[RYR1 myopathies in childhood: phenotype-genotype correlation and incidence]. / Miopatías RYR1 en la infancia: correlación fenotipo-genotipo e incidencia.

INTRODUCTION: Ryanodine receptor type 1-related myopathies (RYR1-RM) represent the most prevalent category of congenital myopathies. The introduction of genetic techniques has shifted the diagnostic paradigm, suggesting the prioritization of molecular studies over biopsies. This study aims to explore the clinical and epidemiological characteristics of patients with RYR1 gene variants in a tertiary pediatric hospital, intending to enhance the understanding of the genotype-phenotype correlation in RYR1-RM. PATIENTS AND METHODS: An observational, descriptive, and cross-sectional study was conducted on patients under 14 years old with myopathic symptoms and potentially pathogenic RYR1 gene variants from January 2013 to December 2023. Variables such as gender, age, motor development, genetic variants, inheritance pattern, and other manifestations were considered. All variables were tabulated against the genetic variant. RESULTS: Of the nine included patients, the estimated incidence was approximately 1 in 10,000 live births. The median age at diagnosis was six years, with significant phenotypic variability. Common symptoms such as weakness and delayed motor development were observed. Genetic variants affected the RYR1 gene diversely, including five previously undescribed variants. Muscle biopsy was performed in five patients, revealing central core myopathy in two, multiminicore in one, congenital fiber-type disproportion in one, and a nonspecific pattern in another. CONCLUSIONS: RYR1-RM in our series exhibited phenotypic and involvement variability, with an incidence in our area of around 1 in 10,000 live births. Most cases were male, with dominant missense variants. We contribute five previously undescribed genetic variants.

TITLE: Miopatías RYR1 en la infancia: correlación fenotipo-genotipo e incidencia.Introducción. Las miopatías relacionadas con el receptor de rianodina de tipo 1 (RYR1-RM) constituyen la categoría más frecuente de miopatías congénitas. La introducción de técnicas genéticas ha cambiado el paradigma diagnóstico y sugiere la prioridad de estudios moleculares sobre biopsias. Este estudio busca explorar las características clinicoepidemiológicas de pacientes con variantes del gen RYR1 en un hospital pediátrico de tercer nivel con el objetivo de ampliar la comprensión de la correlación genotipo-fenotipo en las RYR1-RM. Pacientes y métodos. Estudio observacional, descriptivo y transversal, de pacientes menores de 14 años con síntomas miopáticos y variantes potencialmente patógenas del gen RYR1 entre enero de 2013 y diciembre de 2023, considerando variables como sexo, edad, desarrollo motor, variantes genéticas, patrón de herencia y otras manifestaciones. Todas las variables fueron tabuladas frente a la variante genética. Resultados. De los nueve pacientes incluidos, la incidencia estimada fue de aproximadamente 1/10.000 nacidos vivos. La mediana en el momento del diagnóstico fue de 6 años, con una variabilidad fenotípica significativa. Se observaron síntomas comunes, como debilidad y retraso del desarrollo motor. Las variantes genéticas afectaron al gen RYR1 de manera diversa, y hubo cinco variantes previamente no descritas. La biopsia muscular se realizó en cinco pacientes, en dos de ellos de tipo miopatía central core; en uno, multiminicore; en uno, desproporción congénita de fibras; y en otro, de patrón inespecífico. Conclusiones. Las RYR1-MR de nuestra serie ofrecieron variabilidad fenotípica y de afectación, con una incidencia en nuestra área de en torno a 1/10.000 recién nacidos. La mayoría de los casos fueron varones, de variantes missense dominantes. Aportamos cinco variantes genéticas no descritas con anterioridad.

The challenges faced by patients with hereditary myopathy during the COVID-19 pandemic.

BACKGROUND: Neuromuscular diseases are inherited and the prevalance of neuromuscular disease is estimated to be around 1:2000. METHODS: This cross-sectional research was conducted with a qualitative research model. Data were collected from patients with an online survey using the snowball sampling method. The study was conducted in accordance with the STROBE checklist methodology. Frequencies and percentages were used to analyse demographic data, and content analysis was used for qualitative opinions. RESULTS: Most of the participants were men and their education levels were low. Participants reported experiencing physical and socio-economic barriers to accessing healthcare. Participants also stated that these barriers have worsened since COVID-19. CONCLUSIONS: Patients with hereditary myopathy are stigmatised by society and face different problems depending on the type of disease and level of function. It is recommended that decision-makers enable patients with hereditary myopathy in exceptional situations to access healthcare services and take steps to resolve their problems.

Hospital admissions from the emergency department of adult patients affected by myopathies.

BACKGROUND AND PURPOSE: Myopathies are associated with classic signs and symptoms, but also with possible life-threatening complications that may require assistance in an emergency setting. This phenomenon is understudied in the literature. We aimed to assess the presentation, management, and outcomes of clinical manifestations potentially related to a muscle disorder requiring referral to the adult emergency department (ED) and hospitalization. METHODS: Anonymized patient data retrieved using the International Classification of Diseases, Ninth Revision codes related to muscle disorders over 4 years were retrospectively analyzed. Medical reports were evaluated to extract demographic and clinical variables, along with outcomes. Two groups were defined based on the presence (known diagnosis [KD] group) or absence (unknown diagnosis [UD] group) of a diagnosed muscle disorder at arrival. RESULTS: A total of 244 patients were included, 51% of whom were affected by a known myopathy, predominantly limb-girdle muscular dystrophies and myotonic dystrophies. The main reasons for ED visits in the KD group were respiratory issues, worsening of muscle weakness, and gastrointestinal problems. Heart complications were less prevalent. In the UD group, 27 patients received a new diagnosis of a specific primary muscle disorder after the ED access, mostly an inflammatory myopathy. Death during hospitalization was recorded in 26 patients, with a higher rate in the KD group and in patients affected by mitochondrial and inflammatory myopathies. Sepsis and dyspnea were associated with increased death risk. CONCLUSIONS: Respiratory complications are the most common reason for myopathic patients accessing the ED, followed by gastrointestinal issues. Infections are severe threats and, once hospitalized, these patients have relatively high mortality.

Patient-reported muscle symptoms and their characterization in a hypertensive population eligible for statin therapy: An exploratory study.

BACKGROUND AND AIMS: Statin-associated muscle symptoms (SAMS) are claimed to be frequent in clinical practice. We evaluated the prevalence and characteristics of patient-reported muscle symptoms (PRMS) attributed to drugs/nutraceuticals in hypertensive patients, focusing the attention on statin treatment. METHODS AND RESULTS: Observational study on 390 consecutive outpatients. All patients were asked the following question: "Have you ever taken a drug/nutraceutical that you think gave you muscle symptoms?". Patients who answered "yes" were evaluated with a modified version of the SAMS-clinical index (SAMS-CI). Mean age: 60.5 ± 13.5 years (males 53.8%.). Patients who have ever taken a statin: 250. Patients who have never taken a statin: 140. Prevalence of PRMS (48.5% of the entire study population) did not differ between groups (p = 0.217). Only age, followed by number of drugs taken, was significantly associated with PRMS at multivariate analysis. A high prevalence of low scores to all the questions of "modified" SAMS-CI was found in both groups. Localization and pattern of PRMS did not differ between groups (p = 0.170). Timing of PRMS onset after starting the drug (p = 0.036) and timing of improvement after withdrawal (p = 0.002) were associated with statin therapy. CONCLUSION: PRMS are highly prevalent among the hypertensive population and are believed to be drug-related, especially with aging and regardless of whether the drug taken is a statin or not. These findings are in line with the growing evidence that subjective muscle symptoms are often misattributed to statins, while they may more likely be related to the nocebo/drucebo effect or to other common undiagnosed conditions.

ASSOCIATION OF SOLUTE CARRIER ORGANIC ANION TRANSPORTER 1B1 GENE POLYMORPHISM WITH RESPONSE TO ATORVASTATIN AND ASSOCIATED MYOPATHY IN IRAQI DYSLIPIDEMIA PATIENTS.

OBJECTIVE: Aim: The study aims to investigate the effect of solute carriers organic anions transporters 1B1 (SLCO1B1) gene polymorphisms rs4149056, rs2306283, rs55901008, and rs729559745 in a sample of patients with dyslipidemia, and relate it to atorvastatin response and associated myopathy. PATIENTS AND METHODS: Materials and Methods: A cross sectional enrolled 200 patients both males and females of Arabic race, Iraqi nationality aged between 30-65 years. The patients were divided into two groups: Group 1 (Atorvastatin responders and tolerant), Group 2 (Atorvastatin non responder and intolerant). Blood samples collected from the patients for biochemical studies and analyzed statistically by Student T-test and Chi-square, and DNA extracted for polymerase chains reactions (PCR). RESULTS: Results: The results showed insignificant association P≥0.05 between the demographic characteristics of the study population with different genotypes, and significant difference P<0.05 in the biochemical parameters regarding (T-cholesterol, triglycerides, low density lipoproteins, and Creatine kinase-MM) when comparing the two groups. Odds ratio (OR) with confidence intervals CI (95%) used to evaluate the risk association to develop myopathy and poor response to atorvastatin therapy show relevant association for CC and CT genotype of rs4149056, while rs2306283 GG genotype show low association, also rs55901008 show low association for CC genotype, and moderate association for rs72559745 genotypes GG, AG. CONCLUSION: Conclusions: The mutant allele's genotypes of rs4149056, rs55901008, and rs72559745, and the wild allele genotype of rs2306283 show significant association with the development of poor response to atorvastatin and elevated the level of CK-MM plasma concentration.

The incidence and associated risk factors affecting myopathies in broiler chickens in Lithuania.

The objectives of this research were to highlight the main factors, which have relevant significance for etiology of myopathies and to assess the incidence of myopathies in a representative population of broilers raised in Lithuania. Eighteen flocks were evaluated to assess the incidence of musculus pectoralis major myopathies (PMM) (total 54,000 broilers) and dorsal cranial myopathy (DCM) (total 124,200 broilers). Thirteen flocks (total 19,500 broilers) were evaluated to find out deep pectoral myopathy (DPM) occurrence in Lithuania. Investigated parameters of each flock were: average broiler live body weight (BW) at slaughter, average slaughter age, treatment and seasons. A correlation analysis was used to measure the strength of the linear relationship between the investigated traits and incidence of these myopathies. Overall, the incidence of PMM in Lithuania was 18.19%. DCM and DPM were 5.16% and 0.27%, respectively. The percentage of PMM in flocks was strongly associated with average broiler live BW at slaughter (r=0.898, p<0.001) and age at slaughter (r=0.693, p<0.001). The percentage of PMM in flocks was negatively related with treatment of broilers (rs=-0.535, p<0.05). The percentage of DCM was positively associated with average broiler live BW at slaughter (r=0.537, p<0.05) and with seasons (rs=0.658, p<0.01). However, our study results revealed, that the analyzed parameters are not so important in DPM etiology. Furthermore, predisposing factors of PMM, DCM and DPM are different. These findings suggest that not only broiler's heavy weight and age at slaughter could have influence for etiology of myopathies.

Long-term Natural History of Pediatric Dominant and Recessive RYR1-Related Myopathy.

BACKGROUND AND OBJECTIVES: RYR1-related myopathies are the most common congenital myopathies, but long-term natural history data are still scarce. We aim to describe the natural history of dominant and recessive RYR1-related myopathies. METHODS: A cross-sectional and longitudinal retrospective data analysis of pediatric cases with RYR1-related myopathies seen between 1992-2019 in 2 large UK centers. Patients were identified, and data were collected from individual medical records. RESULTS: Sixty-nine patients were included in the study, 63 in both cross-sectional and longitudinal studies and 6 in the cross-sectional analysis only. Onset ranged from birth to 7 years. Twenty-nine patients had an autosomal dominant RYR1-related myopathy, 31 recessive, 6 de novo dominant, and 3 uncertain inheritance. Median age at the first and last appointment was 4.0 and 10.8 years, respectively. Fifteen% of patients older than 2 years never walked (5 recessive, 4 de novo dominant, and 1 dominant patient) and 7% lost ambulation during follow-up. Scoliosis and spinal rigidity were present in 30% and 17% of patients, respectively. Respiratory involvement was observed in 22% of patients, and 12% needed ventilatory support from a median age of 7 years. Feeding difficulties were present in 30% of patients, and 57% of those needed gastrostomy or tube feeding. There were no anesthetic-induced malignant hyperthermia episodes reported in this cohort. We observed a higher prevalence of prenatal/neonatal features in recessive patients, in particular hypotonia and respiratory difficulties. Clinical presentation, respiratory outcomes, and feeding outcomes were consistently more severe at presentation and in the recessive group. Conversely, longitudinal analysis suggested a less progressive course for motor and respiratory function in recessive patients. Annual change in forced vital capacity was -0.2%/year in recessive vs -1.4%/year in dominant patients. DISCUSSION: This clinical study provides long-term data on disease progression in RYR1-related myopathies that may inform management and provide essential milestones for future therapeutic interventions.

Impact of metformin on statin-associated myopathy risks in dyslipidemia patients.

A growing number of patients with metabolic disorders are receiving statin and antidiabetic therapies as comedications. A signal of increased risk of myotoxicity due to potential interactions between antidiabetics and statins has been detected in previous studies. To investigate the effects of metformin on myopathy risks when added to preexisting statin therapy in dyslipidemia patients, we performed a retrospective cohort study using the Korean national health insurance data in statin-treated dyslipidemia patients with or without concomitant metformin use. We compared the risk of myopathy in statin + metformin users against statin-only users. Hazard ratios (HRs) and 95% confidence intervals (CIs) have been calculated following propensity score (PS) matching between study groups and subsequent stratification per patient factors. We included 4092 and 8161 patients in PS-matched statin + metformin and statin-only groups, respectively. The risk of myopathy decreased when metformin was used together with statins (adjusted HR 0.84; 95% CI 0.71-0.99). In subgroup analyses per individual statin agent and in stratified risk analyses, no specific statin agents or patient factors were associated with statistically significant myopathy risk. This study found that a comedication with metformin was associated with decreased myopathy risk in statin-treated dyslipidemia patients compared to statin-only users. Our findings suggest that metformin may provide protective effects on potential muscle toxicities induced by statin therapy.

Concomitant use of statins and sodium-glucose co-transporter 2 inhibitors and the risk of myotoxicity reporting: A disproportionality analysis.

AIMS: Recent case reports have suggested that sodium-glucose co-transporter 2 (SGLT2) inhibitors may interact with statins to increase their risk of myotoxicity. We assessed the risk of myotoxicity reporting associated with concomitant use of SGLT2 inhibitors and statins. METHODS: We queried the US Food and Drug Administration Adverse Event Reporting System (FAERS) from 2013 to 2021 for reports including SGLT2 inhibitors, statins or both. We estimated several measures of disproportionate reporting of myopathy and rhabdomyolysis associated with concomitant use of SGLT2 inhibitors and statins: reporting odds ratio (ROR) with 95% confidence interval (CI), Ω shrinkage measure (safety signal if >0) and an extension of the proportional reporting ratio (PRR) (two-criteria set, safety signal if both criteria are met), using the full FAERS dataset as the reference set. In sensitivity analyses, we focussed on specific SGLT2 inhibitor-statin pairs with higher interaction potential (canagliflozin-rosuvastatin, empagliflozin-rosuvastatin) and accounted for stimulated reporting. RESULTS: There were 456 myopathy and 77 rhabdomyolysis reports involving both an SGLT2 inhibitor and a statin. Concomitant use of SGLT2 inhibitors and statins was not associated with an increased risk of myopathy (ROR 0.79, 95% CI 0.70 to 0.89) or rhabdomyolysis (ROR 0.58, 95% CI 0.41 to 0.83) reporting. For both outcomes, the Ω shrinkage measure was negative and only one criterion of the PRR extension was met. SGLT2 inhibitor-statin pairs with higher interaction potential yielded potential signals for rhabdomyolysis; these signals disappeared after accounting for stimulated reporting. CONCLUSION: There was no increased risk of myotoxicity reporting associated with concomitant use of SGLT2 inhibitors and statins or for specific drug pairs.

Anoctamin-5 related muscle disease: clinical and genetic findings in a large European cohort.

Anoctamin-5 related muscle disease is caused by biallelic pathogenic variants in the anoctamin-5 gene (ANO5) and shows variable clinical phenotypes: limb-girdle muscular dystrophy type 12 (LGMD-R12), distal muscular dystrophy type 3 (MMD3), pseudometabolic myopathy or asymptomatic hyperCKaemia. In this retrospective, observational, multicentre study we gathered a large European cohort of patients with ANO5-related muscle disease to study the clinical and genetic spectrum and genotype-phenotype correlations. We included 234 patients from 212 different families, contributed by 15 centres from 11 European countries. The largest subgroup was LGMD-R12 (52.6%), followed by pseudometabolic myopathy (20.5%), asymptomatic hyperCKaemia (13.7%) and MMD3 (13.2%). In all subgroups, there was a male predominance, except for pseudometabolic myopathy. Median age at symptom onset of all patients was 33 years (range 23-45 years). The most frequent symptoms at onset were myalgia (35.3%) and exercise intolerance (34.1%), while at last clinical evaluation most frequent symptoms and signs were proximal lower limb weakness (56.9%) and atrophy (38.1%), myalgia (45.1%) and atrophy of the medial gastrocnemius muscle (38.4%). Most patients remained ambulatory (79.4%). At last evaluation, 45.9% of patients with LGMD-R12 additionally had distal weakness in the lower limbs and 48.4% of patients with MMD3 also showed proximal lower limb weakness. Age at symptom onset did not differ significantly between males and females. However, males had a higher risk of using walking aids earlier (P = 0.035). No significant association was identified between sportive versus non-sportive lifestyle before symptom onset and age at symptom onset nor any of the motor outcomes. Cardiac and respiratory involvement that would require treatment occurred very rarely. Ninety-nine different pathogenic variants were identified in ANO5 of which 25 were novel. The most frequent variants were c.191dupA (p.Asn64Lysfs*15) (57.7%) and c.2272C>T (p.Arg758Cys) (11.1%). Patients with two loss-of function variants used walking aids at a significantly earlier age (P = 0.037). Patients homozygous for the c.2272C>T variant showed a later use of walking aids compared to patients with other variants (P = 0.043). We conclude that there was no correlation of the clinical phenotype with the specific genetic variants, and that LGMD-R12 and MMD3 predominantly affect males who have a significantly worse motor outcome. Our study provides useful information for clinical follow up of the patients and for the design of clinical trials with novel therapeutic agents.

Osteomalacic myopathy: A re-emerging scourge hiding in plain sight.

We present a cluster of patients with osteomalacic myopathy in the aftermath of the COVID-19 pandemic. We believe that the home confinement of these children may have contributed to the resurgence of this condition. This deficiency is eminently reversible.

Characterization of dorsal recumbency syndrome associated with woody breast in broiler flocks from Ontario, Canada.

A dorsal recumbency syndrome (DRS) has been recently described in market-age broiler chickens. Affected broilers fall onto their backs, and are unable to right themselves, and eventually die of cardiopulmonary insufficiency. These broilers are referred to as turtle chickens. A previous report and anecdotal evidence suggest that breast myopathies, such as woody breast (WB), may be associated with DRS due to impaired contractility of the pectoral muscles. In this study, we aimed to provide additional evidence to document DRS in broilers, and its possible association with breast myopathies. A total of 64 broilers (Ross 708), 33 DRS-affected and 31 controls, were culled between 42 and 48 d of age from 3 different commercial farms over 4 visits. All broilers underwent postmortem analysis; breast muscles were scored grossly and/or histologically to determine the presence and severity of myopathies, and sera were used to determine the level of aspartate aminotransferase (AST) and creatine kinase (CK). A gross diagnosis of WB was moderately associated with DRS broilers, and DRS broilers displayed a greater microscopic severity of lesions (P < 0.001) in the Pectoralis major, as typically observed with WB. Levels of AST and CK were greater (P < 0.001) in the sera of DRS-affected compared to control broilers, consistent with muscular damage. The frequency of cardiac changes, such as mild hydropericardium and right ventricular dilation, or severity of microscopic pulmonary lesions, such as edema, were not significantly different between the 2 groups. The odds of DRS increased with the histology score of the P. major (OR = 1.37, 95% CI 1.02-1.85). The data presented in this study support an association between DRS and muscular damage of the P. major, suggesting that WB may predispose broilers to DRS. DRS might be a cause of broiler death, and this syndrome could be responsible for significant financial loss to the farmers and to the whole poultry industry.

Prevalence of Genetic Mutations in Horses With Muscle Disease From a Neuromuscular Disease Laboratory.

Deleterious genetic variants are an important cause of skeletal muscle disease. Immunohistochemical evaluation of muscle biopsies is standard for the diagnosis of muscle disorders. The prevalence of alleles causing hyperkalemic periodic paralysis (HYPP), malignant hyperthermia (MH), polysaccharide storage myopathy 1 (PSSM1), glycogen branching enzyme deficiency (GBED), myotonia congenita (MC), and myosin heavy chain myopathy (MYHM) in horses with muscle disease is unknown. Archived slides processed for immunohistochemical analysis from 296 horses with muscle disease were reviewed blinded and clinical information obtained. DNA isolated from stored muscle samples from these horses were genotyped for disease variants. Histological findings were classified as myopathic in 192, neurogenic in 41, and normal in 63 horses. A third of the population had alleles that explained disease which constituted 45% of the horses with confirmed histological myopathic process. Four of six muscle disease alleles were identified only in Quarter horse breeds. The allele causing PSSM1 was detected in other breeds, and MC was not detected in these samples. The My allele, associated with susceptibility for MYHM, was the most common (62%) with homozygotes (16/27) presenting a more severe phenotype compared to heterozygotes (6/33). All cases with the MH allele were fatal upon triggering by anesthesia, stress or concurrent myopathy. Both, muscle histological and genetic analyses are essential in the investigation of muscle disease, since 10% of the horses with muscle disease and normal histology had a muscle disease causing genetic variant, and 63% of histologically confirmed muscle with alterations had no known genetic variants.

COVID-19 associated myopathy.

PURPOSE OF REVIEW: The global spread of severe acute respiratory syndrome coronavirus 2 resulted in many cases of acute and postacute muscular symptoms. In this review, we try to decipher the potential underlying pathomechanisms and summarize the potential links between viral infection and muscle affection. RECENT FINDINGS: Disregarding single case studies that do not allow safe conclusions due to the high number of infections, histopathological evidence of myositis has only been reported in deceased individuals with severe COVID-19. Postacute myalgia and weakness seem to occur in a subset of patients up to one year after initial infection, reminiscent of postinfectious syndromes (PIS) described in prior epidemics and pandemics of the past. SUMMARY: COVID-19 associated myopathy likely comprises different entities with heterogeneous pathomechanisms. Individual factors such as disease severity and duration, age, sex, constitutional susceptibilities, and preexisting conditions are important to consider when formulating a diagnosis. Persisting symptoms show overlapping features with PIS or postintensive care syndrome. In lack of strong evidence for a direct infection of myocytes, inflammatory myopathies associated with COVID-19 are presumably immune-mediated. Differential diagnosis of rheumatological and nonmuscular neurological origin coinciding with the infection need to be considered, due to the extremely high numbers of newly occurring infections the last 2 years.

Does COVID-19 increase the incidence of spontaneous rectus sheath hematoma?

BACKGROUND: The COVID-19 pandemic started to affect Turkey in March 2020. In this study, we retrospectively investigated spontaneous rectus sheath hematoma (S-RSH) in patients with COVID-19 presenting with acute abdominal pain during the ongoing pandemic. METHODS: The demographic characteristics, laboratory findings, length of hospital stay, and treatment processes of COVID-19 cases with S-RSH detected between March and December 2020 were recorded. The rectus sheath hematoma diagnosis of the patients was made using abdominal computed tomography, and the patients were followed up. Low-molecular-weight heparin treatment, which was initiated upon admission, was continued during the follow-up. RESULTS: S-RSH was detected in 13 out of 220 patients with COVID-19 who were referred to general surgery for consultation due to acute abdominal pain. The mean age of these patients was 78±13 years, and the female-to-male ratio was 1.6. Mechanical ven-tilation support was applied to three patients, all of whom were followed up in the intensive care unit. Two patients died for reasons independent of rectus sheath hematoma during their treatment. Among the laboratory findings, the activated partial thromboplastin time (aPTT) values did not deviate from the normal range. While there was no correlation between the international normalized ratio (INR) and aPTT (p>0.01), a significant correlation was found between INR and interleukin-6 (IL-6) (p<0.002). None of the patients required surgical or endovascular interventional radiology procedures. CONCLUSION: In the literature, the incidence of S-RSH in patients presenting with acute abdominal pain is 1.8%. However, in our series, this rate was approximately 3 times higher. Our patients' normal INR and aPTT values suggest that coagulopathy was mostly secondary to endothelial damage. In addition, the significantly higher IL-6 values (p<0.002) indicate the development of vasculitis along with the acute inflammatory process. S-RSH can be more commonly explained the high severity of vasculitis and endothelial damage due to viral infection.

Statin-associated muscle symptoms: Myth or reality?

Statin-associated muscle symptoms is an entity that encompasses a constellation of various clinical manifestations of variyng severity. Since the introduction of the first statins, numerous studies have been published regarding its incidence, pathophysiology, diagnosis and treatment; however, to this day these aspects are still controversial. With the progressive increase in the use of statins in the general population, notifications of adverse reactions related to its use have multiplied, particularly those related to muscular toxicity. Nevertheless, the differences between the published studies, both in methodology and in the results obtained, make this relationship a complex issue of great interest for clinicians and patients. The integration of the evidence that we currently have can help us understand better this entity and facilitate its management in clinical practice.

Genetic Appraisal of Hereditary Muscle Disorders In A Cohort From Mumbai, India.

BACKGROUND: Hereditary muscle disorders are clinically and genetically heterogeneous. Limited information is available on their genetic makeup and their prevalence in India. OBJECTIVE: To study the genetic basis of prevalent hereditary myopathies. MATERIAL AND METHODS: This is a retrospective study conducted at a tertiary care center. The study was approved by the institutional ethics board. The point of the collection was the genetic database. The genetic data of myopathy patients for the period of two and half years (2019 to mid-2021) was evaluated. Those with genetic diagnoses of DMD, FSHD, myotonic dystrophies, mitochondriopathies, and acquired myopathies were excluded. The main outcome measures were diagnostic yield and the subtype prevalence with their gene variant spectrum. RESULTS: The definitive diagnostic yield of the study was 39% (cases with two pathogenic variants in the disease-causing gene). The major contributing genes were GNE (15%), DYSF (13%), and CAPN3 (7%). Founder genes were documented in Calpainopathy and GNE myopathy. The uncommon myopathies identified were Laminopathy (0.9%), desminopathy (0.9%), and GMPPB-related myopathy (1.9%). Interestingly, a small number of patients showed pathogenic variants in more than one myopathy gene, the multigenic myopathies. CONCLUSION: This cohort study gives hospital-based information on the prevalent genotypes of myopathies (GNE, Dysferlinopathy, and calpainopathy), founder mutations, and also newly documents the curious occurrence of multigenicity in a small number of myopathies.

Epidemiological and genetic features of anti-3­hydroxy-3-methylglutaryl-CoA reductase necrotizing myopathy: Single-center experience and literature review.

OBJECTIVE: To characterize the demographic, genetic, clinical, and serological features of patients with anti-3­hydroxy-3-methylglutaryl-CoA reductase (HMGCR) immune-mediated necrotizing myopathy (IMNM) in a region of northern Spain. METHODS: Study of all patients diagnosed with anti-HMGCR IMNM during a 5-year period at a reference hospital in northern Spain. Besides clinical and laboratory data, we analyzed the genetic influence of HLA genes and the rs4149056 (c.521T>C) single nucleotide polymorphism (SNP) in the SLCO1B1 gene. RESULTS: 8 patients (5 women, 3 men) with a mean ± SD age of 64.9 ± 7.3 years, fulfilled the criteria for anti-HMGCR IMNM. The incidence rate was 0.6 per 100.000 person-years and the prevalence 3 per 100.000 population. All patients had been exposed to statins. All of them had predominant lower limb proximal and symmetric muscle weakness that was severe in 2 and had elevated serum CK levels with a median [IQR] of 4488 [2538-9194] IU/L. Serum 25­hydroxy vitamin D levels were decreased in all patients in whom it was determined. The 3 patients with a previous diagnosis of hypothyroidism had abnormal levels of TSH at the time of diagnosis. All patients experienced improvement with different schemes of immunosuppressive therapy. Noteworthy, 7 of 8 patients carried the HLA-DRB1*11 allele. The frequency of the rs4149056 C allele in the SLCO1B1 gene (12.5%) was similar to that of the general population. CONCLUSION: In northern Spain, anti-HMGCR IMNM preferentially affects people over 50 years of age who are carriers of the HLA-DRB1*11 allele and take statins. Both low vitamin D levels and hypothyroidism may play a potential predisposing role in the development of this disease.

The frequencies of very long-chain acyl-CoA dehydrogenase deficiency genetic variants in Japan have changed since the implementation of expanded newborn screening.

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency has been a target of expanded newborn screening (ENBS) using tandem mass spectrometry in Japan. Since the implementation of ENBS, a number of novel ACADVL variants responsible for VLCAD deficiency have been identified. In this study, genotypic differences in Japanese patients with VLCAD deficiency were investigated before and after ENBS. The ACADVL variants in 61 subjects identified through ENBS (ENBS group) and in 40 patients who subsequently developed clinical symptoms without undergoing ENBS (pre-ENBS group) were compared. Subjects in the ENBS group underwent genetic testing and/or VLCAD enzyme activity measurements. Patients in the pre-ENBS group were stratified into three clinical phenotypes and underwent genetic testing. This study revealed that the variants p.K264E, p.K382Q and c.996dupT were found in both groups, but their frequencies were lower in the ENBS group (5.2%, 3.1% and 4.2%, respectively) than in the pre-ENBS group (16.5%, 12.7% and 10.1%, respectively). In addition, p.C607S, p.T409M, p.M478I, p.G289R, p.C237R, p.T260M, and p.R229* were exclusively identified in the ENBS group. Among these variants, p.C607S exhibited the highest frequency (18.8%). The patients who were heterozygous for p.C607S demonstrated 7-42% of control enzyme activity. p.C607S is suspected to be unique to Japanese individuals. According to a comparison of enzyme activity, patients with the p.C607S variant may exhibit higher enzyme activity than those with the p.A416T, p.A180T, p.R450H, and p.K264E variants, which are responsible for the myopathic form of the disease. The VLCAD deficiency genotypes have changed since the initiation of ENBS in Japan.