used as an index of severe diabetic peripheral neuropathy …Method: This was a prospective cross sectional study in which 74 patients with diabetes (38 positive and 36 negative for SSS) underwent ultrasonography and NCS of the right sural nerve by an examiner blinded to SSS status. Findings were evaluated against demography, clinical history, anthropometry as well as traditional clinical and autonomic neuropathic scores. Results: Patients without the SSS [median (IQR) = 10.0 years (4.0–20.3)] had a significantly shorter duration of diabetes compared with those with the SSS [median (IQR) = 15.0 years (8.5–25.0)], p  = 0.028. The frequencies of retinopathy (36.8% vs 2.8%, p  <  0.05) and cerebrovascular accidents (18.4% vs 13.9 %, p  <  0.05) were higher among those with SSS compared with those without. Differences in nerve conduction characteristics were markedly significant. The amplitude of the sural sensory nerve action potential (SNAP) was ([median (IQR)] 0 microvolts vs 4.0 microvolts (0.0–10.8) p  <  0.002) between those with and without SSS, respectively whilst none of patients with SSS had a recordable SNAP vs 78% without a SSS. Similarly, maximal thickness of the right sural nerve at the ankle 3.0 mm (2.3–3.4) vs 3.5 mm (3.0–3.9), and leg 3.4 mm (2.7–3.8) vs 3.9 mm (3.3–4.2) was reduced, p  <  0.01 in patients with the SSS compared with those with a negative SSS. Conclusion: The SSS identifies feet with objective neurophysiological and imaging characteristics of severe neuropathy. Show more

Keywords: Slipping Slipper Sign, Diabetes Mellitus, Diabetic Peripheral Neuropathy, Screening test

DOI: 10.3233/JND-190422

Citation: Journal of Neuromuscular Diseases, vol. 7, no. 2, pp. 175-181, 2020

Authors: Dunaway Young, Sally | Montes, Jacqueline | Salazar, Rachel | Glanzman, Allan M. | Pasternak, Amy | Mirek, Elizabeth | Martens, William | Finkel, Richard S. | Darras, Basil T. | De Vivo, Darryl C.

Article Type: Research Article

Abstract: Background: Weakness affects motor performance and causes skeletal deformities in spinal muscular atrophy (SMA). Scoliosis surgery decision-making is based on curve progression, pulmonary function, and skeletal maturity. Benefits include quality of life, sitting balance, and endurance. Post-operative functional decline has not been formally assessed. Objective: To assess the impact of scoliosis surgery on motor function in SMA types 2 and 3. Methods: Prospective data were acquired during a multicenter natural history study. Seventeen participants (12 type 2, 5 type 3 with 4 of the 5 having lost the ability to ambulate) had motor function assessed using …the Hammersmith Functional Motor Scale Expanded (HFMSE) performed pre-operatively and at least 3 months post-operatively. Independent t -tests determined group differences based on post-operative HFMSE changes, age, and baseline HFMSE scores. Results: Three participants had minimal HFMSE changes (±2 points) representing stability (mean change = –0.7). Fourteen participants lost >3 points, representing a clinically meaningful progressive change (mean change = –12.1, SD = 8.9). No participant improved >2 points. There were no age differences between stable and progressive groups (p  = 0.278), but there were significant differences between baseline HFMSE (p  = 0.006) and change scores (p  = 0.001). Post-operative changes were permanent over time. Conclusions: Scoliosis surgery has an immediate impact on function. Baseline HFMSE scores anticipate post-operative loss as higher motor function scores were associated with worse decline. Instrumentation that includes fixation to the pelvis reduces flexibility, limiting the ability for compensatory maneuvers. These observations provide information to alert clinicians regarding surgical risk and to counsel families. Show more

Keywords: Spinal muscular atrophy, scoliosis, surgery, motor function

DOI: 10.3233/JND-190462

Citation: Journal of Neuromuscular Diseases, vol. 7, no. 2, pp. 183-192, 2020

Authors: Taminato, Tomoya | Mori-Yoshimura, Madoka | Miki, Jun | Sasaki, Ryogen | Sato, Noriko | Oya, Yasushi | Nishino, Ichizo | Takahashi, Yuji

Article Type: Case Report

Abstract: Background: Paramyotonia congenita (PC; OMIM 168300) is a non-dystrophic myotonia caused by mutations in the SCN4A gene. Transient muscle stiffness, usually induced by exposure to cold and aggravated by exercise, is the predominant clinical symptom, and interictal persistent weakness is uncommon. Case report: We report a family with a history of PC accompanied by persistent hand muscle weakness with masticatory muscle involvement. Persistent weakness was exacerbated with age, and MR analysis showed marked atrophy of temporal, masseter, and finger flexor muscles with fatty replacement. The PC causative mutation T1313M in the SCN4A gene was prevalent in …the family. Administration of acetazolamide chloride improved clinical symptoms and the results of cold and short exercise tests. Phenotypic variation within the family was remarkable, as the two younger affected patients did not present with persistent weakness or muscle atrophy. Conclusions: PC associated with the T1313M mutation is a possible cause of persistent distal hand weakness. Show more

Keywords: Paramyotonia congenita, persistent distal hand weakness, temporal muscle, strabismus, SCN4A, T1313M, short exercise test, acetazolamide chloride

DOI: 10.3233/JND-190440

Citation: Journal of Neuromuscular Diseases, vol. 7, no. 2, pp. 193-201, 2020