Cardiac involvement in two rare neuromuscular diseases: LAMA2-related muscular dystrophy and SELENON-related myopathy

Bouman, Karlijn; Gubbels, Madelief; Heuvel, Frederik M.A. van den; Erasmus, Corrie E.; Nijveldt, Robin; Cate, Floris E.A. Udink ten; Voermans, N.C.

doi:10.1016/j.nmd.2022.06.004

Cited by 8 publications

(3 citation statements)

References 74 publications

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“…While the specific deletion in our study was not directly linked to arrhythmias in the existing literature, the established connection between LAMA2 mutations and cardiac abnormalities, including arrhythmias, is a crucial area of research. This relationship may provide valuable insights into how LAMA2 mutations contribute to arrhythmia conditions, emphasizing the need for cardiac monitoring in patients with these mutations [27].…”

Section: Discussionmentioning

confidence: 99%

Genetic Susceptibility to Arrhythmia Phenotypes in a Middle Eastern Cohort of 14,259 Whole-Genome Sequenced Individuals

Qafoud,

Elshrif,

Kunji

et al. 2024

JCM

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Background: The current study explores the genetic underpinnings of cardiac arrhythmia phenotypes within Middle Eastern populations, which are under-represented in genomic medicine research. Methods: Whole-genome sequencing data from 14,259 individuals from the Qatar Biobank were used and contained 47.8% of Arab ancestry, 18.4% of South Asian ancestry, and 4.6% of African ancestry. The frequency of rare functional variants within a set of 410 candidate genes for cardiac arrhythmias was assessed. Polygenic risk score (PRS) performance for atrial fibrillation (AF) prediction was evaluated. Results: This study identified 1196 rare functional variants, including 162 previously linked to arrhythmia phenotypes, with varying frequencies across Arab, South Asian, and African ancestries. Of these, 137 variants met the pathogenic or likely pathogenic (P/LP) criteria according to ACMG guidelines. Of these, 91 were in ACMG actionable genes and were present in 1030 individuals (~7%). Ten P/LP variants showed significant associations with atrial fibrillation p < 2.4 × 10−10. Five out of ten existing PRSs were significantly associated with AF (e.g., PGS000727, p = 0.03, OR = 1.43 [1.03, 1.97]). Conclusions: Our study is the largest to study the genetic predisposition to arrhythmia phenotypes in the Middle East using whole-genome sequence data. It underscores the importance of including diverse populations in genomic investigations to elucidate the genetic landscape of cardiac arrhythmias and mitigate health disparities in genomic medicine.

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Section: Discussionmentioning

confidence: 99%

Genetic Susceptibility to Arrhythmia Phenotypes in a Middle Eastern Cohort of 14,259 Whole-Genome Sequenced Individuals

Qafoud,

Elshrif,

Kunji

et al. 2024

JCM

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“…We found decreased LVEF in a subset of patients, which is in line with our scoping review based on case reports and retrospective case series. 37 QRS fragmentation is considered as a predictor of worse clinical outcomes and is related to lower LVEF and ventricular arrhythmias in Duchenne muscular dystrophy (DMD). 38 GLS detects subtle left ventricular dysfunction in patients with DMD before the decline in LVEF.…”

Section: Discussionmentioning

confidence: 99%

LAMA2 -Related Muscular Dystrophy Across the Life Span

et al. 2023

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Background and ObjectivesLAMA2-related muscular dystrophy (LAMA2-MD) is a rare neuromuscular disease characterized by proximal and axial muscle weakness, rigidity of the spine, scoliosis, and respiratory impairment. No curative treatment options exist, yet promising preclinical studies are ongoing. Currently, there is a paucity on natural history data, and appropriate clinical and functional outcome measures are needed. We aim for deep clinical phenotyping, establishment of a well-characterized baseline cohort for prospective follow-up and recruitment for future clinical trials, improvement of clinical care, and selection of outcome measures for reaching trial readiness.MethodsWe performed a cross-sectional, single-center, observational study. This study included neurologic examination and functional measurements among others the Motor Function Measure 20/32 (MFM-20/32) as primary outcome measure, accelerometry, questionnaires, muscle ultrasound, respiratory function tests, electrocardiography and echocardiography, and dual-energy X-ray absorptiometry.ResultsTwenty-seven patients with genetically confirmedLAMA2-MD were included (21 ± 13 years; M = 9; ambulant = 7). Axial and proximal muscle weakness was most pronounced. The mean MFM-20/32 score was 42.0% ± 29.4%, with domain 1 (standing and transfers) being severely affected and domain 3 (distal muscle function) relatively spared. Physical activity as measured through accelerometry showed very strong correlations to MFM-20/32 (Pearson correlation, −0.928,p< 0.01). Muscle ultrasound showed symmetrically increased echogenicity, with the sternocleidomastoid muscle most affected. Respiratory function was impaired in 85% of patients without prominent diaphragm dysfunction and was independent of age. Ten patients (37%) needed (non)invasive ventilatory support. Cardiac assessment revealed QRS fragmentation in 62%, abnormal left ventricular global longitudinal strain in 25%, and decreased left ventricular ejection fraction in 14% of patients. Decreased bone quality leading to fragility fractures was seen in most of the patients.DiscussionLAMA2-MD has a widely variable phenotype. Based on the results of this cross-sectional study and current standards of care for congenital muscular dystrophies, we advise routine cardiorespiratory follow-up and optimization of bone quality. We propose MFM-20/32, accelerometry, and muscle ultrasound for assessing disease severity and progression. For definitive clinical recommendations and outcome measures, natural history data are needed.Clinical Trials RegistrationThis study was registered atclinicaltrials.gov(NCT04478981, 21 July 2020). The first patient was enrolled in September 2020.

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“…In our study, we frequently observed decreased bone quality. Although our recent scoping review showed that decreased bone quality is prevalent in congenital myopathies, this is a new finding in SELENON-RM, and so far only general recommendations for congenital myopathies were previously reported [10,63]. Decreased bone quality can be caused by a combination of physical inactivity, atrophied muscles, and nutritional issues and decreased outdoor time leading to deficiency of calcium and vitamin D [64][65][66][67][68][69].…”

Section: Optimizing Clinical Care For Selenon-rm Patientsmentioning

confidence: 99%

SELENON-Related Myopathy Across the Life Span, a Cross-Sectional Study for Preparing Trial Readiness

Bouman,

Groothuis,

Doorduin

et al. 2023

Journal of Neuromuscular Diseases

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Background: SELENON(SEPN1)-related myopathy (SELENON-RM) is a rare congenital neuromuscular disease characterized by proximal and axial muscle weakness, spinal rigidity, scoliosis and respiratory impairment. No curative treatment options exist, but promising preclinical studies are ongoing. Currently, natural history data are lacking, while selection of appropriate clinical and functional outcome measures is needed to reach trial readiness. Objective: We aim to identify all Dutch and Dutch-speaking Belgian SELENON-RM patients, deep clinical phenotyping, trial readiness and optimization of clinical care. Methods: This cross-sectional, single-center, observational study comprised neurological examination, functional measurements including Motor Function Measurement 20/32 (MFM-20/32) and accelerometry, questionnaires, muscle ultrasound, respiratory function tests, electro- and echocardiography, and dual-energy X-ray absorptiometry. Results: Eleven patients with genetically confirmed SELENON-RM were included (20±13 (3–42) years, 73% male). Axial and proximal muscle weakness were most pronounced. The mean MFM-20/32 score was 71.2±15.1%, with domain 1 (standing and transfers) being most severely affected. Accelerometry showed a strong correlation with MFM-20/32. Questionnaires revealed impaired quality of life, pain and problematic fatigue. Muscle ultrasound showed symmetrically increased echogenicity in all muscles. Respiratory function, and particularly diaphragm function, was impaired in all patients, irrespective of the age. Cardiac assessment showed normal left ventricular systolic function in all patients but abnormal left ventricular global longitudinal strain in 43% of patients and QRS fragmentation in 80% . Further, 80% of patients showed decreased bone mineral density on dual-energy X-ray absorptiometry scan and 55% of patients retrospectively experienced fragility long bone fractures. Conclusions: We recommend cardiorespiratory follow-up as a part of routine clinical care in all patients. Furthermore, we advise vitamin D supplementation and optimization of calcium intake to improve bone quality. We recommend management interventions to reduce pain and fatigue. For future clinical trials, we propose MFM-20/32, accelerometry and muscle ultrasound to capture disease severity and possibly disease progression.

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Cardiac involvement in two rare neuromuscular diseases: LAMA2-related muscular dystrophy and SELENON-related myopathy

Cited by 8 publications

References 74 publications

Genetic Susceptibility to Arrhythmia Phenotypes in a Middle Eastern Cohort of 14,259 Whole-Genome Sequenced Individuals

Genetic Susceptibility to Arrhythmia Phenotypes in a Middle Eastern Cohort of 14,259 Whole-Genome Sequenced Individuals

LAMA2 -Related Muscular Dystrophy Across the Life Span

SELENON-Related Myopathy Across the Life Span, a Cross-Sectional Study for Preparing Trial Readiness

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