Related Myopathy Research Articles

31P Nutritional status of patients with nemaline myopathy and related congenital myopathies in Finland

31P Nutritional status of patients with nemaline myopathy and related congenital myopathies in Finland

27P Muscle ultrasound findings in paediatric patients with TTN gene related congenital myopathy

27P Muscle ultrasound findings in paediatric patients with TTN gene related congenital myopathy

05P Pediatric cardiomyopathy may be more prevalent amongst ACTA1 mutation related myopathies: a single center case-series

05P Pediatric cardiomyopathy may be more prevalent amongst ACTA1 mutation related myopathies: a single center case-series

08P SRPK3-TTN related myopathy: early clinical characteristics and muscle imaging findings

08P SRPK3-TTN related myopathy: early clinical characteristics and muscle imaging findings

Clinical and genetic evaluation of hereditary myopathies in an adult Saudi cohort

BackgroundDiagnosis of hereditary myopathy is often challenging owing to overlapping clinical phenotypes and muscle histopathological findings. This retrospective study aimed to identify the phenotypic and genotypic spectra of hereditary myopathies at a tertiary hospital in Riyadh, Saudi Arabia.MethodsWe reviewed the medical records of patients with hereditary myopathy who were evaluated between January 2018 and December 2022.ResultsEighty-seven patients (78 families) were included, two-thirds were men with a mean age of 35 (SD 14.2) years. Limb-girdle muscular dystrophy (LGMD) was the most prevalent clinical diagnosis (25 cases; 29%), of whom, a genetic diagnosis was achieved in 15 of 22 patients tested (68%). In genetically confirmed LGMD, the most prevalent disorders were dysferlinopathy (27%) followed by fukutin-related protein (FKRP) - related limb girdle muscular dystrophy (20%), sarcoglycanopathy (20%), lamin A/C related myopathy (13%), and calpain-3 myopathy (13%). In 26 patients with pathogenic/likely pathogenic variants, the genetic testing method was whole exome sequencing (WES) (42%), Next generation sequencing (NGS) (31%), and targeted single gene analysis (27%). The sensitivity of each genetic testing method was as follows: 100% for targeted single-gene analysis, 100% for targeted analysis of D4Z4 repeat array units, 88% for myotonic dystrophy protein kinase (DMPK) repeat expansion analysis, 42% for NGS-neuromuscular panel, and 46% for WES.ConclusionThe prevalent types of hereditary myopathies were consistent with those reported locally and internationally. This study highlights the diagnostic yield of various molecular genetic tests for the diagnosis of hereditary myopathy in an adult cohort and the need for improved access to advanced molecular testing in cases suspected to have facioscapulohumeral muscular dystrophy (FSHD) or mitochondrial myopathies.

Identification of a novel variant in a patient with Calsequestrin 1 related myopathy

To explore the genetic basis of a myopathic patient with pathological characteristics including tubular aggregates and vacuoles. Next generation sequencing was carried out for the patient, and candidate variant was verified by Sanger sequencing. Genetic testing revealed that the patient has harbored a heterozygous c.730G>C (p.D244H) variant of Calsequestrin 1 (CASQ1) gene. The same variant was not found in his unaffected parents. Based on guidelines from the American College of Medical Genetics and Genomics, the variant was rated as pathogenic (PS1+PM2+PP3). The novel c.730G>C (p.D244H) variant of the CASQ1 gene probably underlay the myopathy in this patient. Above finding has enriched the mutational spectrum of the CASQ1 gene.

Altered autophagic flux in GNE mutant cells of Indian origin: Potential drug target for GNE myopathy

Autophagy phenomenon in the cell maintains proteostasis balance by eliminating damaged organelles and protein aggregates. Imbalance in autophagic flux may cause accumulation of protein aggregates in various neurodegenerative disorders. Regulation of autophagy by either calcium or chaperone play a key role in the removal of protein aggregates from the cell. The neuromuscular rare genetic disorder, GNE Myopathy, is characterized by accumulation of rimmed vacuoles having protein aggregates of β-amyloid and tau that may result from altered autophagic flux. In the present study, the autophagic flux was deciphered in HEK cell-based model for GNE Myopathy harbouring GNE mutations of Indian origin. The refolding activity of HSP70 chaperone was found to be reduced in GNE mutant cells compared to wild type controls. The autophagic markers LC3II/I ratio was altered with increased number of autophagosome formation in GNE mutant cells compared to wild type cells. The cytosolic calcium levels were also increased in GNE mutant cells of Indian origin. Interestingly, treatment of GNE mutant cells with HSP70 activator, BGP-15, restored the expression and refolding activity of HSP70 along with autophagosome formation. Treatment with calcium chelator, BAPTA-AM restored the cytoplasmic calcium levels and autophagosome formation but not LC3II/I ratio significantly. Our study provides insights towards GNE mutation specific response for autophagy regulation and opens up a therapeutic advancement area in calcium signalling and HSP70 function for GNE related Myopathy.

Identification of a Novel Intronic Mutation in VMA21 Associated with a Classical Form of X-Linked Myopathy with Autophagy.

Introduction VMA21 -related myopathy is one of the rare forms of slowly progressive myopathy observed in males. Till now, there have been only a handful of reports, mainly from Europe and America, and two reports from India. Method Here, we describe a case of genetically confirmed VMA21 -associated myopathy with clinical, histopathological, and imaging features with a list of known VMA21 mutations. Results A 29-year-old man had the onset of symptoms at 18 years of age with features of proximal lower limb weakness. Muscle magnetic resonance imaging showed the preferential involvement of vasti and adductor magnus. A biopsy of the left quadriceps femoris showed features of autophagic vacuolar myopathy with vacuoles containing granular eosinophilic materials. In targeted next-generation sequencing, hemizygous mutation in the 3' splice site of intron 2 of the VMA21 gene (c.164-7 T > A) was identified and confirmed the diagnosis of X-linked myopathy with excessive autophagy. Conclusion This report expands the phenotypic and genotypic profile of VMA21 -related myopathy, with a yet unreported mutation in India.

Two zebrafish cacna1s loss-of-function variants provide models of mild and severe CACNA1S-related myopathy.

CACNA1S-related myopathy, due to pathogenic variants in the CACNA1S gene, is a recently described congenital muscle disease. Disease associated variants result in loss of gene expression and/or reduction of Cav1.1 protein stability. There is an incomplete understanding of the underlying disease pathomechanisms and no effective therapies are currently available. A barrier to the study of this myopathy is the lack of a suitable animal model that phenocopies key aspects of the disease. To address this barrier, we generated knockouts of the two zebrafish CACNA1S paralogs, cacna1sa and cacna1sb. Double knockout fish exhibit severe weakness and early death, and are characterized by the absence of Cav1.1 α1 subunit expression, abnormal triad structure, and impaired excitation-contraction coupling, thus mirroring the severe form of human CACNA1S-related myopathy. A double mutant (cacna1sa homozygous, cacna1sb heterozygote) exhibits normal development, but displays reduced body size, abnormal facial structure, and cores on muscle pathologic examination, thus phenocopying the mild form of human CACNA1S-related myopathy. In summary, we generated and characterized the first cacna1s zebrafish loss-of-function mutants, and show them to be faithful models of severe and mild forms of human CACNA1S-related myopathy suitable for future mechanistic studies and therapy development.

P433 Clinical features of two patients with FHL1 related myopathy in Korea

P433 Clinical features of two patients with FHL1 related myopathy in Korea

Modulating fast skeletal muscle contraction protects skeletal muscle in animal models of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a lethal muscle disease caused by absence of the protein dystrophin, which acts as a structural link between the basal lamina and contractile machinery to stabilize muscle membranes from mechanical stress. In DMD, mechanical stress leads to exaggerated membrane injury and fiber breakdown, with fast fibers being the most susceptible to damage. A major contributor to this injury is muscle contraction, controlled by the motor protein myosin. However, the relationship between how muscle contraction and fast muscle fiber damage contribute to the pathophysiology of DMD has not been well characterized. We explored the role of fast skeletal muscle contraction in DMD with a novel, selective, orally active inhibitor of fast skeletal muscle myosin, EDG-5506. Surprisingly, even modest decreases of contraction (<15%) were sufficient to protect skeletal muscles in dystrophic mdx mice from stress injury. Longer-term treatment also decreased muscle fibrosis in key disease-implicated tissues. Importantly, therapeutic levels of myosin inhibition with EDG-5506 did not detrimentally affect strength or coordination. Finally, in dystrophic dogs, EDG-5506 reversibly reduced circulating muscle injury biomarkers and increased habitual activity. This unexpected biology may represent an important alternative treatment strategy for Duchenne and related myopathies.

Novel ACTA1 Mutation in a Family with Congenital Myopathy and Variably-penetrant Cardiomyopathy (P6-8.008)

<h3>Objective:</h3> To describe characteristics of a family with congenital myopathy, variably-penetrant dilated cardiomyopathy, and a novel, likely pathogenic variant in <i>ACTA1</i>, c.81C&gt;A (p.Asp27Glu). <h3>Background:</h3> <i>ACTA1</i> encodes skeletal muscle alpha-actin, the primary actin isoform in human skeletal muscle, also expressed to a lesser degree in cardiac muscle. Mutations in <i>ACTA1</i> are common in patients with congenital myopathies; however, associated cardiomyopathy is rare. <h3>Design/Methods:</h3> Retrospective chart review of the proband and 3 family members. <h3>Results:</h3> The proband was a 47-year-old Caucasian male of Ukrainian heritage. His mother (73), sister (40), and nephew (18) were similarly affected. All were hypotonic at birth, had delayed motor milestones, and presented with high-arched palate, elongated facies, and mild-moderate axial and proximal-predominant weakness. The proband had dilated cardiomyopathy with congestive heart failure and intraventricular conduction delay, his sister had dilated cardiomyopathy with left anterior fascicular block, his nephew had left ventricular dilatation with preserved function and normal conduction, and his mother had atrial fibrillation without structural heart disease. Biceps brachii biopsy in the proband demonstrated congenital fiber-type disproportion (CFTD), in addition to rare nemaline rods on electron microscopy. Next-generation sequencing identified a novel, likely pathogenic variant in <i>ACTA1</i>, c.81C&gt;A (p.Asp27Glu), segregating in affected family members. This missense variant is not present in population databases and affects a highly conserved amino acid. In silico models predicted a deleterious effect on protein structure and function (PolyPhen-2: probably damaging; SIFT: 0.0; MutationTaster: disease-causing). <h3>Conclusions:</h3> This family expands the genotypic and phenotypic spectrum of <i>ACTA1-</i>related myopathies. The novel missense variant c.81C&gt;A (p.Asp27Glu) associates with autosomal dominant congenital myopathy, CFTD, and variable, non-age-dependent penetrance of cardiac structural abnormalities along the spectrum of left ventricular dilatation and systolic dysfunction. Dilated cardiomyopathy and CFTD are rare in both isolation and combination in <i>ACTA1</i>-related myopathies. We emphasize that early cardiac surveillance is important in patients with <i>ACTA1-</i>related myopathies. <b>Disclosure:</b> Dr. Putko has nothing to disclose. Dr. Schmitt has nothing to disclose. Dr. Oudit has nothing to disclose. Dr. Phan has nothing to disclose. Dr. Beecher has nothing to disclose.

Markedly prolonged compound muscle action potential duration in a patient with coronavirus disease 2019 related critical illness myopathy

AbstractA 56‐year‐old man admitted with coronavirus disease 2019 (COVID‐19) became severely ill, required ventilator support and intensive care unit management. After ventilator weaning, he was found to have quadriparesis. Guillain–Barré syndrome (GBS) was suspected and administration of high‐dose intravenous immunoglobulin (IVIg) was considered. However, markedly prolonged compound muscle action potential (CMAP) duration was observed, leading to a diagnosis of critical illness myopathy (CIM). Therefore, IVIg was not given at all, and supportive care was continued. A good functional recovery was obtained. Prolonged CMAP duration is a characteristic finding to CIM. CIM following severe COVID‐19 infection is probably common, although the diagnostic value of prolonged CMAP duration is not widely recognized. This characteristic finding deserves more attention because it contributes to early differentiation between CIM and GBS and the use of IVIg in patients with COVID‐19 may cause thrombotic complications and worsen the prognosis.

CASQ1‐related myopathy: The first report from China and the literature review

Calsequestrin 1 (CASQ1) is the most crucial Ca2+ binding protein localized in the sarcoplasmic reticulum (SR) of skeletal muscle. With high capacity and low affinity for Ca2+, CASQ1 plays a significant role in maintaining a large amount of Ca2+ necessary for muscle contraction. However, only five mutations in CASQ1 have been identified to date. Here, we report a 42-year-old Chinese female patient who presented with a 12 years history of slowly progressive upper limb weakness, predominantly affecting distal muscles, which was uncommon comparing to other CASQ1-related patients. Next-generation sequencing (NGS) analysis revealed a novel heterozygous mutation (c.766G > A, p.Val256Met) in CASQ1. Functional studies confirmed the likely pathogenicity of this variant. Muscle histopathology revealed rare optically empty vacuoles in myofibers and atypical eosinophilic granules in the cytoplasm, which has not been observed before. We also performed a literature review on all the pathogenic mutations in CASQ1 and summarized their genetic and clinical characteristics. This is the first report on CASQ1-related myopathy from China, further expanding the mutation spectrum of CASQ1 gene and provides new insights into the function of CASQ1.

P.08 Phase 1 open-label trial of Rycal S48168 (ARM210) for RYR1-related myopathies

Pathogenic variants in the <i>RYR1</i> gene, encoding the skeletal muscle ryanodine receptor (RyR1), are the most common cause of non-dystrophic neuromuscular disorders. Pathogenic <i>RYR1</i> variants exhibit downstream consequences, including aberrant sarcoplasmic reticulum (SR) Ca²⁺ leak, hypersensitivity to RyR1 agonists, diminished SR Ca²⁺ release, and/or decreased RyR1 protein expression. Decreased RyR1-calstabin1 association, due to <i>RYR1</i> variants and/or post-translational modifications of the RyR1 channel, exacerbates SR Ca²⁺ leak with detrimental downstream effects on muscle function. Rycal compounds have been shown to restore RyR1-calstabin1 association, stabilize the <i>RyR1</i> closed state, and mitigate aberrant Ca²⁺ leak in <i>RYR1</i>-related myopathy (<i>RYR1</i>-RM) muscle biopsies. We conducted a phase 1 trial of S48168 (ARM210), a Rycal compound, in ambulatory adults with <i>RYR1</i>-RM (NCT04141670). The primary endpoint was safety and tolerability over a one-month dosing period. Pharmacokinetic (PK) studies, muscle biopsies, motor/muscle function tests, and a patient-reported fatigue questionnaire were also included. Seven eligible individuals were enrolled and received either the low dose (120 mg, n=3) or high dose (200 mg, n=4) of S48168 (ARM210) daily. Three treatment emergent adverse effects grade 2 or above were reported, all unrelated to S48168 (ARM210) and there were no serious adverse events. S48168 (ARM210) showed a dose-dependent PK profile and C_max remained within pre-defined safety margins. At one month, self-reported fatigue scores decreased and shoulder abduction strength trended higher in the high dose group, while handgrip strength increased in both dose groups, though these exploratory comparisons were descriptive. Other preliminary efficacy results were mixed. Given the favorable safety profile and efficacy trends, further clinical development of S48168 (ARM210) is warranted for <i>RYR1</i>-RM.

STAC3 related congenital myopathy: A case series of seven Comorian patients

The Bailey-Bloch congenital myopathy, also known as Native American myopathy (NAM), is an autosomal recessive congenital myopathy first reported in the Lumbee tribe people settled in North Carolina (USA), and characterized by congenital weakness and arthrogryposis, cleft palate, ptosis, short stature, kyphoscoliosis, talipes deformities, and susceptibility to malignant hyperthermia (MH) triggered by anesthesia. NAM is linked to STAC3 gene coding for a component of excitation-contraction coupling in skeletal muscles. A homozygous missense variant (c.851G > C; p.Trp284Ser) in STAC3 segregated with NAM in the Lumbee families. Non-Native American patients with STAC3 related congenital myopathy, and with other various variants of STAC3 have been reported. Here, we present seven patients from the Comoros Islands (located in the Mozambique Channel) diagnosed with STAC3 related congenital myopathy and having the recurrent variant identified in the Lumbee people. The series is the second largest series of patients having STAC3 related congenital myopathy with a shared ethnicity after le Lumbee series. Local history and geography may explain the overrepresentation of NAM in the Comorian Archipelago with a founder effect. Further researches would be necessary for the understanding of the onset of the NAM in Comorian population as search of the “classical” STAC3 variant in East African population, and haplotypes comparison between Comorian and Lumbee patients.

Nuclear receptors as potential therapeutic targets in peripheral arterial disease and related myopathy.

Peripheral arterial disease (PAD) is a prevalent cardiovascular complication of limb vascular insufficiency, causing ischemic injury, mitochondrial metabolic damage and functional impairment in the skeletal muscle, and ultimately leading to immobility and mortality. While potential therapies have been mostly focussed on revascularization, none of the currently available pharmacological treatments are fully effective in PAD, often leading to amputations, particularly in chronic metabolic diseases. One major limitation of focussed angiogenesis and revascularization as a therapeutic strategy is a limited effect on metabolic restoration and muscle regeneration in the affected limb. Therefore, additional preclinical investigations are needed to discover novel treatment options for PAD preferably targeting multiple aspects of muscle recovery. In this review, we propose nuclear receptors expressed in the skeletal muscle as potential candidates for ischemic muscle repair in PAD. We review classic steroid and orphan receptors that have been reported to be involved in the regulation of paracrine muscle angiogenesis, oxidative metabolism, mitochondrial biogenesis and muscle regeneration, and discuss how these receptors could be critical for recovery from ischemic muscle damage. Furthermore, we identify existing gaps in our understanding of nuclear receptor signalling in the skeletal muscle and propose future areas of research that could be instrumental in exploring nuclear receptors as therapeutic candidates for treating PAD.

P.043 Plasmapheresis for treatment of light chain amyloidosis related myopathy

Background: Light chain (AL) amyloidosis is a plasma cell disorder characterized by abnormal fibrillary light chain deposition causing cardiac, renal, hepatic, gastrointestinal and peripheral nervous system dysfunction. Muscle disease occurs in 1.5% of individuals causing progressive proximal weakness thus far considered untreatable. Methods: We reviewed two cases of AL amyloidosis associated myopathy at our institution who had robust response to plasmapheresis. Both were at stringent clinical response following CyBorME therapy during peak severity of their myopathy. Results: In case 1, a 70-year-old male with recently diagnosed kappa light chain multiple myeloma and cardiac/renal amyloidosis developed severe subacute proximal weakness preventing ambulation. CK was normal and electromyography was consistent with irritable myopathy. Deltoid biopsy showed perimysial and endomysial amyloidosis. A trial of plasmapheresis in a tapering schedule resulted in robust recovery of strength. In case 2, a 67-year-old female with recently diagnosed kappa light chain multiple myeloma with amyloidosis on fat pad aspirate developed severe subacute proximal weakness requiring prolonged hospital admission. CK was normal and electromyography demonstrated non-irritable myopathy. Bicep biopsy showed perivascular amyloidosis. A trial of plasmapheresis in a tapering schedule resulted in robust recovery of strength. Conclusions: Plasmapheresis is a novel and potentially effective treatment for patients with AL amyloidosis associated myopathy.

P165 CARDIOVASCULAR RISK FACTORS AND HYPOGONADISM INFLUENCE ON CARDIAC OUTCOMES IN AN AGING POPULATION OF BETA–THALASSEMIA PATIENTS: LOOKING AT THE HEART OF THE PROBLEM

Abstract Background β–thalassemia major (β–TM) is a hereditary genetic disease hindered by many comorbidities due to transfusion–related iron. Despite iron chelation therapy increased the life expectancy up to 50 years today, Iron–related heart disease is still a leading complication, with an expected change in cardiac disease drivers with the ageing of these patients. This study aims to evaluate the distribution and prevalence of cardiovascular risk factors in a population of thalassemia major patients, and their relationship with observed cardiovascular events and potential modifying factors. Methods and Results One–hundred fifty–nine β–TM patients older than 18 years of age were included in this study. Mean age was 40.9 ± 8.4 years. Low serum lipid levels with low HDL levels were noted, with 28% having diabetes mellitus and 62% with hypogonadism; Splenectomy was reported in 70%. During the observed period, 3.8% of patients had at least one episode of heart failure, 35.9% showed early signs of heart failure, 22% received a diagnosis of diastolic dysfunction, 38% had a left ventricular ejection fraction &amp;lt;55%, and 21.4% showed supraventricular arrhythmias. Cardiovascular risk was then assessed using two algorithms (CUORE and Pooled Cohort Risk Equation – PCRE) and was generally low despite the high burden of cardiac–related events. Patients with hypogonadism (who showed lower cardiac T2* value than those without; p &amp;lt; 0.001) showed a statistically significant correlation with the occurrence of cardiovascular events. Discussion The β–TM population has a relatively low mean age, but shows a particular metabolic profile associated with numerous comorbidities: an increased prevalence of diabetes mellitus, low HDL values and frequent hypogonadism, which tends to be associated with increased iron deposition in the myocardium. The cardiovascular risk estimated by specific algorithms (CUORE and PCRE) was generally low, probably due to the young age of the cohort and derivation pitfalls when applied to this specific population, but the prevalence of cardiac events was not negligible. Conclusions The chronic accumulation of iron in the heart and the specific metabolic profile, mainly observed in patients with hypogonadism, allows us to define β–TM as a condition with high cardiovascular risk from many points of view (iron–related myopathy, atherosclerosis and arrhythmias), which requires better stratification tools and specific follow–up program.

Characterization of a novel zebrafish model of SPEG-related centronuclear myopathy.

ABSTRACTCentronuclear myopathy (CNM) is a congenital neuromuscular disorder caused by pathogenic variation in genes associated with membrane trafficking and excitation–contraction coupling (ECC). Bi-allelic autosomal-recessive mutations in striated muscle enriched protein kinase (SPEG) account for a subset of CNM patients. Previous research has been limited by the perinatal lethality of constitutive Speg knockout mice. Thus, the precise biological role of SPEG in developing skeletal muscle remains unknown. To address this issue, we generated zebrafish spega, spegb and spega;spegb (speg-DKO) mutant lines. We demonstrated that speg-DKO zebrafish faithfully recapitulate multiple phenotypes associated with CNM, including disruption of the ECC machinery, dysregulation of calcium homeostasis during ECC and impairment of muscle performance. Taking advantage of zebrafish models of multiple CNM genetic subtypes, we compared novel and known disease markers in speg-DKO with mtm1-KO and DNM2-S619L transgenic zebrafish. We observed Desmin accumulation common to all CNM subtypes, and Dnm2 upregulation in muscle of both speg-DKO and mtm1-KO zebrafish. In all, we establish a new model of SPEG-related CNM, and identify abnormalities in this model suitable for defining disease pathomechanisms and evaluating potential therapies. This article has an associated First Person interview with the joint first authors of the paper.