Journal of Neuromuscular Diseases - Volume 10, issue 5

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