Journal of Neuromuscular Diseases - Volume 10, issue 5

Authors: Pugliese, Alessia | Holland, Stephen H. | Rodolico, Carmelo | Lochmüller, Hanns | Spendiff, Sally

Article Type: Review Article

Abstract: Presynaptic congenital myasthenic syndromes (CMS) are a group of genetic disorders affecting the presynaptic side of the neuromuscular junctions (NMJ). They can result from a dysfunction in acetylcholine (ACh) synthesis or recycling, in its packaging into synaptic vesicles, or its subsequent release into the synaptic cleft. Other proteins involved in presynaptic endplate development and maintenance can also be impaired. Presynaptic CMS usually presents during the prenatal or neonatal period, with a severe phenotype including congenital arthrogryposis, developmental delay, and apnoeic crisis. However, milder phenotypes with proximal muscle weakness and good response to treatment have been described. Finally, many presynaptic …genes are expressed in the brain, justifying the presence of additional central nervous system symptoms. Several animal models have been developed to study CMS, providing the opportunity to identify disease mechanisms and test treatment options. In this review, we describe presynaptic CMS phenotypes with a focus on in vivo models, to better understand CMS pathophysiology and define new causative genes. Show more

Keywords: Congenital myasthenic syndromes, neuromuscular junction, animal models, gene mutations

DOI: 10.3233/JND-221646

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 5, pp. 731-759, 2023

Authors: Caron, Leslie | Testa, Stefano | Magdinier, Frédérique

Article Type: Review Article

Abstract: Neuromuscular disorders (NMDs) are a large group of diseases associated with either alterations of skeletal muscle fibers, motor neurons or neuromuscular junctions. Most of these diseases is characterized with muscle weakness or wasting and greatly alter the life of patients. Animal models do not always recapitulate the phenotype of patients. The development of innovative and representative human preclinical models is thus strongly needed for modeling the wide diversity of NMDs, characterization of disease-associated variants, investigation of novel genes function, or the development of therapies. Over the last decade, the use of patient’s derived induced pluripotent stem cells (hiPSC) has resulted …in tremendous progress in biomedical research, including for NMDs. Skeletal muscle is a complex tissue with multinucleated muscle fibers supported by a dense extracellular matrix and multiple cell types including motor neurons required for the contractile activity. Major challenges need now to be tackled by the scientific community to increase maturation of muscle fibers in vitro , in particular for modeling adult-onset diseases affecting this tissue (neuromuscular disorders, cachexia, sarcopenia) and the evaluation of therapeutic strategies. In the near future, rapidly evolving bioengineering approaches applied to hiPSC will undoubtedly become highly instrumental for investigating muscle pathophysiology and the development of therapeutic strategies. Show more

Keywords: Induced pluripotent stem cells, neuromuscular disorders, satellite cells, myoblasts, myotubes, motor neurons, neuromuscular junctions, 3D culture, therapy

DOI: 10.3233/JND-230076

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 5, pp. 761-776, 2023

Authors: Middelink, Marloes | Voermans, Nicol C. | van Engelen, Baziel G.M. | Janssen, Mirian C.H. | Groothuis, Jan T. | Knuijt, Simone | Zweers-van Essen, Heidi

Article Type: Systematic Review

Abstract: Background: Eating an adequate diet and maintaining a healthy body weight can be challenging for patients with muscular disorders (MD). Starting tube feeding can have a positive impact on nutritional status, functioning and quality of life. Guidelines on when to start tube feeding in adults with MD are lacking. Objective: We aim to review the scientific literature on indications to start tube feeding in adults with facioscapulohumeral dystrophy (FSHD), inclusion body myositis (IBM), muscular dystrophy type 1 (DM1), oculopharyngeal muscular dystrophy (OPMD) and congenital myopathies. Methods: This scoping review was conducted according to the Preferred Reporting …Items for Systematic Reviews and Meta-Analyses extension for scoping reviews (PRISMA-ScR) guidelines. Relevant studies were identified in Pubmed, Embase and Cinahl (April 2022). The medical subject headings (MeSH) and text words used were related to FSHD, IBM, DM1, OPMD or congenital myopathies and dysphagia, enteral nutrition or malnutrition. Results: Of 1046 unique articles, 9 case reports and 2 retrospective case series were included. Indications to start tube feeding were dysphagia, malnutrition/weight loss and respiratory infections (due to aspiration). Percutaneous endoscopic gastrostomy (PEG) tubes were used most often and complications were respiratory failure, problems with the tube itself, accidental tube removal, cutaneous symptoms, digestive symptoms, and peritonitis. Conclusion: Data on tube feeding in MD is scarce. Indications to start tube feeding were similar across the various MD. We call for more research in this field and suggest to include screening for dysphagia, aspiration and malnutrition in for the treatment of various MD. Show more

Keywords: Enteral nutrition, dysphagia, pneumonia, aspiration, malnutrition, weight loss, muscular dystrophies, myositis, inclusion body, myopathies, structural, congenital

DOI: 10.3233/JND-230014

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 5, pp. 777-785, 2023

Authors: Markvardsen, Lars K. | Sindrup, Søren H. | Christiansen, Ingelise | Sheikh, Aisha M. | Holbech, Jakob V. | Andersen, Henning

Article Type: Research Article

Abstract: Background: Attempting discontinuation of treatment in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) is recommended. However, there is no evidence based regimen for tapering off subcutaneous immunoglobulin (SCIG). This trial investigated stepwise tapering off SCIG to detect remission and the lowest effective dosage. During tapering off, frequent vs less frequent clinical evaluation was compared. Methods: Patients with CIDP receiving a stable SCIG dosage followed a standardized tapering off regimen: 90%, 75%, 50%, 25% and 0% of the initial dose every 12th week, pending no deterioration occurred. In case of relapse during tapering off, the lowest effective dose was …identified. Treatment with SCIG was registered for two years after participation. Disability score and grip strength were primary parameters. Participants were randomized to clinical evaluation every 6th week (frequent) or 12th week (less frequent). Results: Fifty-five patients were included of which thirty-five relapsed. Twenty patients (36%) were able to discontinue treatment without relapse. In relapsing patients, median dosage could be reduced by 10% (range, 0–75). After two years, 18 of 20 patients were still in remission without treatment. Frequent clinical evaluation did not detect deterioration more frequently than less frequent evaluation; RR 0.5 (95% CI, 0.2–1.2) (p  = 0.17). Conclusion: In stable CIDP patients, SCIG could be completely tapered off in 36% of the patients and only in 10% of these patients relapse occurred during the following two years. More frequent evaluation was not superior to detect deterioration. Show more

Keywords: Inflammatory neuropathy, immunoglobulin

DOI: 10.3233/JND-221615

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 5, pp. 787-796, 2023

Authors: Zygmunt, Deborah A. | Lam, Patricia | Ashbrook, Anna | Koczwara, Katherine | Lek, Angela | Lek, Monkol | Martin, Paul T.

Article Type: Research Article

Abstract: Background: GNE myopathy (GNEM) is a severe muscle disease caused by mutations in the UDP-GlcNAc-2-epimerase/ManNAc-6-kinase (GNE ) gene, which encodes a bifunctional enzyme required for sialic acid (Sia) biosynthesis. Objective: To develop assays to demonstrate the potency of AAV gene therapy vectors in making Sia and to define the dose required for replacement of endogenous mouse Gne gene expression with human GNE in skeletal muscles. Methods: A MyoD -inducible Gne -deficient cell line, Lec3MyoDI , and a GNE- deficient human muscle cell line, were made and tested to define the potency of various AAV …vectors to increase binding of Sia-specific lectins, including MAA and SNA. qPCR and qRT-PCR methods were used to quantify AAV biodistribution and GNE gene expression after intravenous delivery of AAV vectors designed with different promoters in wild-type mice. Results: Lec3 cells showed a strong deficit in MAA binding, while GNE –/– MB135 cells did not. Overexpressing GNE in Lec3 and Lec3MyoDI cells by AAV infection stimulated MAA binding in a dose-dependent manner. Use of a constitutive promoter, CMV, showed higher induction of MAA binding than use of muscle-specific promoters (MCK, MHCK7). rAAVrh74.CMV.GNE stimulated human GNE expression in muscles at levels equivalent to endogenous mouse Gne at a dose of 1×1013 vg/kg, while AAVs with muscle-specific promoters required higher doses. AAV biodistribution in skeletal muscles trended higher when CMV was used as the promoter, and this correlated with increased sialylation of its viral capsid. Conclusions: Lec3 and Lec3MyoDI cells work well to assay the potency of AAV vectors in making Sia. Systemic delivery of rAAVrh74.CMV.GNE can deliver GNE gene replacement to skeletal muscles at doses that do not overwhelm non-muscle tissues, suggesting that AAV vectors that drive constitutive organ expression could be used to treat GNEM. Show more

Keywords: GNE myopathy, gene therapy, sialic acid, AAV, muscular dystrophy

DOI: 10.3233/JND-221596

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 5, pp. 797-812, 2023

Authors: Finkel, Richard S. | Day, John W. | Pascual Pascual, Samuel Ignacio | Ryan, Monique M. | Mercuri, Eugenio | De Vivo, Darryl C. | Montes, Jacqueline | Gurgel-Giannetti, Juliana | Monine, Michael | Gambino, Giulia | Makepeace, Corinne | Foster, Richard | Berger, Zdenek

Article Type: Research Article

Abstract: Background: Pharmacokinetic/pharmacodynamic modeling indicates that the higher dose of nusinersen may be associated with a clinically meaningful increase in efficacy above that seen with the 12-mg approved dose. Objective: Here we describe both the design of DEVOTE (NCT04089566), a 3-part clinical study evaluating safety, tolerability, and efficacy of higher dose of nusinersen, and results from the initial Part A. Methods: DEVOTE Part A evaluates safety and tolerability of a higher nusinersen dose; Part B assesses efficacy in a randomized, double-blind design; and Part C assesses safety and tolerability of participants transitioning from the 12-mg dose to …higher doses. Results: In the completed Part A of DEVOTE, all 6 enrolled participants aged 6.1–12.6 years have completed the study. Four participants experienced treatment-emergent adverse events (TEAEs), the majority of which were mild. Common TEAEs of headache, pain, chills, vomiting, and paresthesia were considered related to the lumbar puncture procedure. There were no safety concerns regarding clinical or laboratory parameters. Nusinersen levels in the cerebrospinal fluid were within the range of modeled predictions for higher dose of nusinersen. While Part A was not designed for assessing efficacy, most participants showed stabilization or improvement in motor function. Parts B and C of DEVOTE are ongoing. Conclusions: The findings from Part A of the DEVOTE study support further development of higher dose of nusinersen. Show more

Keywords: Spinal muscular atrophy, nusinersen, safety, pharmacokinetics

DOI: 10.3233/JND-221667

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 5, pp. 813-823, 2023

Authors: van Kleef, Esmee S.B. | Langer, Daniel | van Engelen, Baziel G.M. | Ottenheijm, Coen A.C. | Voermans, Nicol C. | Doorduin, Jonne

Article Type: Research Article

Abstract: Background: Respiratory muscle weakness is a common feature in nemaline myopathy. Inspiratory muscle training (IMT) is an intervention that aims to improve inspiratory muscle strength. Objective: The aim of this controlled before-and-after pilot study was to investigate if IMT improves respiratory muscle strength in patients with nemaline myopathy. Methods: Nine patients (7 females; 2 males, age 36.6±20.5 years) with respiratory muscle weakness and different clinical phenotypes and genotypes were included. Patients performed eight weeks of sham IMT followed by eight weeks of active threshold IMT. The patients trained twice a day five days a week for …15 minutes at home. The intensity was constant during the training after a gradual increase to 30% of maximal inspiratory pressure (MIP). Results: Active IMT significantly improved MIP from 43±15.9 to 47±16.6 cmH2 O (p  = 0.019). The effect size was 1.22. There was no significant effect of sham IMT. Sniff nasal inspiratory pressure, maximal expiratory pressure, spirometry, and diaphragm thickness and thickening showed no significant improvements. Conclusions: This pilot study shows that threshold IMT is feasible in patients with nemaline myopathy and improves inspiratory muscle strength. Our findings provide valuable preliminary data for the design of a larger, more comprehensive trial. Show more

Keywords: Respiratory muscle weakness, nemaline myopathy, inspiratory muscle training, diaphragm

DOI: 10.3233/JND-221665

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 5, pp. 825-834, 2023

Authors: Kleinle, Stephanie | Scholz, Veronika | Benet-Pagés, Anna | Wohlfrom, Tobias | Gehling, Stefanie | Scharf, Florentine | Rost, Simone | Prott, Eva-Christina | Grinzinger, Susanne | Hotter, Anna | Haug, Verena | Niemeier, Sabine | Wiethoff-Ubrig, Lucia | Hagenacker, Tim | Goldhahn, Klaus | von Moers, Arpad | Walter, Maggie C. | Reilich, Peter | Eggermann, Katja | Kraft, Florian | Kurth, Ingo | Erdmann, Hannes | Holinski-Feder, Elke | Neuhann, Teresa | Abicht, Angela

Article Type: Research Article

Abstract: Background: The importance of early diagnosis of 5q-Spinal muscular atrophy (5q-SMA) has heightened as early intervention can significantly improve clinical outcomes. In 96% of cases, 5q-SMA is caused by a homozygous deletion of SMN1 . Around 4 % of patients carry a SMN1 deletion and a single-nucleotide variant (SNV) on the other allele. Traditionally, diagnosis is based on multiplex ligation probe amplification (MLPA) to detect homozygous or heterozygous exon 7 deletions in SMN1 . Due to high homologies within the SMN1/SMN2 locus, sequence analysis to identify SNVs of the SMN1 gene is unreliable by standard Sanger or …short-read next-generation sequencing (srNGS) methods. Objective: The objective was to overcome the limitations in high-throughput srNGS with the aim of providing SMA patients with a fast and reliable diagnosis to enable their timely therapy. Methods: A bioinformatics workflow to detect homozygous SMN1 deletions and SMN1 SNVs on srNGS analysis was applied to diagnostic whole exome and panel testing for suggested neuromuscular disorders (1684 patients) and to fetal samples in prenatal diagnostics (260 patients). SNVs were detected by aligning sequencing reads from SMN1 and SMN2 to an SMN1 reference sequence. Homozygous SMN1 deletions were identified by filtering sequence reads for the ,, gene-determining variant“ (GDV). Results: 10 patients were diagnosed with 5q-SMA based on (i) SMN1 deletion and hemizygous SNV (2 patients), (ii) homozygous SMN1 deletion (6 patients), and (iii) compound heterozygous SNVs in SMN1 (2 patients). Conclusions: Applying our workflow in srNGS-based panel and whole exome sequencing (WES) is crucial in a clinical laboratory, as otherwise patients with an atypical clinical presentation initially not suspected to suffer from SMA remain undiagnosed. Show more

Keywords: 5q-SMA, spinal muscular atrophy, clinical genetics, neuromuscular disorders, bioninformatics, dark genes

DOI: 10.3233/JND-221668

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 5, pp. 835-846, 2023

Authors: Sun, Jianli | Harrington, Melissa A. | Porter, Ben

Article Type: Research Article

Abstract: Background: Sex is a significant risk factor in many neurodegenerative disorders. A better understanding of the molecular mechanisms behind sex differences could help develop more targeted therapies that would lead to better outcomes. Untreated spinal muscular atrophy (SMA) is the leading genetic motor disorder causing infant mortality. SMA has a broad spectrum of severity ranging from prenatal death to infant mortality to normal lifespan with some disability. Scattered evidence points to a sex-specific vulnerability in SMA. However, the role of sex as a risk factor in SMA pathology and treatment has received limited attention. Objective: Systematically investigate sex …differences in the incidence, symptom severity, motor function of patients with different types of SMA, and in the development of SMA1 patients. Methods: Aggregated data of SMA patients were obtained from the TREAT-NMD Global SMA Registry and the Cure SMA membership database by data enquiries. Data were analyzed and compared with publicly available standard data and data from published literature. Results: The analysis of the aggregated results from the TREAT-NMD dataset revealed that the male/female ratio was correlated to the incidence and prevalence of SMA from different countries; and for SMA patients, more of their male family members were affected by SMA. However, there was no significant difference of sex ratio in the Cure SMA membership dataset. As quantified by the clinician severity scores, symptoms were more severe in males than females in SMA types 2 and 3b. Motor function scores measured higher in females than males in SMA types 1, 3a and 3b. The head circumference was more strongly affected in male SMA type 1 patients. Conclusions: The data in certain registry datasets suggest that males may be more vulnerable to SMA than females. The variability observed indicates that more investigation is necessary to fully understand the role of sex differences in SMA epidemiology, and to guide development of more targeted treatments. Show more

Keywords: Spinal muscular atrophy, sex difference, male/female ratio, severity, motor function, development

DOI: 10.3233/JND-230011

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 5, pp. 847-867, 2023

Authors: Keene, Kevin R. | Notting, Irene C. | Verschuuren, Jan J.G.M. | Voermans, N. | de Keizer, Ronald. O.B. | Beenakker, Jan-Willem M. | Tannemaat, Martijn R. | Kan, Hermien E.

Article Type: Research Article

Abstract: Introduction: MRI of extra-ocular muscles (EOM) in patients with myasthenia gravis (MG) could aid in diagnosis and provide insights in therapy-resistant ophthalmoplegia. We used quantitative MRI to study the EOM in MG, healthy and disease controls, including Graves’ ophthalmopathy (GO), oculopharyngeal muscular dystrophy (OPMD) and chronic progressive external ophthalmoplegia (CPEO). Methods: Twenty recently diagnosed MG (59±19yrs), nineteen chronic MG (51±16yrs), fourteen seronegative MG (57±9yrs) and sixteen healthy controls (54±13yrs) were included. Six CPEO (49±14yrs), OPMD (62±10yrs) and GO patients (44±12yrs) served as disease controls. We quantified muscle fat fraction (FF), T2water and volume. Eye ductions and gaze …deviations were assessed by synoptophore and Hess-charting. Results: Chronic, but not recent onset, MG patients showed volume increases (e.g. superior rectus and levator palpebrae [SR+LPS] 985±155 mm3 compared to 884±269 mm3 for healthy controls, p  < 0.05). As expected, in CPEO volume was decreased (e.g. SR+LPS 602±193 mm3 , p  < 0.0001), and in GO volume was increased (e.g. SR+LPS 1419±457 mm3 , p  < 0.0001). FF was increased in chronic MG (e.g. medial rectus increased 0.017, p  < 0.05). In CPEO and OPMD the FF was more severely increased. The severity of ophthalmoplegia did not correlate with EOM volume in MG, but did in CPEO and OPMD. No differences in T2water were found. Interpretation: We observed small increases in EOM volume and FF in chronic MG compared to healthy controls. Surprisingly, we found no atrophy in MG, even in patients with long-term ophthalmoplegia. This implies that even long-term ophthalmoplegia in MG does not lead to secondary structural myopathic changes precluding functional recovery. Show more

Keywords: Myasthenia gravis, quantitative MRI, eye muscles, extra-ocular muscles, chronic progressive external ophthalmoplegia (CPEO), diplopia, ptosis, oculopharyngeal muscular dystrophy (OPMD) and Graves’ orbitopathy

DOI: 10.3233/JND-230023

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 5, pp. 869-883, 2023

Authors: Havner, Christina | Roussakis, Anna Ödman | Sjögreen, Lotta | Westerlund, Anna

Article Type: Research Article

Abstract: Open bite (OB) is a common malocclusion in individuals with orofacial dysfunction and syndromes, especially in neuromuscular diseases. Objectives: The objectives were to explore the prevalence of OB in myotonic dystrophy type 1 (DM1) and Duchenne muscular dystrophy (DMD) and to create and compare orofacial dysfunction profiles. Methods: In this database study, 143 individuals with DM1 and 99 with DMD were included. The Mun-H-Center questionnaire and observation chart were used together with the Nordic Orofacial Test –Screening (NOT-S) to create orofacial dysfunction profiles. OB was categorised as: lateral (LOB); anterior (AOB); severe anterior (AOBS ); or both …types of anterior OB (AOBTot ). Descriptive and multivariate statistics were used to compare the OB prevalence and to study associations with orofacial variables, respectively. Results: There was a statistically significant difference in OB prevalence between the DM1 (37%) and DMD (49%) groups (p  = 0.048). LOB was seen in < 1% of DM1 and 18% of DMD. LOB was associated with macroglossia and closed mouth posture, AOB with hypotonic lips, and open mouth posture and AOBS with hypotonic jaw muscles. The orofacial dysfunction profiles showed similar patterns, although the mean NOT-S total scores for DM1 and DMD were 4.2±2.8 (median 4.0, min-max 1–8) and 2.3±2.0 (median 2.0, min-max 0–8), respectively. Limitations: The two groups were not age- or gender-matched. Conclusion: OB malocclusion is common in patients with DM1 and DMD and is associated with different types of orofacial dysfunction. This study highlights the need for multi-disciplinary assessments to support tailored treatment strategies that improve or sustain orofacial functions. Show more

Keywords: Open bite, facial muscles, myotonic dystrophy type 1, Duchenne muscular dystrophy

DOI: 10.3233/JND-230025

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 5, pp. 885-896, 2023

Authors: Uher, David | Yoon, Lisa | Garber, Carol Ewing | Montes, Jacqueline

Article Type: Research Article

Abstract: Background: Physical activity (PA) provides many substantial benefits to help reduce risk for cardiometabolic disease, improve cognitive function, and improve quality of life. Individuals with neuromuscular disorders (NMDs), such as spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD) are characterized by muscular weakness and fatigue, which limits the capacity to reach the recommended guidelines of PA. Measuring PA in these populations can provide insight to participation in daily activities, track disease progression, and monitor efficacy of drug treatments. Objective: The objective of this study was to identify how PA is measured in SMA and DMD using instrumented …and self-report methods, and how these methods are employed in ambulatory and non-ambulatory groups. Methods: A scoping review was performed to identify studies that reported PA in these neuromuscular disorders. Inclusion was determined after a multi-stage review process by several reviewers, followed by an in-depth analysis of metrics reported by each tool that was used. Results: A total of nineteen studies were identified and included in this review. Sixteen studies included instrumented measures and four studies utilized self-reported measures, with eleven studies also reporting PA information from a non-ambulatory group. A variety of metrics have been reported using both classes of measurement tools. Conclusion: Although a wide variety of research exists that details both instrumented and self-reported measurement tools, feasibility, cost, and study aims are important factors to consider in addition to testing methodology when selecting which type of tool to use. We recommend using a combination of instrumented and self-report measures to provide context to the PA measured in these populations. Improvements in both instrumented and self-report methodologies will add valuable knowledge about the disease burden and efficacy of treatment and disease management methods in SMA and DMD. Show more

Keywords: Duchenne muscular dystrophy, neuromuscular, neuromuscular disorder, physical activity, spinal muscular atrophy

DOI: 10.3233/JND-230033

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 5, pp. 897-914, 2023

Authors: Öz Tunçer, Gökçen | Sanri, Aslıhan | Aydin, Seren | Hergüner, Özlem M. | Özgün, Nezir | Kömür, Mustafa | İçağasioğlu, Dilara F. | Toker, Rabia Tütüncü | Yilmaz, Sanem | Arslan, Elif Acar | Güngör, Mesut | Kutluk, Gültekin | Erol, İlknur | Mert, Gülen Gül | Polat, Burçin Gönüllü | Aksoy, Ayşe

Article Type: Research Article

Abstract: Background: Myotonia congenita is the most common form of nondystrophic myotonia and is caused by Mendelian inherited mutations in the CLCN1 gene encoding the voltage-gated chloride channel of skeletal muscle. Objective: The study aimed to describe the clinical and genetic spectrum of Myotonia congenita in a large pediatric cohort. Methods: Demographic, genetic, and clinical data of the patients aged under 18 years at time of first clinical attendance from 11 centers in different geographical regions of Türkiye were retrospectively investigated. Results: Fifty-four patients (mean age:15.2 years (±5.5), 76% males, with 85% Becker, 15% …Thomsen form) from 40 families were included. Consanguineous marriage rate was 67%. 70.5% of patients had a family member with Myotonia congenita. The mean age of disease onset was 5.7 (±4.9) years. Overall 23 different mutations (2/23 were novel) were detected in 52 patients, and large exon deletions were identified in two siblings. Thomsen and Becker forms were observed concomitantly in one family. Carbamazepine (46.3%), mexiletine (27.8%), phenytoin (9.3%) were preferred for treatment. Conclusions: The clinical and genetic heterogeneity, as well as the limited response to current treatment options, constitutes an ongoing challenge. In our cohort, recessive Myotonia congenita was more frequent and novel mutations will contribute to the literature. Show more

Keywords: Myotonia congenita, CLCN1, genetic heterogeneity, child

DOI: 10.3233/JND-230046

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 5, pp. 915-924, 2023

Authors: Shelly, Shahar | Ramon-Gonen, Roni | Paul, Pritikanta | Klein, Christopher J. | Klang, Eyal | Rahman, Nisim | Nikitin, Vera | Ben David, Merav | Dori, Amir

Article Type: Research Article

Abstract: Background: The normal limits of nerve conduction studies are commonly determined by testing healthy subjects. However, in comprehensive real-life nerve conduction electrodiagnostic (EDX) evaluations, multiple nerves are tested, including normal nerves, for purposes of comparison with abnormal ones. Objective: This study aims to evaluate the average values of normal nerve conduction studies in a large population and examined the influence of age and sex. Methods: EDX parameters were extracted from an electronic database of studies performed from May 2016 to February 2022. Established normal values were used to determine the classification of a nerve study as …normal. Results: We identified 10,648 EDX reports with 5077 normally interpreted nerve conduction studies (47.6%) of which 57% (n  = 2890) were for females. The median age of studies with no abnormalities was 45.1 years (range < 1 to 92) overall and 42.5 years (range: 0.16 –89.5 years) for males and 47.5 years (range:<1 –91.7) for females. Correlations between age and amplitude, latency, and velocity (p  < 0.001) were observed in most nerves. Amplitude correlated negatively with age in adults in all nerves with a mean of –0.44 (range: –0.24 to –0.62). However, in the pediatric population (age < 18 years), amplitude as well as velocity increased significantly with age. In the adult cohort, sex differences were noted, where females had higher mean sensory nerve action potentials in ulnar, median, and radial evaluations (p  < 0.001). In older patients (aged > 70 years) with normally interpreted EDX studies (845 records of 528 patients), sural responses were present in 97%. Conclusions: This real-life study confirms that advanced aging is associated with decreased nerve conduction amplitudes, increased latency, and the slowing of conduction velocity. The findings also indicate higher sensory amplitudes and conduction velocities in females. Sural nerve responses were identified in most adults over age 70. Show more

Keywords: Sex differences, nerve conduction tests, reference ranges, standards, personalized medicine

DOI: 10.3233/JND-230052

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 5, pp. 925-935, 2023

Authors: Glascock, Jacqueline | Darras, Basil T. | Crawford, Thomas O. | Sumner, Charlotte J. | Kolb, Stephen J. | DiDonato, Christine | Elsheikh, Bakri | Howell, Kelly | Farwell, Wildon | Valente, Marta | Petrillo, Marco | Tingey, Jessica | Jarecki, Jill

Article Type: Research Article

Abstract: Background: Spinal muscular atrophy (SMA) is caused by bi-allelic, recessive mutations of the survival motor neuron 1 (SMN1 ) gene and reduced expression levels of the survival motor neuron (SMN) protein. Degeneration of alpha motor neurons in the spinal cord causes progressive skeletal muscle weakness. The wide range of disease severities, variable rates of decline, and heterogenous clinical responses to approved disease-modifying treatment remain poorly understood and limit the ability to optimize treatment for patients. Validation of a reliable biomarker(s) with the potential to support early diagnosis, inform disease prognosis and therapeutic suitability, and/or confirm response to treatment(s) represents a …significant unmet need in SMA. Objectives: The SMA Multidisciplinary Biomarkers Working Group, comprising 11 experts in a variety of relevant fields, sought to determine the most promising candidate biomarker currently available, determine key knowledge gaps, and recommend next steps toward validating that biomarker for SMA. Methods: The Working Group engaged in a modified Delphi process to answer questions about candidate SMA biomarkers. Members participated in six rounds of reiterative surveys that were designed to build upon previous discussions. Results: The Working Group reached a consensus that neurofilament (NF) is the candidate biomarker best poised for further development. Several important knowledge gaps were identified, and the next steps toward filling these gaps were proposed. Conclusions: NF is a promising SMA biomarker with the potential for prognostic, predictive, and pharmacodynamic capabilities. The Working Group has identified needed information to continue efforts toward the validation of NF as a biomarker for SMA. Show more

Keywords: Spinal muscular atrophy (SMA), biomarker, neurofilament (NF), motor neuron disease

DOI: 10.3233/JND-230054

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 5, pp. 937-954, 2023

Authors: Crescimanno, Grazia | Greco, Francesca | Bertini, Manuela | Maltese, Giacomo | Marrone, Oreste

Article Type: Research Article

Abstract: Background: In Duchenne muscular dystrophy (DMD), dysphagia is a common but often overlooked symptom, which may affect quality of life (QoL). Its possible causes are progressive deterioration of muscle groups involved in swallowing function (oropharyngeal, inspiratory muscles) or impairment of autonomic function. Objectives: In adult patients with DMD, we aimed to identify predictors of swallowing-related QoL and to compare swallowing-related QoL at different ages. Methods: Forty-eight patients aged 30.0±6.6 years were enrolled. Questionnaires were administered: the Swallowing Quality of Life questionnaire (SWAL-QOL) for swallowing-related QoL assessment, and the Compass 31 for autonomic symptoms assessment. The Brooke …Upper Extremity Scale was used for upper limbs muscular function assessment. Respiratory and muscle function tests were performed, including spirometry, arterial blood gases, polysomnography, maximal inspiratory pressure (MIP), maximal expiratory pressure and sniff nasal inspiratory pressure. Results: An abnormal composite SWAL-QOL score (≤86) was found in 33 patients. Autonomic symptoms were mild, while a severe impairment was shown by the Brooke Upper Extremity Scale. Spirometry and muscle strength tests demonstrated severe alterations, while diurnal and nocturnal blood gases were normal, due to effective use of noninvasive ventilation. Independent predictors of the composite SWAL-QOL score were age, MIP and Compass 31. A MIP < 22 had an accuracy of 92% in predicting altered swallowing-related QoL. The composite SWAL-QOL score was worse in subjects > 30 years old than in younger patients (64.5±19.2 vs 76.6±16.3, p  < 0.02), due to worse scores in items pertinent to mental and social functioning; scores in domains pertinent to the physical function were similar in both groups. Conclusions: In adult DMD, swallowing-related QoL, which is altered in most patients, can be predicted by age, inspiratory muscles strength and autonomic dysfunction symptoms. While swallowing function is already altered in young patients, swallowing-related QoL can progressively worsen with advancing age due to psychological and social factors. Show more

Keywords: Swallowing dysfunction, respiratory function, autonomic symptoms, quality of life, Duchenne muscular dystrophy

DOI: 10.3233/JND-230055

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 5, pp. 955-962, 2023

Authors: Maulet, Théo | Cattagni, Thomas | Dubois, Fabien | Roche, Nicolas | Laforet, Pascal | Bonnyaud, Céline

Article Type: Research Article

Abstract: Background: The late-onset form of Pompe disease (LOPD) is characterized by muscle weakness, locomotor limitations and a risk of falls. The mechanisms responsible for altered locomotion in adults with LOPD are unknown. The identification of clinical biomarkers is essential for clinical follow-up and research. Objectives: To identify muscle determinants of impaired locomotor performance, gait stability and gait pattern, and biomechanical determinants of falls in adults with LOPD. Methods: In this cross-sectional, case-control study, LOPD and control participants underwent 3D gait analysis, locomotor performance tests and muscle strength measurements (isokinetic dynamometer). We explored the muscular determinants of …locomotor performance (gait speed, 6-minute walk test distance and timed up and go test), gait stability (spatiotemporal gait variables) and the gait pattern. We also explored biomechanical gait determinants of falls. After intergroup comparisons, determinants were sought to use forward stepwise multiple regression. Results: Eighteen participants with LOPD and 20 control participants were included. Locomotor performance, gait stability, and the gait pattern were significantly altered in LOPD compared to control participants. Hip abductor strength was the main common determinant of locomotor performance, gait stability and pelvic instability. Hip flexor strength was the main determinant of abnormal gait kinematics at the hip and knee. Percentage duration of single support phase during the gait cycle was the main determinant of falls. Conclusions: Hip abductor strength and percentage duration of single support during gait were the major determinants of locomotor performance, gait stability, falls and the gait pattern in LOPD. These new clinical biomarkers should therefore be systematically assessed using instrumented tools to improve the follow-up of adults with LOPD. They should also be considered in future studies to accurately assess the effects of new therapies. Hip abductor strength and single support phase should also be priority targets for rehabilitation. Show more

Keywords: Glycogen storage disease type II, locomotion, gait neurologic disorders, gait analysis, muscle weakness, postural balance, muscle strength dynamometer

DOI: 10.3233/JND-230060

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 5, pp. 963-976, 2023

Authors: Pelin, Katarina | Sagath, Lydia | Lehtonen, Johanna | Kiiski, Kirsi | Tynninen, Olli | Paetau, Anders | Johari, Mridul | Savarese, Marco | Wallgren-Pettersson, Carina | Lehtokari, Vilma-Lotta

Article Type: Research Article

Abstract: Background: Pathogenic variants in the TPM3 gene, encoding slow skeletal muscle α -tropomyosin account for less than 5% of nemaline myopathy cases. Dominantly inherited or de novo missense variants in TPM3 are more common than recessive loss-of-function variants. The recessive variants reported to date seem to affect either the 5’ or the 3’ end of the skeletal muscle-specific TPM3 transcript. Objectives: The aim of the study was to identify the disease-causing gene and variants in a Finnish patient with an unusual form of nemaline myopathy. Methods: The genetic analyses included Sanger sequencing, …whole-exome sequencing, targeted array-CGH, and linked-read whole genome sequencing. RNA sequencing was done on total RNA extracted from cultured myoblasts and myotubes of the patient and controls. TPM3 protein expression was assessed by Western blot analysis. The diagnostic muscle biopsy was analyzed by routine histopathological methods. Results: The patient had poor head control and failure to thrive, but no hypomimia, and his upper limbs were clearly weaker than his lower limbs, features which in combination with the histopathology suggested TPM3 -caused nemaline myopathy. Muscle histopathology showed increased fiber size variation and numerous nemaline bodies predominantly in small type 1 fibers. The patient was found to be compound heterozygous for two splice-site variants in intron 1a of TPM3 : NM_152263.4:c.117+2_5delTAGG, deleting the donor splice site of intron 1a, and NM_152263.4:c.117 + 164 C>T, which activates an acceptor splice site preceding a non-coding exon in intron 1a. RNA sequencing revealed inclusion of intron 1a and the non-coding exon in the transcripts, resulting in early premature stop codons. Western blot using patient myoblasts revealed markedly reduced levels of the TPM3 protein. Conclusions: Novel biallelic splice-site variants were shown to markedly reduce TPM3 protein expression. The effects of the variants on splicing were readily revealed by RNA sequencing, demonstrating the power of the method. Show more

Keywords: Nemaline myopathy, alpha-tropomyosin, TPM3, RNA sequencing, NMD-CGH array, linked-read sequencing

DOI: 10.3233/JND-230026

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 5, pp. 977-984, 2023

Authors: McGrattan, Katlyn E. | Shell, Richard D. | Hurst-Davis, Rebecca | Young, Sally Dunaway | O’Brien, Eamonn | Lavrov, Arseniy | Wallach, Shiri | LaMarca, Nicole | Reyna, Sandra P. | Darras, Basil T.

Article Type: Correction

DOI: 10.3233/JND-239002

Citation: Journal of Neuromuscular Diseases, vol. 10, no. 5, pp. 985-986, 2023