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