Journal of Neuromuscular Diseases - Volume 11, issue 5

Authors: Martí, Yasmina | Aponte Ribero, Valerie | Batson, Sarah | Mitchell, Stephen | Gorni, Ksenija | Gusset, Nicole | Oskoui, Maryam | Servais, Laurent | Deconinck, Nicolas | McGrattan, Katlyn Elizabeth | Mercuri, Eugenio | Sutherland, C. Simone

Article Type: Systematic Review

Abstract: Background: Respiratory and bulbar dysfunctions (including swallowing, feeding, and speech functions) are key symptoms of spinal muscular atrophy (SMA), especially in its most severe forms. Demonstrating the long-term efficacy of disease-modifying therapies (DMTs) necessitates an understanding of SMA natural history. Objective: This study summarizes published natural history data on respiratory, swallowing, feeding, and speech functions in patients with SMA not receiving DMTs. Methods: Electronic databases (Embase, MEDLINE, and Evidence-Based Medicine Reviews) were searched from database inception to June 27, 2022, for studies reporting data on respiratory and/or bulbar function outcomes in Types 1–3 SMA. Data were …extracted into a predefined template and a descriptive summary of these data was provided. Results: Ninety-one publications were included: 43 reported data on respiratory, swallowing, feeding, and/or speech function outcomes. Data highlighted early loss of respiratory function for patients with Type 1 SMA, with ventilatory support typically required by 12 months of age. Patients with Type 2 or 3 SMA were at risk of losing respiratory function over time, with ventilatory support initiated between the first and fifth decades of life. Swallowing and feeding difficulties, including choking, chewing problems, and aspiration, were reported in patients across the SMA spectrum. Swallowing and feeding difficulties, and a need for non-oral nutritional support, were reported before 1 year of age in Type 1 SMA, and before 10 years of age in Type 2 SMA. Limited data relating to other bulbar functions were collated. Conclusions: Natural history data demonstrate that untreated patients with SMA experience respiratory and bulbar function deterioration, with a more rapid decline associated with greater disease severity. This study provides a comprehensive repository of natural history data on bulbar function in SMA, and it highlights that consistent assessment of outcomes in this area is necessary to benefit understanding and approval of new treatments. Show more

Keywords: Spinal muscular atrophy, neuromuscular diseases, rare diseases, natural history, respiratory function tests, speech, deglutition, review

DOI: 10.3233/JND-230248

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 5, pp. 889-904, 2024

Authors: Harazi, Avi | Yakovlev, Lena | Ilouz, Nili | Selke, Philipp | Horstkorte, Rudiger | Fellig, Yakov | Lahat, Olga | Lifschytz, Tzuri | Abudi, Nathalie | Abramovitch, Rinat | Argov, Zohar | Mitrani-Rosenbaum, Stella

Article Type: Research Article

Abstract: Background: GNE Myopathy is a unique recessive neuromuscular disorder characterized by adult-onset, slowly progressive distal and proximal muscle weakness, caused by mutations in the GNE gene which is a key enzyme in the biosynthesis of sialic acid. To date, the precise pathophysiology of the disease is not well understood and no reliable animal model is available. Gne KO is embryonically lethal in mice. Objective: To gain insights into GNE function in muscle, we have generated an inducible muscle Gne KO mouse. To minimize the contribution of the liver to the availability of sialic acid to muscle via …the serum, we have also induced combined Gne KO in liver and muscle. Methods: A mouse carrying loxp sequences flanking Gne exon3 was generated by Crispr/Cas9 and bred with a human skeletal actin (HSA) promoter driven CreERT mouse. Gne muscle knock out was induced by tamoxifen injection of the resulting homozygote GneloxpEx3loxp/HSA Cre mouse. Liver Gne KO was induced by systemic injection of AAV8 vectors carrying the Cre gene driven by the hepatic specific promoter of the thyroxine binding globulin gene. Results: Characterization of these mice for a 12 months period showed no significant changes in their general behaviour, motor performance, muscle mass and structure in spite of a dramatic reduction in sialic acid content in both muscle and liver. Conclusions: We conclude that post weaning lack of Gne and sialic acid in muscle and liver have no pathologic effect in adult mice. These findings could reflect a strong interspecies versatility, but also raise questions about the loss of function hypothesis in Gne Myopathy. If these findings apply to humans they have a major impact on therapeutic strategies. Show more

Keywords: GNE myopathy, GNE, sialic acid, GNE KO model, muscle GneKO, liver GneKO, animal model

DOI: 10.3233/JND-240056

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 5, pp. 905-917, 2024

Authors: Bouman, Karlijn | van den Heuvel, Frederik M.A. | Evertz, Reinder | Boesaard, Ewout | Groothuis, Jan T. | van Engelen, Baziel G.M. | Nijveldt, Robin | Erasmus, Corrie E. | Udink ten Cate, Floris E.A. | Voermans, Nicol C.

Article Type: Research Article

Abstract: Background: LAMA2-related muscular dystrophy (LAMA2-MD) and SELENON-related myopathy (SELENON-RM) are two rare neuromuscular diseases characterized by proximal and axial muscle weakness, scoliosis, spinal rigidity, low bone quality and respiratory impairment. Cardiac involvement has previously been described in retrospective studies and case reports, but large case series and prospective studies in unselected cohorts are lacking. Objective: The objective of this study is to conduct prevalence estimations, perform cardiac phenotyping, and provide recommendations for clinical care. Methods: In this case series including two time points, we conducted comprehensive assessments with electrocardiography (ECG) and transthoracic echocardiography (TTE). ECGs were …systematically assessed for a large subset of variables. TTE included left and right ventricular ejection fraction (LVEF/RVEF) and left ventricular global longitudinal strain (GLS), the latter being a more early and sensitive marker of left ventricular dysfunction. Results: 21 LAMA2-MD (M = 5; 20±14 years) and 10 SELENON-RM patients (M = 7; 18±12 years) were included. In most patients, QRS fragmentation and Q waves, markers of heterogeneous ventricular activation, were present both at baseline and at follow-up. GLS was abnormal (age specific in children, > –18% in adults) in 33% of LAMA2-MD and 43% of SELENON-RM patients at baseline. Reduced LVEF (<52% in males, <54% in females and <55% in pediatric population) was observed in three LAMA2-MD patients at baseline and in none of the SELENON-RM patients. GLS and LVEF did not change between baseline and follow-up. RVEF was normal in all patients. Conclusion: ECG abnormalities and abnormal GLS are prevalent in LAMA2-MD and SELENON-RM, yet abnormal LVEF was only seen in LAMA2-MD patients. One LAMA2-MD patient had a clinically relevant deterioration in LVEF during 1.5-year follow-up. We advise routine screening of all patients with LAMA2-MD or SELENON-RM with ECG and echocardiography at diagnosis, minimally every two years from second decade of life and if new cardiac signs arise. Show more

Keywords: Muscular dystrophy, myopathy, electrocardiography, echocardiography, global longitudinal strain, ventricular dysfunction, left, ventricular dysfunction, right, cardiomyopathy, dilated, atrioventricular block

DOI: 10.3233/JND-230190

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 5, pp. 919-934, 2024

Authors: Harikrishna, Ganaraja Valakunja | Padmanabha, Hansashree | Polavarapu, Kiran | Anjanappa, Ram Murthy | Preethish-Kumar, Veeramani | Nandeesh, Bevinahalli Nanjegowda | Vengalil, Seena | Nashi, Saraswati | Baskar, Dipti | Thomas, Aneesha | Bardhan, Mainak | Arunachal, Gautham | Menon, Deepak | Sanka, Sai Bhargava | Manjunath, Nisha | Nalini, Atchayaram

Article Type: Research Article

Abstract: Background: Congenital myopathies (CMs) are a diverse group of inherited muscle disorders with broad genotypic and phenotypic heterogeneity. While the literature on CM is available from European countries, comprehensive data from the Indian subcontinent is lacking. Objectives: This study aims to describe the clinical and histopathological characteristics of a cohort of genetically confirmed CMs from India and attempts to do phenotype-genotype correlation. Methods: A retrospective chart review of genetically confirmed CMs was evaluated between January 2016 and December 2020 at the neuromuscular clinic. The clinical, genetic, and follow-up data were recorded in a pre-structured proforma as …per the medical records, and the data was analyzed. Results: A total of 31(M: F  = 14 : 17) unrelated patients were included. The median age at onset and duration of illness are 2.0(IQR:1–8) years and 6.0(IQR:3–10) years respectively. Clinical features observed were proximodistal weakness (54.8%), facial weakness (64.5%), and myopathic facies (54.8%), followed by ptosis (33.3%), and ophthalmoplegia (19.4%). Muscle histopathology was available in 38.7% of patients, and centronuclear myopathy was the most common histopathology finding. The pathogenic genetic variants were identified in RYR1 (29.0%), DNM2 (19.4%), SELENON (12.9%), KBTBD13 (9.7%), NEB (6.5%), and MYPN (6.5%) genes. Novel mutations were observed in 30.3% of the cohort. Follow-up details were available in 77.4% of children, and the median duration of follow-up and age at last follow-up was 4.5 (Range 0.5–11) years and 13 (Range 3–35) years, respectively. The majority were ambulant with minimal assistance at the last follow-up. Mortality was noted in 8.3% due to respiratory failure in Centronuclear myopathy 1 and congenital myopathy 3 with rigid spines (SELENON) . Conclusion: This study highlights the various phenotypes and patterns of genetic mutations in a cohort of pediatric patients with congenital myopathy from India. Centronuclear myopathy was the most common histological classification and the mutations in RYR1 followed by DNM2 gene were the common pathogenic variants identified. The majority were independent in their activities of daily living during the last follow-up, highlighting the fact that the disease has slow progression irrespective of the genotype. Show more

Keywords: Congenital myopathy, phenotype-genotype, histopathology, creatine phosphokinase, RYR1 gene, DMN2 gene, SELENON gene, KBTBD13 gene

DOI: 10.3233/JND-230021

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 5, pp. 935-957, 2024

Authors: Baskar, Dipti | Reddy, Nishanth | Preethish-Kumar, Veeramani | Polavarapu, Kiran | Nishadham, Vikas | Vengalil, Seena | Nashi, Saraswati | Sanka, Sai Bhargava | Bardhan, Mainak | Huddar, Akshata | Unnikrishnan, Gopikrishnan | Harikrishna, Ganaraja Valakunja | Gunasekaran, Swetha | Thomas, Priya Treesa | Keerthipriya, Muddasu Suhasini | Girija, Manu Santhappan | Arunachal, Gautham | Anjanappa, Ram Murthy | Nishino, Ichizo | Pogoryelova, Oksana | Lochmuller, Hanns | Nalini, Atchayaram

Article Type: Research Article

Abstract: Introduction: GNE myopathy is a rare slowly progressive adult-onset distal myopathy with autosomal recessive inheritance. It has distinctive features of quadriceps sparing with preferential anterior tibial involvement. Most patients eventually become wheelchair bound by 10–20 years after onset. This study analyzes the phenotype-genotype characteristics and disease progression in a large cohort of GNEM patients from India. Materials and methods: Retrospective observational study on GNEM from a quaternary neurology referral hospital in southern India. Data was collected from clinical phenotyping, serum creatine kinase levels, muscle biopsy histopathology, genetic analysis and functional assessment scales – IBMFRS and MDFRS. …Results: 157 patients were included with mean age at onset and diagnosis: 26.5±6.2 years and 32.8±7.8 years, respectively. M:F ratio was 25 : 13. Most common presenting symptom: foot drop (46.5%) and limb girdle weakness (19.1%). Wasting and weakness of small muscles of hand and finger flexors seen in 66.2% and as an initial symptoms in 5.2%. Though tibialis anterior involvement was most common (89.2%), early quadriceps weakness was noted in 3.2% and Beevor’s sign in 59.2%. Rimmed vacuoles were present in 75% of patients with muscle biopsy. Most common variant was the Indian Founder variant identified in 129 patients (c.2179 G>A, p.Val727Met - 82.2%) and most common zygosity being compound heterozygous state (n  = 115, 87.5%). Biallelic kinase domain variations predisposed to a more severe phenotype. Wheelchair bound state noted in 8.9% with a mean age and duration of 32.0±7.1 and 6.3±4.9 years respectively, earlier than previous studies on other ethnic groups. Conclusion: This is the largest GNEM cohort reported from South Asia. The p.Val727Met variant in compound heterozygous state is noted in majority (82.2%) of the cases. Observed relationships between genotype and clinical parameters shows that severity of the disease might be attributable to specific GNE genotype and thus could aid in predicting the disease progression. Show more

Keywords: GNE myopathy, genotype-phenotype, disease progression, India, hIBM

DOI: 10.3233/JND-230130

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 5, pp. 959-968, 2024

Authors: Baskar, Dipti | Preethish-Kumar, Veeramani | Polavarapu, Kiran | Vengalil, Seena | Nashi, Saraswati | Menon, Deepak | Ganaraja, Valakunja Harikrishna | Girija, Manu Santhappan | Nandeesh, Bevinahalli Nanjegowda | Arunachal, Gautham | Nalini, Atchayaram

Article Type: Research Article

Abstract: Introduction: Nuclear envelopathies occur due to structural and/or functional defects in various nuclear envelope proteins such as lamin A/C and lamin related proteins. This study is the first report on the phenotype-genotype patterns of nuclear envelopathy-related muscular dystrophies from India. Methods: In this retrospective study, we have described patients with genetically confirmed muscular dystrophy associated with nuclear envelopathy. Data on clinical, laboratory findings and muscle MRI were collected. Results: Sixteen patients were included with median age at onset of 3 years (range: 1 month – 17 years). Three genes were involved: LMNA (11, 68.75%), EMD …(4, 25%) and SYNE1 (1, 6.25%). The 11 patients with LMNA variants were Congenital muscular dystrophy (MDCL)=4, Limb Girdle Muscular Dystrophy (LGMD1B)=4 and Emery-Dreifuss Muscular Dystrophy (EDMD2)=3. On muscle biopsy, one patient from each laminopathy phenotype (n  = 3) revealed focal perivascular inflammatory infiltrate. Other notable features were ophthalmoparesis in one and facial weakness in one. None had cardiac involvement. Patients with EDMD1 had both upper (UL) and lower limb (LL) proximo-distal weakness. Cardiac rhythm disturbances such as sick sinus syndrome and atrial arrhythmias were noted in two patients with EDMD1. Only one patient with variant c.654_658dup (EMD ) lost ambulation in the 3rd decade, 18 years after disease onset. Two had finger contractures with EMD and SYNE1 variants respectively. All patients with LMNA and SYNE1 variants were ambulant at the time of evaluation. Mean duration of illness (years) was 11.6±13 (MDCL), 3.2±1.0 (EDMD2), 10.4±12.8 (LGMD1B), 11.8±8.4 (EDMD1) and 3 (EDMD4). One patient had a novel SYNE1 mutation (c.22472dupA, exon 123) and presented with UL phenotype and prominent finger and wrist contractures. Conclusion: The salient features included ophthalmoparesis and facial weakness in LMNA , prominent finger contractures in EMD and SYNE1 and upper limb phenotype with the novel pathogenic variant in SYNE1 . Show more

Keywords: Nuclear envelopathy, emery-dreifuss muscular dystrophy, lamin A/C, Emerin, Nesprin-1, MDCL, LGMD1B

DOI: 10.3233/JND-230172

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 5, pp. 969-979, 2024

Authors: Roussel, Marie-Pier | Ravel-Chapuis, Aymeric | Gobin, Jonathan | Jasmin, Bernard J. | Leduc-Gaudet, Jean-Philippe | Gagnon, Cynthia | Duchesne, Elise

Article Type: Research Article

Abstract: Background: Myotonic dystrophy type 1 (DM1) is a slowly progressive disease caused by abnormal CTG repetitions on the dystrophia myotonica protein kinase (DMPK ) gene. Long mRNA from CTG repetitions stabilizes in nuclear foci and sequester muscleblind-like splicing regulator 1 (MBNL1). Cardinal signs of DM1 include muscle wasting and weakness. The impacts of DM1 progression on skeletal muscle are under-researched. Objective: Identifying physiopathological markers related to maximal strength loss over time in DM1. Methods: Twenty-two individuals with DM1 participated in two maximal isometric muscle strength (MIMS) evaluations of their knee extensors and two vastus lateralis …muscle biopsies, 3 years apart. Muscle fiber typing, size (including minimal Feret’s diameter [MFD] and atrophy/hypertrophy factors [AF/HF]), and nuclear foci and MBNL1 colocalization (foci/MBNL1+) were evaluated. Immunoblotting was used to measure glycogen synthase kinase-3 beta (GSK3β ), p62, LC3BI, LC3BII, and oxidative phosphorylation proteins. Results: There are significant correlations between the fold changes of MIMS with type 1 fiber MFD (ρ = 0.483) and AF (ρ = –0.514). Regression analysis shows that baseline percentage of foci/MBNL1+ nuclei and strength training explain 44.1% of foci/MBNL1+ nuclei percentage variation over time. There are fair to excellent correlations between the fold changes of MIMS and GSK3β (ρ = 0.327), p62 (ρ = 0.473), LC3BI (ρ = 0.518), LC3BII (ρ = –0.391) and LC3BII/LC3BI (ρ = –0.773). Conclusion: Type 1 MFD decrease and AF increase are correlated with MIMS loss. There seems to be a plateau effect in foci/MBNL1+ nuclei accumulation and strength training helps decrease this accumulation. Autophagy marker LC3BII/LC3BI ratio has a good biomarker potential of MIMS loss, but more investigations are needed. Show more

Keywords: Myotonic dystrophy type 1, natural history study, maximal muscle strength, histomorphology, nuclear foci and MBNL1 colocalization, protein expression

DOI: 10.3233/JND-230139

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 5, pp. 981-995, 2024

Authors: Schlaffke, Lara | Rehmann, Robert | Froeling, Martijn | Güttsches, Anne-Katrin | Vorgerd, Matthias | Enax-Krumova, Elena | Forsting, Johannes

Article Type: Research Article

Abstract: Background: Sporadic inclusion body myositis (sIBM) is the predominant idiopathic inflammatory myopathy (IIM) in older people. Limitations of classical clinical assessments have been discussed as possible explanations for failed clinical trials, underlining the need for more sensitive outcome measures. Quantitative muscle MRI (qMRI) is a promising candidate for evaluating and monitoring sIBM. Objective: Longitudinal assessment of qMRI in sIBM patients. Methods: We evaluated fifteen lower extremity muscles of 12 sIBM patients (5 females, mean age 69.6, BMI 27.8) and 12 healthy age- and gender-matched controls. Seven patients and matched controls underwent a follow-up evaluation after one …year. Clinical assessment included testing for muscle strength with Quick Motor Function Measure (QMFM), IBM functional rating scale (IBM-FRS), and gait analysis (6-minute walking distance). 3T-MRI scans of the lower extremities were performed, including a Dixon-based sequence, T2 mapping and Diffusion Tensor Imaging. The qMRI-values fat-fraction (FF), water T2 relaxation time (wT2), fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (λ 1 ), and radial diffusivity (RD) were analysed. Results: Compared to healthy controls, significant differences for all qMRI parameters averaged over all muscles were found in sIBM using a MANOVA (p  < 0.001). In low-fat muscles (FF < 10%), a significant increase of wT2 and FA with an accompanying decrease of MD, λ 1 , and RD was observed (p ≤0.020). The highest correlation with clinical assessments was found for wT2 values in thigh muscles (r ≤–0.634). Significant changes of FF (+3.0%), wT2 (+0.6 ms), MD (–0.04 10-3 mm2 /s), λ 1 (–0.05 10-3 mm2 /s), and RD (–0.03 10-3 mm2 /s) were observed in the longitudinal evaluation of sIBM patients (p ≤0.001). FA showed no significant change (p  = 0.242). Conclusion: qMRI metrics correlate with clinical findings and can reflect different ongoing pathophysiological mechanisms. While wT2 is an emerging marker of disease activity, the role of diffusion metrics, possibly reflecting changes in fibre size and intracellular deposits, remains subject to further investigations. Show more

Keywords: Diffusion tensor imaging, sporadic inclusion body myositis, quantitative muscle MRI, fat fraction, water T2 relaxation time

DOI: 10.3233/JND-240053

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 5, pp. 997-1009, 2024

Authors: Kastreva, Kristina | Chamova, Teodora | Blagoeva, Stanislava | Bichev, Stoyan | Mihaylova, Violeta | Meyer, Stefanie | Thompson, Rachel | Cherninkova, Sylvia | Guergueltcheva, Velina | Lochmuller, Hanns | Tournev, Ivailo

Article Type: Research Article

Abstract: Background: Congenital myasthenic syndromes (CMS) are a group of rare but often treatable inherited disorders of neuromuscular transmission characterized by fatigable skeletal muscle weakness. In this paper we present the largest phenotypic analysis to date of a cohort of patients carrying the pathogenic variant c.1327delG in the CHRNE gene, leading to CHRNE-CMS. Objective: This study aims to identify the phenotypic variability in CMS associated with c.1327delG mutation in the CHRNE gene. Methods: Disease specific symptoms were assessed using specific standardized tests for autoimmune myasthenia (Quantitative Myasthenia Gravis score) as well as patient-reported scales for symptom severity. …Evaluated clinical manifestations included ocular symptoms (ophthalmoparesis and ptosis), bulbar weakness, axial muscle weakness, proximal and distal muscle weakness, and respiratory function. Patients were allocated into three groups according to clinical impression of disease severity: mild, moderate, and severe. Results: We studied 91 Bulgarian Roma patients, carrying the same causative homozygous CHRNE c.1327delG mutation. Bulbar weakness was present in patients throughout all levels of severity of CHRNE-CMS in this study. However, difficulties in eating and swallowing are more prominent characteristics in the moderate and severe clinical phenotypes. Diplopia and ptosis resulting from fatigue of the extraocular muscles were permanent features regardless of disease severity or age. Levels of axial, proximal and distal muscle weakness were variable between disease groups. The statistical analysis showed significant differences between the patients in the three groups, emphasizing a possible variation in symptom manifestation in the evaluated patient population despite the disease originating from the same genetic mutation. Impairment of respiratory function was more prominent in severely affected patients, which might result from loss of compensatory muscle function in those individuals. Conclusion: Results from our study indicate significant phenotypic heterogeneity leading to mild, moderate, or severe clinical manifestation in CHRNE-CMS, despite the genotypic homogeneity. Show more

Keywords: Myasthenic syndromes, fatigable weakness, CHRNE gene

DOI: 10.3233/JND-230235

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 5, pp. 1011-1020, 2024

Authors: Enzmann, Cornelia | Steiner, Leonie | Pospieszny, Katarzyna | Zweier, Christiane | Plattner, Kevin | Baumann, Dominique | Henzi, Bettina | Galiart, Elea | Fink, Mirjam | Jacquier, David | Stettner, Georg M. | Ripellino, Paolo | Fluss, Joel | Klein, Andrea | Baumann, Dominique | Enzmann, Cornelia | Jacquier, David | Jung, Hans H. | Klein, Andrea | Kuehni, Claudia E. | Mathis, Andrea | Ripellino, Paolo | Scheidegger, Oliver | Schreiner, Bettina | Schwarz, Esther I. | Stettner, Georg M. | Tscherter, Anne

Article Type: Research Article

Abstract: Background: LAMA2-related muscular dystrophy (LAMA2-RD) is an autosomal-recessive disorder and one of the most common congenital muscular dystrophies. Due to promising therapies in preclinical development, there is an increasing effort to better define the epidemiology and natural history of this disease. Objective: The present study aimed to describe a well-characterized baseline cohort of patients with LAMA2-RD in Switzerland. Methods: The study used data collected by the Swiss Registry for Neuromuscular Disorders (Swiss-Reg-NMD). Diagnostic findings were derived from genetics, muscle biopsy, creatine kinase-level and electrophysiological testing, as well as from brain MRIs. Further clinical information included motor …assessments (CHOP INTEND, MFM20/32), joint contractures, scoliosis, ophthalmoplegia, weight gain, feeding difficulties, respiratory function, cardiac investigations, EEG findings, IQ and schooling. Results: Eighteen patients with LAMA-RD were included in the Swiss-Reg-NMD as of May 2023 (age at inclusion into the registry: median age 8.7 years, range 1 month – 31 years F = 8, M = 10). Fourteen patients presented with the severe form of LAMA2-RD (were never able to walk; CMD), whereas four patients presented with the milder form (present or lost walking capability; LGMD). All patients classified as CMD had symptoms before 12 months of age and 11/14 before the age of six months. 15 carried homozygous or compound heterozygous pathogenic or likely pathogenic variants in LAMA2 and two were homozygous for a variant of unknown significance (one patient unknown). Brain MRI was available for 14 patients, 13 had white matter changes and 11 had additional structural abnormalities, including cobblestone malformations, pontine hypoplasia and an enlarged tegmento-vermial angle not reported before. Conclusion: This study describes the Swiss cohort of patients with LAMA2-RD and gives insights into measuring disease severity and disease progression, which is important for future clinical trials, as well as for a better clinical understanding and management of patients with LAMA2-RD. Show more

Keywords: LAMA2, Swiss-Reg-NMD, congenital muscular dystrophy. MDC1A, natural history

DOI: 10.3233/JND-240023

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 5, pp. 1021-1033, 2024

Authors: Baumgartner, Daniel | Mušová, Zuzana | Zídková, Jana | Hedvičáková, Petra | Vlčková, Eva | Joppeková, Lubica | Kramářová, Tereza | Fajkusová, Lenka | Stránecký, Viktor | Geryk, Jan | Votýpka, Pavel | Mazanec, Radim

Article Type: Research Article

Abstract: Background: Genetic factors are involved in the pathogenesis of familial and sporadic amyotrophic lateral sclerosis (ALS) and constitute a link to its association with frontotemporal dementia (FTD). Gene-targeted therapies for some forms of ALS (C9orf72, SOD1) have recently gained momentum. Genetic architecture in Czech ALS patients has not been comprehensively assessed so far. Objective: We aimed to deliver pilot data on the genetic landscape of ALS in our country. Methods: A cohort of patients with ALS (n  = 88), recruited from two Czech Neuromuscular Centers, was assessed for hexanucleotide repeat expansion (HRE) in C9orf72 and also for …genetic variations in other 36 ALS-linked genes via next-generation sequencing (NGS). Nine patients (10.1%) had a familial ALS. Further, we analyzed two subgroups of sporadic patients – with concomitant FTD (n  = 7) and with young-onset of the disease (n  = 22). Results: We detected the pathogenic HRE in C9orf72 in 12 patients (13.5%) and three other pathogenic variants in FUS, TARDBP and TBK1, each in one patient. Additional 7 novel and 9 rare known variants with uncertain causal significance have been detected in 15 patients. Three sporadic patients with FTD (42.9%) were harbouring a pathogenic variant (all HRE in C9orf72). Surprisingly, none of the young-onset sporadic patients harboured a pathogenic variant and we detected no pathogenic SOD1 variant in our cohort. Conclusion: Our findings resemble those from other European populations, with the highest prevalence of HRE in the C9orf72 gene. Further, our findings suggest a possibility of a missing genetic variability among young-onset patients. Show more

Keywords: Amyotrophic lateral sclerosis, neurogenetics, mutation screening, C9orf72 repeat expansion, next-generation sequencing, gene variants

DOI: 10.3233/JND-230236

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 5, pp. 1035-1048, 2024

Authors: Arteaga-Bracho, Eduardo | Cosne, Gautier | Kanzler, Christoph | Karatsidis, Angelos | Mazzà, Claudia | Penalver-Andres, Joaquin | Zhu, Cong | Shen, Changyu | Erb M., Kelley | Freigang, Maren | Lapp, Hanna-Sophie | Thiele, Simone | Wenninger, Stephan | Jung, Erik | Petri, Susanne | Weiler, Markus | Kleinschnitz, Christoph | Walter, Maggie C. | Günther, René | Campbell, Nolan | Belachew, Shibeshih | Hagenacker, Tim

Article Type: Research Article

Abstract: Background: More responsive, reliable, and clinically valid endpoints of disability are essential to reduce size, duration, and burden of clinical trials in adult persons with spinal muscular atrophy (aPwSMA). Objective: The aim is to investigate the feasibility of smartphone-based assessments in aPwSMA and provide evidence on the reliability and construct validity of sensor-derived measures (SDMs) of mobility and manual dexterity collected remotely in aPwSMA. Methods: Data were collected from 59 aPwSMA (23 walkers, 20 sitters and 16 non-sitters) and 30 age-matched healthy controls (HC). SDMs were extracted from five smartphone-based tests capturing mobility and manual dexterity, …which were administered in-clinic and remotely in daily life for four weeks. Reliability (Intraclass Correlation Coefficients, ICC) and construct validity (ability to discriminate between HC and aPwSMA and correlations with Revised Upper Limb Module, RULM and Hammersmith Functional Scale - Expanded HFMSE) were quantified for all SDMs. Results: The smartphone-based assessments proved feasible, with 92.1% average adherence in aPwSMA. The SDMs allowed to reliably assess both mobility and dexterity (ICC > 0.75 for 14/22 SDMs). Twenty-one out of 22 SDMs significantly discriminated between HC and aPwSMA. The highest correlations with the RULM were observed for SDMs from the manual dexterity tests in both non-sitters (Typing, ρ = 0.78) and sitters (Pinching, ρ = 0.75). In walkers, the highest correlation was between mobility tests and HFMSE (5 U-Turns, ρ = 0.79). Conclusions: This exploratory study provides preliminary evidence for the usability of smartphone-based assessments of mobility and manual dexterity in aPwSMA when deployed remotely in participants’ daily life. Reliability and construct validity of SDMs remotely collected in real-life was demonstrated, which is a pre-requisite for their use in longitudinal trials. Additionally, three novel smartphone-based performance outcome assessments were successfully established for aPwSMA. Upon further validation of responsiveness to interventions, this technology holds potential to increase the efficiency of clinical trials in aPwSMA. Show more

Keywords: Remote monitoring, accelerometers, wearable sensors, walking, drawing, typing, pinching, turning

DOI: 10.3233/JND-240004

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 5, pp. 1049-1065, 2024

Authors: van de Camp, Sanne A.J.H. | Stinissen, Lizan | Huseth, Andrew | Simon, Brentney | Ryan, Jennifer | Sarkozy, Anna | Van Petegem, Filip | Goldberg, Michael F. | Jungbluth, Heinz | Böhm, Johann | Oortwijn, Wija | Dirksen, Robert T. | Voermans, Nicol C.

Article Type: Research Article

Abstract: Background and objective: Pathogenic variants of RYR1 , the gene encoding the principal sarcoplasmic reticulum calcium release channel (RyR1) with a crucial role in excitation-contraction coupling, are among the most common genetic causes of non-dystrophic neuromuscular disorders. We recently conducted a questionnaire study focusing on functional impairments, fatigue, and quality of life (QoL) in patients with RYR1 -related diseases (RYR1 -RD) throughout the recognized disease spectrum. In this previous questionnaire study the medical perspective was taken, reflective of a study protocol designed by neurologists and psychologists. With this present study we wanted to specifically address the patient perspective. …Methods: Together with affected individuals, family members, and advocates concerned with RYR1 -RD, we developed an online patient survey that was completed by 227 patients or their parents/other caretakers (143 females and 84 males, 0–85 years). We invited 12 individuals, representing most of the patient group based on age, sex, race, and type and severity of diagnosis, to share their personal experiences on living with a RYR1 -RD during an international workshop in July 2022. Data were analyzed through a mixed-methods approach, employing both a quantitative analysis of the survey results and a qualitative analysis of the testimonials. Results: Data obtained from the combined quantitative and qualitative analyses provide important insights on six topics: 1) Diagnosis; 2) Symptoms and impact of the condition; 3) Physical activity; 4) Treatment; 5) Clinical research and studies; and 6) Expectations. Conclusions: Together, this study provides a unique patient perspective on the RYR1 -RD spectrum, associated disease impact, suitable physical activities and expectations of future treatments and trials, and thus, offers an essential contribution to future research. Show more

Keywords: Myopathy, central core, malignant hyperthermia, patient participation, qualitative research, global burden of disease

DOI: 10.3233/JND-240029

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 5, pp. 1067-1083, 2024

Authors: Cope, Heidi | Fischer, Ryan | Heslop, Emma | McNiff, Megan | Johnson, Alexandra | Camino, Eric | Denger, Brian | Armstrong, Niki | Thakrar, Sejal | Bateman-House, Alison | Beaverson, Katherine L. | Woollacott, Ione O.C. | Phillips, Dawn | Fernandez, Vivian | Ganot, Annie | Donisa-Dreghici, Roxana | Mansfield, Carol | Peay, Holly

Article Type: Research Article

Abstract: Background: Duchenne muscular dystrophy (DMD) is a progressive, life-limiting, neuromuscular disorder. Clinicians play an important role in informing families about therapy options, including approved gene therapies and clinical trials of unapproved therapies. Objective: This study aimed to understand the perspectives of clinicians about gene therapy for DMD, which has not previously been studied. Methods: We conducted interviews with specialist clinicians treating patients with DMD in the United States (n  = 8) and United Kingdom (n  = 8). Interviews were completed in 2022, before any approved gene therapies, to gain insight into barriers and facilitators to implementing gene therapy …and educational needs of clinicians. Results: Most respondents expressed cautious optimism about gene therapy. Responses varied regarding potential benefits with most expecting delayed progression and duration of benefit (1 year to lifelong). Concern about anticipated risks also varied; types of anticipated risks included immunological reactions, liver toxicity, and cardiac or renal dysfunction. Clinicians generally, but not uniformly, understood that gene therapy for DMD would not be curative. Most reported needing demonstrable clinical benefit to justify treatment-related risks. Conclusions: Our data demonstrate variability in knowledge and attitudes about gene therapy among clinicians who follow patients with DMD. As our knowledge base about DMD gene therapy grows, clinician education is vital to ensuring that accurate information is communicated to patients and families. Show more

Keywords: Patient preference, duchene muscular dystrophy, gene therapy, clinical trials, clinician perspectives

DOI: 10.3233/JND-240033

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 5, pp. 1085-1093, 2024

Authors: van de Velde, N.M. | Krom, Y.D. | Bongers, J. | Hoek, R.J.A. | Ikelaar, N.A. | van der Holst, M. | Naarding, K.J. | van den Bergen, J.C. | Vroom, E. | Horemans, A. | Hendriksen, J.G.M. | de Groot, I.J.M. | Houwen-van Opstal, S.L.S. | Verschuuren, J.J.G.M. | van Duyvenvoorde, H.A. | Snijder, R.R. | Niks, E.H.

Article Type: Research Article

Abstract: Background: Duchenne and Becker muscular dystrophy lack curative treatments. Registers can facilitate therapy development, serving as a platform to study epidemiology, assess clinical trial feasibility, identify eligible candidates, collect real-world data, perform post-market surveillance, and collaborate in (inter)national data-driven initiatives. Objective: In addressing these facets, it’s crucial to gather high-quality, interchangeable, and reusable data from a representative population. We introduce the Dutch Dystrophinopathy Database (DDD), a national registry for patients with DMD or BMD, and females with pathogenic DMD variants, outlining its design, governance, and use. Methods: The design of DDD is based on a …system-independent information model that ensures interoperable and reusable data adhering to international standards. To maximize enrollment, patients can provide consent online and participation is allowed on different levels with contact details and clinical diagnosis as minimal requirement. Participants can opt-in for yearly online questionnaires on disease milestones and medication and to have clinical data stored from visits to one of the national reference centers. Governance involves a general board, advisory board and database management. Results: On November 1, 2023, 742 participants were enrolled. Self-reported data were provided by 291 Duchenne, 122 Becker and 38 female participants. 96% of the participants visiting reference centers consented to store clinical data. Eligible patients were informed about clinical studies through DDD, and multiple data requests have been approved to use coded clinical data for quality control, epidemiology and natural history studies. Conclusion: The Dutch Dystrophinopathy Database captures long-term patient and high-quality standardized clinician reported healthcare data, supporting trial readiness, post-marketing surveillance, and effective data use using a multicenter design that is scalable to other neuromuscular disorders. Show more

Keywords: Duchenne muscular dystrophy, Becker muscular dystrophy, registry, real-world data, FAIR, trial readiness

DOI: 10.3233/JND-240061

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 5, pp. 1095-1109, 2024

Authors: Sagerer, Elena | Wirner-Piotrowski, Corinna | Mijic, Marko | Arndt, Marcela | Garcia-Angarita, Natalia | Schoser, Benedikt | Wenninger, Stephan

Article Type: Research Article

Abstract: Background: Muscle pain is a common symptom in patients with neuromuscular disorders (NMD) and accounts for severely reduced quality of life. OBJECTIVE: This clinical study aimed to observe possible differences in pain prevalence among distinct NMDs and to determine whether the patients’ nociceptive pain is influenced by gender, muscle strength and psychological factors and to examine potential pain-associated alterations in muscle properties. Methods: The cross-sectional study on nociceptive pain in various NMDs involved patient-reported outcomes, muscle strength evaluations (dynamometry and quick motor function test (QMFT)), nociceptive pain evaluations (muscular pressure pain threshold (PPT)), and non-invasive measurement of muscle …stiffness, frequency, decrement, relaxation, and creep (myotonometry). Results: Involving 81 NMD patients and a control group, the study found high variability in pain prevalence among the subgroups. Patients with DM2 and FSHD had significantly higher levels of pain prevalence compared to other examined NMD subgroups and the control group. Female gender, high fatigue levels (representing factors such as depression, anxiety, stress, and impairment of quality of life), and low QMFT scores (representing reduced muscle strength) showed an association with increased sensitivity to pressure pain in the arm and leg region. As assessed by myotonometry, less pain is experienced in neck muscles with a high muscle tone, high stiffness, and a short relaxation time highlighting the importance of intrinsic muscular tone for their pressure pain sensitivity. Conclusion: Individualized therapeutic concepts including psychological and physical approaches in the pain management of patients with NMDs, especially in women, should be considered. Further research in this field is necessary to gain a more detailed insight into the perception of muscle pain. Show more

Keywords: Nociceptive pain, neuromuscular diseases, pain threshold, myotonometry, dynamometry

DOI: 10.3233/JND-240068

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 5, pp. 1111-1122, 2024

Authors: Vosse, Bettine A.H. | de Jong, Jasmijn | la Fontaine, Leandre A. | Horlings, Corinne G.C. | van Kuijk, Sander M.J. | Cobben, Nicolle A.M. | Domensino, Anne-Fleur | van Heugten, Caroline | Faber, Catharina G.

Article Type: Research Article

Abstract: Background: Chronic respiratory failure often occurs in myotonic dystrophy type 1 (DM1) and can be treated with noninvasive home mechanical ventilation (HMV). Treatment adherence with HMV is often suboptimal in patients with DM1, but the reasons for that are not well understood. Objective: The aim of this exploratory study was to gain insight in the prevalence of mild cognitive impairment, affective symptoms, and apathy and to investigate their role in HMV treatment adherence in DM1. Methods: The Montreal Cognitive Assessment (MoCA), the Hospital Anxiety and Depression Scale (HADS), and the Apathy Evaluation Scale (AES) were used …to assess cognition, affective symptoms, and apathy in DM1 patients that use HMV. Patients with low treatment adherence (average daily use HMV <5 h or <80% of the days) were compared with patients with high treatment adherence (average daily use of HMV≥5 h and ≥80% of the days). Results: Sixty patients were included. Abnormal scores were found in 40% of the total group for the MoCA, in 72–77% for the AES, and in 18% for HADS depression. There was no difference between the high treatment adherence group (n  = 39) and the low treatment adherence group (n  = 21) for the MoCA, AES, and HADS depression. The HADS anxiety was abnormal in 30% of the total group, and was significantly higher in the low treatment adherence group (p  = 0.012). Logistic regression analysis revealed that a higher age and a higher BMI were associated with a greater chance of high treatment adherence. Conclusions: This exploratory study showed that cognitive impairment and apathy are frequently present in DM1 patients that use HMV, but they are not associated with treatment adherence. Feelings of anxiety were associated with low treatment adherence. Higher age and higher BMI were associated with high treatment adherence with HMV. Show more

Keywords: Treatment adherence, myotonic dystrophy, respiratory insufficiency, artificial respiration, cognitive dysfunction, apathy, affective symptoms

DOI: 10.3233/JND-240081

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 5, pp. 1123-1130, 2024

Authors: Roos, Andreas | Häusler, Martin | Kollipara, Laxmikanth | Topf, Ana | Preusse, Corinna | Stucka, Rolf | Nolte, Kay | Strom, Tim | Berutti, Riccardo | Jiang, Xuehui | Koll, Randi | Lochmüller, Hanns | Schacht, Sabine Maria | Zahedi, René P. | Weis, Joachim | Senderek, Jan

Article Type: Case Report

Abstract: HNRNPA1 variants are known to cause degenerative motoneuron and muscle diseases which manifests in middle age or later. We report on a girl with early childhood onset, rapidly progressive generalized myopathy including ultrastructural findings in line with a proteinopathy. Proteomics of patient-derived muscle and combined screening of genomic data for copy number variations identified a HNRNPA1 de novo intragenic deletion as causative for the phenotype. Our report expands the spectrum of HNRNPA1-related diseases towards early-childhood onset and adds HNRNPA1 to the growing list of ALS and myopathy genes for which certain mutations may cause severe pediatric phenotypes.

Keywords: Inclusion body myopathy, vacuolar myopathy, neuromyopathy, multisystem proteinopathy, muscle proteomics, proteogenomics

DOI: 10.3233/JND-240050

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 5, pp. 1131-1137, 2024

Authors: Lek, Angela | Atas, Evrim | Lin, Brian | Hesterlee, Sharon E. | Abbott, Jordan K. | Byrne, Barry J. | Bönnemann, Carsten G.

Article Type: Meeting Report

Abstract:  This meeting report summarizes the presentations and discussions held at the summit on Challenges in Gene Therapy hosted by the Muscular Dystrophy Association (MDA) in 2023. Topics covered include safety issues, mitigation strategies and practical considerations pertaining to the clinical translation of gene therapies for neuromuscular disease. The listing of actionable recommendations will assist in overall efforts in the field to achieve safe and efficacious translation of gene therapies for neuromuscular disease patients.

DOI: 10.3233/JND-240002

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 5, pp. 1139-1160, 2024

Article Type: Correction

DOI: 10.3233/JND-249002

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 5, pp. 1161-1161, 2024