P39 The effect of corticosteroid treatment on pulmonary function in adults with Duchenne muscular dystrophy
Duchenne Muscular Dystrophy (DMD) is a rapidly progressive genetic condition characterized by lack of functional dystrophin protein. It causes muscle degeneration, weakness, loss of ambulation (LOA) in early teens and respiratory insufficiency being one of the leading causes of premature death. Data from paediatric cohorts showed that CS treatment delays onset of respiratory decline by approximately 2 years and CSs are now part of the international standards of care for DMD. However, evidence on the effect of continuing CSs in adults is limited leading to inconsistent clinical practice. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: A. Pietrusz, R. Astin, M. Guglieri, M. Desikan, K. Waller, S. Chapman, M. Schiava, S. Brady, B. Soleimani, J. Freebody, A. Nickol, G. Ramdharry, F. Muntoni, R. Quinlivan Source Type: research
P40 Long-term effects of corticosteroid treatment in DMD: daily versus intermittent regimes
Duchenne muscular dystrophy (DMD) is treated with corticosteroids (CS) using intermittent or daily regimes. Risk-benefit assessment is essential to optimize treatment choice, but long-term side-effects accumulate well beyond the duration of a clinical trial. We compared retrospective data from patients treated daily (deflazacort (D)) with those of patients treated intermittently (10 days on 10 days off prednisone or deflazacort (I)), acquired as part of outpatient regular care in one national reference center in Belgium and two in the Netherlands (1995-2022). (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: N. Ikelaar, M. van der Holst, Y. Meijer - Krom, M. Stoop, S. Houwen - van Opstal, N. Goemans, S. Geuens, L. de Waele, E. Niks Source Type: research
P168 The burden of titin variants on genetic counseling
We examined titin genetic findings from 8,220 individuals (4,703 affected individuals and 3,517 healthy relatives) submitted to the RD-Connect GPAP, as part of the Solve-RD project. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: M. Di Feo, A. Topf, L. Matalonga, I. Paramonov, A. Perrin, M. Johari, SNV/indels working group, NMD-DITF, SolveRD Consortium, M. Cossee, P. Hackman, M. Savarese, B. Udd Tags: GENETICS OF NEUROMUSCULAR DISORDERS Source Type: research
P169 Childhood onset amyotrophic lateral sclerosis associated with SPTLC2 gain-of-function pathogenic variants: clinical, genetic, and biochemical insights
We report a cohort of eight independent patients with neonatal to juvenile-onset ALS with de-novo recurrent variants in SPTLC2. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: R Or Bach, S. Syeda, P. Mohassel, M. Dohrn, M. Lone, S. Donkervoort, A. Foley, D. Beijer, E. Bayraktar, P. Oflazer, P. Munot, A. Rose, M. Lyons, F. Muntoni, A. Ba şak, T. Dunn, H. Tornemann, Z. Süchner, C. Bönnemann, International SPTLC2 Study Group Source Type: research
P170 TDP-43 seeding and aggregation in skeletal muscle
TDP-43 is a ubiquitously expressed RNA-binding protein which has been found in sarcoplasmic aggregates in several myopathies. TDP-43 is primarily localized in the nucleus but during cell stress is recruited to cytoplasmic stress granules. Under certain conditions, cytoplasmic misfolded TDP-43 oligomers (or seeds) can induce soluble TDP-43 to misfold and aggregate in a prion-like manner, leading to accumulation and spread of insoluble aggregates. TDP-43 seeds are capable of cell-to-cell transmission through neuronal networks, but it is unknown whether it can spread within skeletal muscle. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: E. Lynch, S. Pittman, J. Daw, C. Weihl Source Type: research
P171 LiBi-NMD: liquid biopsies in neuromuscular diseases – the underrated value of white blood cells
Biochemical, histological, and ultra-structural studies are standard procedures in the diagnostic work-up of muscle and nerve biopsies derived from neuromuscular patients and moreover represent important biomedical research approaches toward a better understanding of the etiology of neuromuscular diseases (NMDs). In the era of next-generation-sequencing approaches, evaluation of the pathogenicity of genetic variants on muscle and nerve biopsies is often crucial. However, the investigation of tissue biopsies also harbours significant limitations: sampling is invasive, amount of tissue is often limited, and biopsies can only...
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: A. Hentschel, A. Della Marina, H. K öbel, A. Gangfuss, M. Dohrn, J. Weis, V. Dobelmann, K. Krause, T. Ruck, M. Vorgerd, U. Schara-Schmidt, A. Roos Source Type: research
P172 Exploring the diagnostic ability of RNA-seq to identify disease-causing variants in muscular dystrophy
The muscular dystrophies are caused by genetic mutations that result in progressive weakness in individuals. It is now typical practice to begin genetic diagnostics with a next-generation sequencing (NGS) panel. However, cohort studies have shown that these panels do not provide a confirmatory diagnosis in most of these individuals. Furthermore, these panels can be populated by variants of unknown significance (VUS). One alternative approach is to use transcriptomic analysis of muscle to improve genetic diagnosis. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: A. Gaynor, M. Hale, M. Lek, M. Provenzano, K. Bates, N. Johnson Source Type: research
P173 A highly responsive bioassay for quantification of glucocorticoids
Measurement of total cortisol levels in serum samples is important for the diagnosis of hyper- or hypocortisolism and currently immunoassays or liquid chromatography-mass spectrometry (LC-MS/MS) are the preferred methods. However, most serum cortisol is bound to serum proteins and is not bioavailable. Methods for measurements of bioavailable cortisol are often laborious for a clinical setting, unreliable and inconvenient for the patient. Therefore, a new versatile assay with the ability to measure both total and bioavailable cortisol is in high demand and an important supplement to the current methods. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: M. Poulsen, M. Overgaard, C. Andersen, A. Lodberg Source Type: research
P174 Subtyping of cardiac amyloidosis by mass spectrometry of endomyocardial biopsies
Amyloids are aggregates of proteins characterized by a fibrillar morphology of 7 –13 nm in diameter, a beta sheet secondary structure and ability to be stained by particular dyes, such as Congo red. Amyloid deposits are composed of many proteins but usually one major protein is responsible for the amyloid deposition. Cardiac amyloidosis is a severe condition leading to restric tive cardiomyopathy and heart failure. It has become important to get a correct diagnosis because of novel amyloid specific treatments. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: A. Oldfors, F. Noborn, C. Thomsen, E. Vorontsov, E. Bobbio, C. Sihlbom, J. Nilsson, C. Polte, E. Bollano, K. Vukusic, J. Sandstedt, G. Dellgren, K. Karason, G. Larson Source Type: research
P175 Muscle biopsy methylome analysis creates well-defined clusters for inherited myopathies
Whole genome DNA methylation profiles (methylomes) are epigenetic signatures that reflect cell- or tissue-specific features combined with consequences of germline or somatic variation. Using machine learning techniques, exploitation of global differences between methylomes of normal and neoplastic samples has allowed the creation of artificial intelligence classifiers for central nervous system tumors. The neuropathology field has since been influenced by such classifiers in tumor diagnostic practices and guidelines, as well as in collaborative approaches to discovery and research of novel and existing entities using methy...
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: O Lopes Abath Neto, S. Moore Source Type: research
P176 Immortalized human muscle cells: easy-to-use models to study neuromuscular diseases
In recent years, therapeutic approaches for neuromuscular diseases have been developed and new strategies are currently emerging. Human cellular models adapted to each disease and each mutation, are needed to test these therapeutic strategies. Patient-derived muscle stem cells, also known as myoblasts can be isolated from biopsies, but their use is restricted by 1) the availability of muscle biopsies for research, 2) the limited proliferative capacity of the myoblasts and 3) their potential exhaustion in degenerative diseases. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: G. Butler-Browne, J. Ohana, K. Mamchaoui, M. Bensalah, E. Negroni, C. Trollet, A. Bigot, V. Mouly Source Type: research
P177 Exomiser is an efficient tool to prioritize candidate genes in cohorts of unsolved myopathy patients
Exome and genome sequencing approaches have contributed to the identification of many novel disease genes, deeply changing our understanding of rare diseases. However, the clinical interpretation of sequencing data remains complex. In our study, we tested phenotype-based prioritization on exome data to identify possible novel disease genes. We used Exomiser, a bioinformatic tool which prioritizes genes and variants by combining pathogenicity scores with a phenotypic relevance score. We benchmarked our approach creating 45 mock VCF files, each of them containing two heterozygous truncating variants in a previously identifie...
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: V. Lillback, M. De Feo, M. Johari, G. Vicidomini, P. Hackman, B. Udd, M. Savarese Source Type: research
VP178 Multiomics needed to increase the detection rate of myopathy patients
An estimated 65/100,000 people have inherited muscular disorders. Targeted gene panels are a standard diagnostic procedure for patients with inherited muscle diseases, as they are for many other Mendelian diseases. However, the overall diagnostic rate is still low and, thus, periodically reanalyzing the already available data is suggested to increase it. We reanalyzed data collected between 2014 and 2016 of 1,084 patients who had been analyzed using the targeted gene panel MYOcap, covering over 300 genes that are known or suspected to cause skeletal muscle diseases. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: R. Owusu, M. Johari, S. Lehtinen, M. Jokela, J. Palmio, P. Hackman, B. Udd, M. Savarese Source Type: research
P179 Using Long-read RNA sequencing for the identification of novel transcripts in disease-causing muscle genes
A fundamental limitation in asserting a gene-disease association is the interpretation of variants of uncertain significance (VUS), mainly when the genes are associated with multiple phenotypes. Species- and tissue-specific transcript expression plays a vital role in determining the pathogenicity of a variant. Although bulk RNA sequencing of multiple tissues has successfully revealed tissue-specific expression for many genes, short-read RNA sequencing has known limitations in characterizing disease-associated transcripts. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: M. Johari, G. Ravenscroft Source Type: research
P180 A retrospective chart review evaluating clinical presentation and genetic testing approaches for patients with neuromuscular disorders
Inherited Neuromuscular disorders (NMDs) are a large group of genetic conditions characterized by impaired peripheral nerve, motor neuron, neuromuscular junction, or skeletal muscle function. Diagnosing a patient with NMD can be complex due to clinical similarities, genetic heterogeneity across conditions, and variable ages of onset. Clinical evaluation for NMDs has incorporated molecular genetics as a first or second tier diagnostic practice. However, genetic testing for diagnosis has its challenges due to the variety of testing options and the ambiguity of many NMD phenotypes. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: A. Rosenberg, C. Tian, H. He, E. Ulm, K. Collins, C Bhimarao Nagaraj Source Type: research
