Progressive Proximal Muscle Weakness Research Articles

Clinicogenetic characterization and response to disease-modifying therapies in spinal muscular atrophy: real-world experience from a reference center in Southern Brazil

ObjectiveSpinal Muscular Atrophy linked to chromosome 5q (SMA) is an autosomal recessive neurodegenerative disease characterized by progressive proximal muscle atrophy and weakness. This study addresses the scarcity of research on novel disease-modifying therapies for SMA in Latin America by reporting a real-world experience in Southern Brazil. MethodologyThis is a single-center historical cohort that included all patients diagnosed with spinal muscular atrophy at a Regional Reference Service for rare diseases. ResultsEighty-one patients were included, of whom 7 died during follow-up. Of the remaining 74 patients, 5.4 % were classified as pre-symptomatic, 24.3 % with SMA type 1, 28.4 % with type 2, 36.5 % with type 3, and 5.4 % with type 4. The mean follow-up time ranged from 1.8 years for pre-symptomatic cases to 8.7 years for SMA types 2 and 3. Approximately 42 % of these patients received specific disease-modifying therapy, of these, 96.8 % received Nusinersen, with 19.4 % transitioning to gene therapy using Onasemnogene Abeparvovec, and 6.4 % starting Risdiplam. Most patients with SMA type 1 were on disease-modifying treatment, whereas only slightly over a third of patients with type 2 and about 10 % of type 3 were receiving such treatments. Among treated patients, 80 % demonstrated improvement in motor performance during the follow-up, with a lesser therapeutic response being associated with late initiation of treatment and low motor function scores at baseline. ConclusionThis real-world study reinforces the effectiveness of disease-modifying therapies for SMA in Brazil within the context of low- and middle-income countries, which is greater the earlier and the better the patient's functional status.

Nailfold Capillaroscopy Changes in Patients with Idiopathic Inflammatory Myopathies.

Background/Objectives: Idiopathic inflammatory myopathies (IIMs) are rare autoimmune disorders characterized by progressive proximal muscle weakness and varying extra-muscular manifestations. The latest 2017 EULAR/ACR criteria classify them into subgroups. This study aims to evaluate the role of nailfold capillaroscopy (NFC) as a diagnostic and prognostic tool in IIMs by comparing capillaroscopic patterns across different IIM subtypes. Methods: We conducted an observational, cross-sectional study at the Institute of Rheumatology in Belgrade, analyzing 90 patients diagnosed with IIMs per the 2017 EULAR/ACR criteria. Patients were categorized into dermatomyositis (DM) (n = 37), polymyositis (PM) (n = 35), amyopathic dermatomyositis (ADM) (n = 13), and juvenile dermatomyositis (JDM) (n = 5). A control group of 35 patients with primary Raynaud's phenomenon was also included. NFC findings, clinical manifestations, and laboratory data were compared across the groups. Results: In DM, 81.9% exhibited a scleroderma capillaroscopic pattern, which was also present in 76.9% of ADM patients. In PM, the most common pattern was nonspecific changes (48.6%). JDM patients showed a high prevalence of scleroderma changes (n = 4 (80%)). Scleroderma patterns correlated with Gottron's papules, heliotrope rash, periungual erythema, Raynaud's phenomenon, and interstitial lung disease (ILD). No significant differences were found in laboratory parameters across capillaroscopic groups, except for a higher prevalence of anti-Jo1 antibodies in patients with nonspecific capillaroscopic changes. Conclusions: NFC is a valuable tool for differentiating IIM subtypes and correlating clinical manifestations with specific capillaroscopic patterns. The high prevalence of scleroderma changes in DM and ADM suggests their potential as a diagnostic and prognostic marker in IIMs. Further research with larger cohorts is warranted to validate these findings.

A - 45 Duchenne and Becker Muscular Dystrophy: Sibling Case Studies

Abstract Objective Duchenne Muscular Dystrophy (DMD) is an X-linked recessive neuromuscular condition primarily affecting males. Progressive proximal muscle wasting and weakness is seen and a shortened life span can occur due to cardiac involvement. Becker Muscular Dystrophy (BMD) is a milder form of DMD. Non-progressive cognitive impairment (e.g., lower IQ) in DMD has been well established, while the cognitive profile in BMD is less known. DMD/BMD are caused by mutations in the dystrophin protein. Research suggests that mutations downstream of exon 63 in the DMD gene are associated with poorer cognitive outcomes compared to upstream 1–30. Our cases explore the association between genetic/medical factors upon cognitive and behavioral outcomes, and neuropsychological similarities/differences between DMD and BMD. Method The current sibling case studies include one BMD set (mutations at exon 45–49) and two DMD sets (exon 61–74, and 13, respectively). They are part of a larger IRB-approved research dataset. Notably in DMD set two, the siblings have different biological fathers. Results The BMD siblings have comparable neuropsychological profiles (e.g., below average IQ, academic challenges, attention/executive problems). In DMD set one, one sibling has average intelligence with no academic challenges, while the other sibling has a low average IQ with challenges in math and spelling. In DMD set two, one sibling has intact cognitive functioning, while the other sibling performs well below average across neurocognitive domains. Conclusions Our results indicate variabilities in DMD/BMD, highlighting the contributing role of established factors (e.g., mutation location) and additional non-DMD influences (e.g., genetic contributions from biological father) to understand neuropsychological profiles.

Induced Muscle and Liver Absence of Gne in Postnatal Mice Does Not Result in Structural or Functional Muscle Impairment.

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. 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. 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. 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. 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.

Identification of common mechanisms and biomarkers for dermatomyositis and atherosclerosis based on bioinformatics analysis.

Dermatomyositis (DM) manifests as an autoimmune and inflammatory condition, clinically characterized by subacute progressive proximal muscle weakness, rashes or both along with extramuscular manifestations. Literature indicates that DM shares common risk factors with atherosclerosis (AS), and they often co-occur, yet the etiology and pathogenesis remain to be fully elucidated. This investigation aims to utilize bioinformatics methods to clarify the crucial genes and pathways that influence the pathophysiology of both DM and AS. Microarray datasets for DM (GSE128470, GSE1551, GSE143323) and AS (GSE100927, GSE28829, GSE43292) were retrieved from the Gene Expression Omnibus (GEO) database. The weighted gene co-expression network analysis (WGCNA) was used to reveal their co-expressed modules. Differentially expression genes (DEGs) were identified using the "limma" package in R software, and the functions of common DEGs were determined by functional enrichment analysis. A protein-protein interaction (PPI) network was established using the STRING database, with central genes evaluated by the cytoHubba plugin, and validated through external datasets. Immune infiltration analysis of the hub genes was conducted using the CIBERSORT method, along with Gene Set Enrichment Analysis (GSEA). Finally, the NetworkAnalyst platform was employed to examine the transcription factors (TFs) responsible for regulating pivotal crosstalk genes. Utilizing WGCNA analysis, a total of 271 overlapping genes were pinpointed. Subsequent DEG analysis revealed 34 genes that are commonly found in both DM and AS, including 31 upregulated genes and 3 downregulated genes. The Degree Centrality algorithm was applied separately to the WGCNA and DEG collections to select the 15 genes with the highest connectivity, and crossing the two gene sets yielded 3 hub genes (PTPRC, TYROBP, CXCR4). Validation with external datasets showed their diagnostic value for DM and AS. Analysis of immune infiltration indicates that lymphocytes and macrophages are significantly associated with the pathogenesis of DM and AS. Moreover, GSEA analysis suggested that the shared genes are enriched in various receptor interactions and multiple cytokines and receptor signaling pathways. We coupled the 3 hub genes with their respective predicted genes, identifying a potential key TF, CBFB, which interacts with all 3 hub genes. This research utilized comprehensive bioinformatics techniques to explore the shared pathogenesis of DM and AS. The three key genes, including PTPRC, TYROBP, and CXCR4, are related to the pathogenesis of DM and AS. The central genes and their correlations with immune cells may serve as potential diagnostic and therapeutic targets.

Statin Myopathy: A Case series

Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) immune-mediated necrotizing myopathy (anti-HMGCR IMNM) is a rare adverse effect associated with the use of statin medications [1]. While the investigation remains ongoing, statin exposure is thought to induce mitochondrial dysfunction due to inhibition of HMGCR, subsequently triggering an inflammatory cascade with oxidative stress and autoantibodies (aAbs) against HMGCR, ultimately leading to an immune-mediated necrotizing myopathy (IMNM) [2]. Clinical presentation may involve dermatomyositis-like features ranging from myalgias to severe and progressive proximal muscle weakness, often persisting after cessation of the offending statin [3]. Serum studies typically reveal significantly elevated Creatine Kinase (CK) levels, often ranging from 10 to 100 times the upper limit of normal [4]. Presumptive diagnosis is confirmed via muscle biopsy, which typically reveals necrotic fibers with minimal inflammatory cell infiltrates [5]. In addition to withdrawal of the offending agent, treatment may involve immunomodulatory medications (e.g. intravenous immunoglobulin (IVIG), steroids, and/or Rituximab). For most patients, resolution typically occurs over months, sometimes years. This paper highlights three cases of statin-induced myopathy and the clinical implications for providers in prompt recognition, diagnosis, and management of this rare condition. Further research is needed to better understand both the risk factors and underlying mechanisms in order to increase awareness, optimize care, and minimize the morbidity associated with this adverse drug reaction.

Polymyositis concomitant with hepatitis B virus infection: Treatment challenges.

Polymyositis is a chronic autoimmune disease that presents with symmetrical progressive proximal muscle weakness. The cause of this disease due to abnormal activation of macrophages that might be associated with systemic diseases such as other autoimmune diseases, malignancy or viral infections including hepatitis B virus. The aim of this case report was to highlight treatment challenges in a patient with polymyositis concomitant with hepatitis B. A 28-years-old man with history of completed hepatitis B treatment with negative viral load presented with symmetrical progressive weakness on both inferior proximal extremities. The patient complained of pain predominantly in both tights and calves. No dermatological manifestation was observed. Elevated muscle enzymes and liver function were observed. Along with the course of the disease, hepatitis B reactivation was discovered as hepatitis B virus DNA was re-detected. Treatment options of this patient (polymyositis concomitant with hepatitis B viral infection) remain challenging. The main treatment of polymyositis consists of high dose methylprednisolone and this immunosuppressant could worsen the hepatitis B virus infection. The patient was finally treated with combination of mycophenolic acid and methylprednisolone for polymyositis and entecavir for hepatitis B. After one month of treatment, the patient showed a clinical improvement. This case highlights that viral screening must be done prior to starting polymyositis treatment as it could concomitant with viral infections such as hepatitis B. Antiviral prophylaxis must be given 1-2 weeks before immunosuppression starts. Management for both polymyositis and hepatitis B is important with entecavir or tenofovir as the optimal agents against hepatitis B virus.

Abstract 17245: Statin Induced Necrotizing Autoimmune Myositis

Description of Case: A 64 year old female with hypertension, hyperlipidemia, and type 2 diabetes presented to the emergency room for 3-4 months of progressively worsening bilateral lower extremity weakness with associated edema, but without any reports of pain. The patient had significant impairments in her daily function and now required a cane to ambulate. The patient was found to have significantly impaired strength in the bilateral lower extremities with particular involvement of the proximal thigh muscles. The patient was noted to have a markedly elevated creatine phosphokinase (CPK) to 16,000 and a moderate transaminitis. The patient underwent evaluation with an MRI which revealed several areas of bilateral necrotizing myositis. The patient’s autoimmune markers were remarkable for a positive HMG-CoA reductase antibody and a diagnosis of statin induced necrotizing autoimmune myositis was made. The patient was started on pulse dose steroids without much improvement in her weakness and functional ability. The patient was therefore started on intravenous immunoglobulin with a rapid improvement in her symptoms. The patient was discharged on long term glucocorticoid therapy with appropriate prophylactic medications. Discussion: Statin induced necrotizing autoimmune myositis (SINAM) is a very rare form of autoimmune myopathy that is characterized by rapidly progressive proximal muscle weakness along with other potential extramuscular manifestations in the setting of statin use. SINAM should be suspected in any patient on a statin, regardless of duration of treatment, who presents with proximal muscle weakness and a markedly elevated CPK, often > 1000. Treatment, like other forms of autoimmune myopathies, is often centered around immunomodulatory therapies such as high dose glucocorticoids, intravenous immunoglobulin, and long term immunosuppressants. Despite rapid initiation of aggressive treatment, severe forms of the disease have a high mortality as there may be involvement of the respiratory musculature leading to respiratory failure. Given the rarity of this condition, along with the variability in presentation related to the onset of statin therapy, diagnosis and treatment of this entity remains poorly understood.

Abstract 16715: Rare or Disregarded; A Case of Autoimmune Myopathy

Introduction: Statin-induced myopathy can present with symptoms ranging from mild myalgia to significant muscle weakness. This case report highlights how statin-induced autoimmune myopathy often goes undiagnosed. Case Presentation: We present a 69 year old male with a past medical history of coronary artery disease who presented with myalgia and progressive proximal muscle weakness for 2 months. On admission, creatinine kinase (CK) level was noted to be elevated at 8323 u/L. Atorvastatin was held on admission and the patient received intravenous (IV) fluid as treatment for presumed rhabdomyolysis. Although CK was trending down, the patient did not show any significant improvement in muscle weakness or myalgia. At this point, myositis was suspected, so a myositis panel including anti-HMG Co-A Reductase antibody was ordered and the patient was started on IV steroids. Anti-HMG Co-A Reductase antibody was positive and the rest of myopathy workup was negative; meanwhile, the patient's muscle weakness significantly improved. The patient was discharged on a methylprednisolone with close outpatient rheumatology follow-up. Discussion: Drug-induced rhabdomyolysis is one of many causes of myalgia. It is crucial to review a patient’s medication list and discontinue any possible medications that are possible offenders. Statin-induced myopathy should also be suspected when typical treatment for rhabdomyolysis is failing. Statin induced autoimmune myopathy is associated with muscle weakness, elevated CK and a positive anti-HMG Co-A Reductase antibody, which requires discontinuation of Statin and initiation of immunosuppressive therapy. Conclusions: This case report highlights the importance of early identification and management of statin-induced autoimmune myopathy as a possible differential diagnosis in patients with muscle weakness, elevated CK levels while on statin therapy who do not respond to IV fluid alone.

Registry of Patients with Spinal Muscular Atrophy in a Tertiary Care Unit in Egypt

Background Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by degeneration of alpha motor neurons in the spinal cord, resulting in progressive proximal muscle weakness and paralysis. Objectives To register patients with SMA who are diagnosed clinically and genetically (typical and atypical forms) in a tertiary care unit in Egypt. Patient and methods 80 Patients with SMA who are diagnosed clinically and genetically at Neuromuscular Unit of Ain Shams University Hospital were registered. Demographical data and genetics of the patients were collected and analyzed. The patients were assessed for skeletal deformities, cardiac evaluation by echo and pulmonary evaluation by PFTs (for patients above 5 years old) and functional assessment by motor scales according to age and type of each patient was done. Results SMA was more common in males with predominance of type II and median age of 4.5 years old, a considerable number of cases had positive history of consanguinity and similar cases in family, 98.8% of cases had the typical form of SMA with homozygous deletion of SMN1 gene with variable SMN2 copy number according to type. 32.5% of cases had skeletal deformities in the form of scoliosis with or without kyphosis, extremities contractures and chest cave deformities. 4 cases had restrictive pattern due to scoliosis cardiac abnormalities were detected in 3 cases of type I. 31 cases were assessed by CHOP INTEND and 49 cases were assessed by HFMSE giving a good tool for assessing disease progress and role of physiotherapy. Severe chest infection and respiratory failure was the cause of death of 3 cases of type I during the period of study. Conclusion registry of SMA patients will lead to a better understanding of the natural history of SMA and the influence of drug treatment. This is crucial to improve the care of SMA patients.

Immune-Mediated Necrotizing Myopathy(IMNM)

Immune-mediated necrotizing myopathy (IMNM) has recently been classified from polymyositis, and it clinically shows subacute progressive proximal dominant muscle weakness. Laboratory examinations show a great increase in serum creatine kinase and prominent necrotic muscle fibers without any pathological invasion of inflammatory cells. It is thought to be an autoimmune disease because SRP and HMGCR antibodies have been detected in many cases. These two antibodies affect the pathophysiology of IMNM. Immuno-modulating therapies have usually been induced. Moreover, intensive treatments are necessary in cases of corticosteroid resistant IMNM.

Limb girdle muscular dystrophy 23 caused by compound heterozygous mutations of LAMA2 gene.

Mutations of LAMA2 gene are associated with congenital muscular dystrophy (CMD). The LAMA2-related CMD mainly consists of two diseases, merosin deficient congenital muscular dystrophies type 1A (MDC1A) and limb girdle muscular dystrophy 23 (LGMD23). LGMD23 is characterized by slowly progressive proximal muscle weakness, which primarily affects the lower limbs and results in gait difficulties. Additional clinical features include increased serum creatine kinase, abnormal electromyography with or without white matter abnormalities on brain imaging. Clinical data were collected from a Chinese Han family. Whole-exome sequencing, Sanger sequencing, RT-PCR and TA clone sequencing were performed on the family members. Compound heterozygous mutations of LAMA2: c.1693C > T (p. Q565*) (maternally inherited) and c.9212-6T > G (paternally inherited) were identified and confirmed in the proband. The mutation c.1693C > T (p. Q565*) was classified as pathogenic according to American College of Medical Genetics and Genomics (ACMG) guidelines. By performing RT-PCR and TA clone sequencing, an insertion of 40-bp intronic sequence (intron 64) was found in the transcripts of the proband and her father, which resulted in a frameshift and premature truncation codon of the LAMA2. In particular, the variant truncated the LamG domain of the LAMA2. Therefore, the c.9212-6T>G was classified as likely pathogenic according to American College of Medical Genetics and Genomics (ACMG) guidelines. Our findings described two novel mutations in a girl with LGMDR23, which contributes to the genetic counseling of the family and expands the clinical and molecular spectrums of the rare disease.

0995 Sleep-related Hypoventilation in a 62-Year-Old Female with a Rare Genetic Neuromuscular Disorder

Abstract Introduction Central Core Myopathy (CCM) is a rare genetic neuromuscular disorder involving a mutation in the ‘Ryanodine Receptor’ (RyR1) gene, also known as the gatekeeper of calcium within the muscle cells. CCM typically manifests as slowly progressive proximal muscle weakness Currently, there is limited data regarding the management of nocturnal hypoventilation in adults with neuromuscular disorders. Report of case(s) We present a 62-year-old woman with CCM, as identified via RyR1 mutation (c14818G>A) on genetic testing, as well as muscle biopsy. This genotype is associated with < 10% respiratory muscle involvement. She presented to the sleep clinic with complaints of morning headaches, non-restorative sleep, and daytime sleepiness. Her polysomnogram (PSG) showed an overall Apnea-Hypopnea-Index in the normal range. However, there was a progressive increase in transcutaneous carbon dioxide levels (PtcCO2), reaching a peak of 53 mmHg during rapid eye movement (REM) sleep from 38 mmHg during wakefulness, consistent with sleep-related neuromuscular hypoventilation. On further evaluation, this patient had no evidence of neuromuscular restrictive lung physiology or overt diaphragmatic dysfunction, as suggested by < 20% variation in the supine forced vital capacity. Moreover, her negative inspiratory force (NIF) value was not less than negative 40. However, in the setting of her sleep-related symptoms and evidence of nocturnal hypoventilation, our team decided to trial non-invasive positive pressure ventilation (NIPPV). Since we had concerns about respiratory alkalosis in NREM sleep in the setting of normal body mass index, normal pulmonary function tests, and hypoventilation limited to REM sleep, the patient was sent for in-lab titration of pressures with measurement of PtcCO2 to appropriately recommend NIPPV settings. The study demonstrated bi-level positive airway pressure settings of IPAP 7 cmH20, EPAP 5 cmH20, and a backup rate of 12/min resulting in sustained eucarbia and steady PtcCO2 levels during both REM and NREM sleep. Conclusion This case highlights the importance of evaluation for nocturnal hypoventilation in symptomatic patients with rare neuromuscular disorders and the potential for symptomatic improvement with treatment with NIPPV. Moreover, the case demonstrates the importance of in-lab titration of pressure settings for NIPPV when hypoventilation is limited to REM sleep, due to concern for iatrogenic hyperventilation and respiratory alkalosis. Support (if any)

Severe Hypophosphatemia: The Hidden Truth.

A 52-year-old woman presented with a 14-year history of progressive proximal muscle weakness and myalgia. She had been wheelchair-bound for the previous 10 years, with a significant loss of height since the onset of symptoms. She was previously healthy, with no family history of metabolic bone disease. Clinical examination revealed a proximal myopathy, short stature with marked kyphoscoliosis and pectus carinatum. Her admission laboratory investigations showed severe hypophosphatemia, with a serum phosphate of 0.87 mg/dL (0.28 mmol/L [reference interval 2.5–4.5 mg/dL; 0.8–1.4 mmol/L]). 25-Hydroxy vitamin D (25-OHD) was reduced with a normal 1,25-dihydroxy vitamin D (1,25-OHD). Laboratory results are summarized in Table 1. Of note, the tubular maximum reabsorption of phosphate for glomerular filtration rate (TmP/GFR) was 0.8 mg/dL (0.22 mmol/L [reference interval 2.0–3.4 mg/dL; 0.80–1.35 mmol/L]), suggestive of renal phosphate wasting. Fibroblast growth factor 23 (FGF-23) was elevated at 9207 pg/mL (reference interval 12–49 pg/mL). Despite phosphate and vitamin D replacement, the hypophosphatemia persisted.

Atypical Presentation of MELAS in a 7-year-old Male: A Case Report (P5-8.009)

<h3>Objective:</h3> N/A <h3>Background:</h3> Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a rare, maternally inherited mitochondrial cytopathy that ensues respiratory chain deficiency affecting tissues with more demanding oxidative metabolism. As MELAS is a subtype of the overarching category of mitochondrial myopathies, patients rarely present predominantly with myopathy without typical symptoms of seizures and stroke-like episodes. <h3>Design/Methods:</h3> N/A <h3>Results:</h3> <h3>Case Presentation:</h3> We present a 7-year-old male with no previous medical history who developed progressive proximal muscle weakness and elevated ESR over three years with no response to prednisone, IVIG, or methotrexate. Before the muscle biopsy, he was presumed to have juvenile dermatomyositis, given concurrent pink discoloration over his metacarpophalangeal joints and proximal muscle weakness. The eventual biopsy demonstrated increased SDH and ragged-red fibers, and genetic sequencing confirmed the patient’s m.3251 variant of the MT-TL1 gene. These findings established a highly unusual diagnosis of myopathy-predominant MELAS in a patient lacking seizure or stroke-like episodes, with an unremarkable brain MRI and possessing an uncommon genetic variant. <h3>Conclusions:</h3> <h3>Discussion:</h3> We compare our case to other reports of primary presentation of MELAS in the literature. Though rare for a patient to have the m.3251 variant of the MT-TL1 gene with only two prior reports of this variant cited, it is perhaps even more unique that this patient suffered principally proximal muscle weakness as his presenting symptom, associated only with elevated LDH, CK and liver transaminases while lacking seizures, or stroke symptoms that would be expected. This case demonstrates the utility of reexamining muscle weakness in pediatric patients who are unresponsive to steroids in a presumed myositis-like picture. Through this elusive case of MELAS, we highlight the relevance and application of muscle biopsy, electromyography, and genetic testing to accurately diagnose and treat muscular weakness. <b>Disclosure:</b> Ms. Schrodt has nothing to disclose. Dr. Afzal has nothing to disclose. Dr. Kafaie has nothing to disclose.

Large Region of Homozygous (ROH) Identified in Indian Patients with Autosomal Recessive Limb-Girdle Muscular Dystrophy with p.Thr182Pro Variant in SGCB Gene

The sarcoglycanopathies are autosomal recessive limb-girdle muscular dystrophies (LGMDs) caused by the mutations in genes encoding the α, β, γ, and δ proteins which stabilizes the sarcolemma of muscle cells. The clinical phenotype is characterized by progressive proximal muscle weakness with childhood onset. Muscle biopsy findings are diagnostic in confirming dystrophic changes and deficiency of one or more sarcoglycan proteins. In this study, we summarized 1,046 LGMD patients for which a precise diagnosis was identified using targeted sequencing. The most frequent phenotypes identified in the patients are LGMDR1 (19.7%), LGMDR4 (19.0%), LGMDR2 (17.5%), and MMD1 (14.5%). Among the reported genes, each of CAPN3, SGCB, and DYSF variants was reported in more than 10% of our study cohort. The most common variant SGCB p.Thr182Pro was identified in 146 (12.5%) of the LGMD patients, and in 97.9% of these patients, the variant was found to be homozygous. To understand the genetic structure of the patients carrying SGCB p.Thr182Pro, we genotyped 68 LGMD patients using a whole genome microarray. Analysis of the array data identified a large ~1 Mb region of homozygosity (ROH) (chr4:51817441-528499552) suggestive of a shared genomic region overlapping the recurrent missense variant and shared across all 68 patients. Haplotype analysis identified 133 marker haplotypes that were present in ~85.3% of the probands as a double allele and absent in all random controls. We also identified 5 markers (rs1910739, rs6852236, rs13122418, rs13353646, and rs6554360) which were present in a significantly higher proportion in the patients compared to random control set ( n = 128 ) and the population database. Of note, admixture analysis was suggestive of greater proportion of West Eurasian/European ancestry as compared to random controls. Haplotype analysis and frequency in the population database indicate a probable event of founder effect. Further systematic study is needed to identify the communities and regions where the SGCB p.Thr182Pro variant is observed in higher proportions. After identifying these communities and//or region, a screening program is needed to identify carriers and provide them counselling.

Abstract 10380: A Case of Statin-Induced Necrotizing Autoimmune Myopathy After Covid-19 Vaccination

Introduction: Statins have become the most prescribed medications in the United States. We examine the case of a woman who developed statin induced necrotizing myopathy after receiving the Pfizer COVID-19 vaccine after 15 years of statin use. Case: A 67-year-old woman with history of hypothyroidism, hyperlipidemia, and a remote history of breast cancer, treated with surgical excision, presented with a two-month history of progressive proximal muscle weakness in all four extremities. During this time, she noticed unusual difficulty in her habitual exercise routine, culminating in being suddenly unable to walk or lift her arms. Prior to the onset of her symptoms, she reported that she had received the Pfizer COVID-19 booster vaccine. She had been adherent to her daily medications for over fifteen years (atorvastatin 20mg and levothyroxine 75mcg). Labs revealed creatine phosphokinase of 10,354. Muscle biopsy of the thigh was indicative of necrotizing myopathy. 3-hydroxy-3-methylglutaryl coenzyme A reductase antibodies were elevated at over 200 units, suggesting an immune-mediated myopathy. She was treated with intravenous immune globulin and placed on a prednisone taper. Her strength improved, and she was discharged home with physical therapy. Discussion: Statin-induced necrotizing autoimmune myopathy (SNAM) is a rare manifestation of autoimmune myositis. In the anti-HMG-CoA reductase subtype, the immune system is sensitized to HMG-CoA reductase resulting in immune-mediate cellular injury. The duration of exposure to statins prior to development of SNAM varies from 2 months to 10 years, with an average of 3 years. Our patient had previously been on statin therapy for 15 years without issue and subsequently developed SNAM after receiving a COVID-19 booster. This highlights the possibility that ribonucleotide vaccines, in particular COVID-19, may stimulate immune-mediated autoantibody formation and lead to increased risk for SNAM in patients on statin therapy. These patients would benefit from alternative lipid lowering therapies, such as Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors.

P.89 Immune-mediated necrotizing myopathy associated with anti-SRP Antibodies: Three cases in Korea

Immune-mediated necrotizing myopathy associated with anti-SRP antibodies (anti-SRP myopathy) is characterized by progressive proximal muscle weakness and markedly elevated creatinine kinase (CK. Here, we report the clinical features of three Korean patient with anti-SRP myopathy. A 63-year-old man presented with progressive proximal muscle weakness and dysphagia. He showed symmetrical proximal weakness. The serum CK was 5,560U/L. The muscle biopsy of the biceps brachii showed mild muscle fiber size variation and a few degenerating muscle fibers. Muscle weakness and dysphagia improved after using steroids and azathioprine, but gradually worsen. At the last follow-up study, serum CK was 1,252 IU/L and the serum anti-SRP antibody was positive. A 46-year-old man was referred to our clinic due to progressive proximal muscle weakness. The serum CK was 6,114 U/L. The muscle biopsy of the vastus lateralis muscle showed marked size variation in muscle fibers and many necrotic fibers. Steroid pulse therapy lowered serum CK level, but muscle weakness did not improve. The serum anti- SRP antibody was positive. After the diagnosis, steroid, methotrexate, and intravenous immunoglobulin were used, but his muscle strength did not improve significantly. 43-year-old woman presented with proximal muscle weakness and elevated serum CK level. The serum CK was greater than 13,000 U/L. Needle EMG showed active generalized myopathy. The muscle biopsy of vastus lateralis muscle revealed a few necrotic fibers without endomysial inflammatory cell infiltration. The serum anti-SRP antibody was positive. After steroid pulse therapy, her muscle weakness did not improve and dysphagia was newly developed. She was currently treated with steroid and azathioprine. Anti-SRP myopathy is one of the most disabling and less responsiveness to treatment and we would like to report cases have rarely been reported in Korea.

O.11 Identification of a novel heterozygous DYSF variant in a large family with a dominantly-inherited dysferlinopathy

Dysferlinopathy is an autosomal recessive muscular dystrophy, caused by bi-allelic variants in the gene encoding dysferlin (<i>DYSF</i>). Onset typically occurs in the second to third decade and is characterised by slowly progressive skeletal muscle weakness and atrophy of proximal and/or distal muscles of the limb girdles. There are rare cases of symptomatic <i>DYSF</i> variant carriers. Here, we report a large family with a dominantly inherited hyperCKemia and late-onset muscular dystrophy. Genetic analysis identified a co-segregating novel <i>DYSF</i> variant [NM_003494.4: c.6207del, p.(Tyr2070Metfs*4)]. No secondary variants in <i>DYSF</i> or other dystrophy-related genes were identified on whole genome sequencing and analysis of the proband's DNA. Skeletal muscle involvement was milder and later onset than typical dysferlinopathy presentations; these clinical signs manifested in only three individuals, all between the fourth and sixth decades of life. All individuals heterozygous for the c.6207del variant had hyperCKemia. Histological analysis of skeletal muscle biopsies across three generations showed clear dystrophic signs, including inflammatory infiltrate, regenerating myofibres, increased variability in myofibre size, and internal nuclei. Muscle magnetic resonance imaging revealed fatty replacement of muscle in two individuals. Western blot and immunohistochemical analysis of muscle biopsy demonstrated consistent reduction of dysferlin staining. Allele-specific quantitative PCR analysis of <i>DYSF</i> mRNA from patient muscle found that the variant, localised to the extreme C-terminus of dysferlin, does not activate post-transcriptional mRNA decay. We propose that this inheritance pattern may be underappreciated and that other late-onset muscular dystrophy cases with mono-allelic <i>DYSF</i> variants, particularly C-terminal premature truncation variants, may represent dominant forms of disease.

In vivo and in vitro genome editing to explore GNE functions.

GNE myopathy is an adult onset neuromuscular disorder characterized by slowly progressive distal and proximal muscle weakness, caused by missense recessive mutations in the GNE gene. Although the encoded bifunctional enzyme is well known as the limiting factor in the biosynthesis of sialic acid, no clear mechanisms have been recognized to account for the muscle atrophic pathology, and novel functions for GNE have been hypothesized. Two major issues impair studies on this protein. First, the expression of the GNE protein is minimal in human and mice muscles and there is no reliable antibody to follow up endogenous expression. Second, no reliable animal model is available for the disease and cellular models from GNE myopathy patients’ muscle cells (expressing the mutated protein) are less informative than expected. In order to broaden our knowledge on GNE functions in muscle, we have taken advantage of the CRISPR/Cas9 method for genome editing to first, add a tag to the endogenous Gne gene in mouse, allowing the determination of the spatiotemporal expression of the protein in the organism, using well established and reliable antibodies against the specific tag. In addition we have generated a Gne knock out murine muscle cell lineage to identify the events resulting from the total lack of the protein. A thorough multi-omics analysis of both cellular systems including transcriptomics, proteomics, phosphoproteomics and ubiquitination, unraveled novel pathways for Gne, in particular its involvement in cell cycle control and in the DNA damage/repair pathways. The elucidation of fundamental mechanisms of Gne in normal muscle may contribute to the identification of the disrupted functions in GNE myopathy, thus, to the definition of novel biomarkers and possible therapeutic targets for this disease.