Group Of Myopathies Research Articles

Current diagnosis and treatment of Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is an X-linked progressive disease from the group of primary myopathies caused by mutations in the DMD gene and a lack of dystrophin protein in the muscle fiber in males. The review considered the prevalence of pathology, the most common causes of dystrophinopathy, and the role of dystrophin not only in the functioning of muscles but also in the architectural organization of the Central nervous system. The disease classification based on stages and forms, initial clinical manifestations of the early and late stages of the disease, as well as neuropsychological, orthopedic, respiratory and cardiovascular disorders, are described in detail. The relevant to date diagnostic algorithm for suspected DMD, biochemical blood analysis, genetic, morphological (immunocytochemical staining of muscles with dystrophin antibodies) and instrumental (ultrasound, MRI) methods of examination are presented in detail. Particular attention in the diagnosis of DMD and objectification of disorders is given to assessment tests [Baileys and Griffiths scales, Albert's Test of Infant Posture and Motor Assessment Scale, Expanded Hammersmith Functional Motor Scale (HFMSE), the Gross Motor Function Measure (GMFM), and the 6-minute walk test (6MWT)]. The review presents the advantages and disadvantages of modern invasive and non-invasive diagnostic techniques of the disease, indicating their reliability and the possibility of application at early stages, including prenatal. In conclusion, the treatment of DMD and its most frequent complications, both widely used in practice and at the stage of clinical research, is highlighted. It was emphasized the importance of rehabilitation measures that improve the duration and quality of life of patients with DMD. The main task of analyzing available sources on the most pressing issues of Duchenne muscular dystrophy was to stimulate research and social activity in resolving unsolved problems today.

Characterizing Woody Breast Myopathy in a Meat Broiler Line by Heat Production, Microbiota, and Plasma Metabolites.

Selection for quantitative traits in meat broilers such as breast yield and growth rate exert physiological pressure leading to ante mortem histological and biochemical alterations in muscle tissues. The poultry industry has recently witnessed a myopathy condition affecting Pectoralis major (breast muscle) of broilers, called woody breast (WB), an etiology still unclear to scientific community. A study was conducted to characterize the WB myopathy in a meat broiler line at its finishing phase (d 41) in terms of heat production (HP), microbiota and plasma metabolites. Two treatment groups were studied—WB affected (myopathy) and normal (non-myopathy) broiler; n = 20 in each group. Indirect calorimetry was utilized for HP measurement. Furthermore, body composition (BC) analysis was also performed using dual-energy x-ray absorptiometry (DEXA). Microbiota in ileal digesta was studied with PCR amplified 16s rRNA gene. LC-MS targeted metabolomics was performed to understand differential expression of plasma metabolites. Results showed that there was difference in fasting HP (P < 0.05) between these two treatment groups, with non-myopathy broiler producing more heat which was indicative of higher body protein content validated by higher protein: fat ratio by BC results. Less protein content in myopathy bird could be due to probable higher mixed muscle degradation occurring in lean tissue as marked by elevated 3-methylhistidine expression in plasma. Microbiota results showed unclassified Lactobacillus as predominant genus with higher abundance occurring in myopathy group; whereas at species level, L. acidipiscis was predominant bacteria for non-myopathy broiler. Differentially significant metabolites (P < 0.05) identified from plasma metabolome between these two treatment groups were homocysteine, cyclic GMP, trimethylamine N-oxide (TMAO), tyramine, carnitine, and acetylcarnitine, which were all associated to cardiovascular system. The findings suggest that more research in meat broilers could be opted toward delivering reduced vascularity issues to alleviate this myopathy condition.

Inflammatory muscle disease – An update

Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of inflammatory myopathies whose common feature is immune-mediated muscle injury. There are distinct subgroups including dermatomyositis (DM), polymyositis (PM), inclusion body myositis, and immune-mediated necrotizing myopathy. Antisynthetase syndrome is also emerging as a distinct subgroup with its unique muscle histopathological characteristic of perifascicular necrosis. While the newly updated EULAR/ACR Classification Criteria for IIM have brought advancements in diagnosis and the exclusion of mimickers, the use of only one autoantibody in the derivation of the schema limits its use. Similarly, while the advent of multiple novel therapeutics in the treatment of myositis has been exciting, it has also highlighted the scarcity of validated outcome measures. The purpose of our review is to highlight the updated classification criteria of myositis, newly reported clinical phenotypes associated with myositis autoantibodies, the measurement of outcomes, and emerging treatments in the field.

General Paresis in a Child with Unusual Presentation

Introduction: Acute onset quadriparesis can be a manifestation of a variety of neurological, metabolic or autoimmune conditions. Rarely, it could be one of many clinical presentations of juvenile dermatomyositis which belongs to the group of idiopathic inflammatory myopathies of childhood. We report the case of a 9-year old girl who presented with global myopathy over a two-month period. Case report: A 9-year-old girl referred with a 2 months history of generalised muscular pain and weakness. There were no significant history of preceded illness, trauma or excessive strenuous exercises. She had no other systemic complaints such as fever or skin rash. Past medical history was unremarkable except for recurrent tonsillitis. Physical examination revealed a child with normal alertness and behaviour. She has notable generalised swelling of all four limbs. Her neurological examination revealed normal tone however her power was definitely reduced in all four limbs (Graded 3/5). She demonstrated signs of proximal myopathy. Subsequent investigations revealed high Creatinine Kinase (CK) levels of 6470U/L, ESR 84mm/hr with deranged transaminases and positive serum mycoplasma and CMV IgM. Her MRI brain and spine along with lumbar puncture results were normal. She was referred to tertiary centre for further evaluation as her weakness progressed. An MRI muscle demonstrated marked inflammation in all four limbs including paravertebral muscles. Her muscle biopsy showed inflammatory myopathy leading to a diagnosis of juvenile dermatomyositis (JDM). She is now showing sustained clinical improvements following a course of immunoglobulin and corticosteroids therapy. Discussion: The diagnosis of JDM is generally considered in patients with rash-associated muscle weakness. Essentially, it involves assessment of muscle, skin, lung and cardiac involvement on top of baseline list of investigations that has been outline by Single Hub and Access point for pediatric Rheumatology in Europe (SHARE). This case reflects that JDM is possible despite non-existent of skin involvement.

Cored in the act: the use of models to understand core myopathies.

ABSTRACTThe core myopathies are a group of congenital myopathies with variable clinical expression – ranging from early-onset skeletal-muscle weakness to later-onset disease of variable severity – that are identified by characteristic ‘core-like’ lesions in myofibers and the presence of hypothonia and slowly or rather non-progressive muscle weakness. The genetic causes are diverse; central core disease is most often caused by mutations in ryanodine receptor 1 (RYR1), whereas multi-minicore disease is linked to pathogenic variants of several genes, including selenoprotein N (SELENON), RYR1 and titin (TTN). Understanding the mechanisms that drive core development and muscle weakness remains challenging due to the diversity of the excitation-contraction coupling (ECC) proteins involved and the differential effects of mutations across proteins. Because of this, the use of representative models expressing a mature ECC apparatus is crucial. Animal models have facilitated the identification of disease progression mechanisms for some mutations and have provided evidence to help explain genotype-phenotype correlations. However, many unanswered questions remain about the common and divergent pathological mechanisms that drive disease progression, and these mechanisms need to be understood in order to identify therapeutic targets. Several new transgenic animals have been described recently, expanding the spectrum of core myopathy models, including mice with patient-specific mutations. Furthermore, recent developments in 3D tissue engineering are expected to enable the study of core myopathy disease progression and the effects of potential therapeutic interventions in the context of human cells. In this Review, we summarize the current landscape of core myopathy models, and assess the hurdles and opportunities of future modeling strategies.

P.242Phenotypic variability in a cohort of patients with TTN-related congenital myopathy

The term `titinopathies' encompasses a heterogeneous group of myopathies caused by mutations in TTN. The most common resulting clinical picture is the congenital myopathy. The limb-girdle dystrophy and distal myopathy with onset during the adulthood are other well-known phenotypes related to TTN. A severe myocardiopathy is associated in some cases. Describing the clinical, histopathological, and molecular findings in patients with TTN-related congenital myopathy followed-up in our hospital. A retrospective descriptive study was conducted. Six patients with molecular diagnosis of TTN-related congenital myopathy were included. The onset was observed during the neonatal period in more than 80% of cases. Weakness was detected during the first year of life in the remaining patient. Axial weakness was observed in all the patients. Scoliosis was detected in 50%, whereas ophthalmoparesis/ophthalmoplegia was not showed by any patient. Autonomous ambulation was not acquired in 3 out of the 6 patients and one other patient lost this ability at 4 years of age. Respiratory involvement needing nocturnal non-invasive ventilation was observed in one patient. Cardiac involvement was not detected in any case. Creatin quinase levels were within the normal range in all the cases. The muscle biopsy findings were relatively heterogeneous, mainly characterized by the fiber size variability, internal nucleus, and cores. TTN-related congenital myopathy is characterized by the presence of a marked axial weakness that can lead to an early scoliosis. Roughly 50% of patients are not able to achieve an autonomous ambulation.

Genomewide Association Study of Statin-Induced Myopathy in Patients Recruited Using the UK Clinical Practice Research Datalink.

Statins can be associated with myopathy. We have undertaken a genomewide association study (GWAS) to discover and validate genetic risk factors for statin‐induced myopathy in a “real‐world” setting. One hundred thirty‐five patients with statin myopathy recruited via the UK Clinical Practice Research Datalink were genotyped using the Illumina OmniExpress Exome version 1.0 Bead Chip and compared with the Wellcome Trust Case‐Control Consortium (n = 2,501). Nominally statistically significant single nucleotide polymorphism (SNP) signals in the GWAS (P < 5 × 10−5) were further evaluated in several independent cohorts (comprising 332 cases and 449 drug‐tolerant controls). Only one (rs4149056/c.521C>T in the SLCO1B1 gene) SNP was genomewide significant in the severe myopathy (creatine kinase > 10 × upper limit of normal or rhabdomyolysis) group (P = 2.55 × 10−9; odds ratio 5.15; 95% confidence interval 3.13–8.45). The association with SLCO1B1 was present for several statins and replicated in the independent validation cohorts. The data highlight the role of SLCO1B1 c.521C>T SNP as a replicable genetic risk factor for statin myopathy. No other novel genetic risk factors with a similar effect size were identified.

Difficulties in the Diagnosis of Inclusion Body Myositis-Case Report

Abstract Inclusion body myositis belongs to the group of idiopathic inflammatory myopathies. Two processes, one autoimmune and the other degenerative, appear to occur in parallel. There are two forms of inclusion body myositis, hereditary and sporadic. Case report: 47-year-old woman with muscle weakness and atrophy of the distal and proximal muscles, and involvement of quadriceps and deep finger flexors was admitted for neuromuscular evaluation. These changes have been started gradually and insidiously over three years. Electromyography findings were nonspecific and for this reason in the beginning of the disease it was misdiagnosed as demyelization peripheral neuropathy. Muscle biopsy, with the presence of characteristic structures such as rimmed vacuoles and amyloid deposits definitely confirmed the diagnosis of inclusion body myositis. Conclusion: There are several difficulties in the diagnosis of inclusion body myositis as nonspecific EMG findings and overreliance on electrophysiology and lack of the cardinal histological features in muscle biopsy. Although this disease is rare and incurable, making the correct diagnosis is crucial to directing the patient to physical therapy for weakness and occupational therapy to improve a patient’s ability in activities of daily living.

Nemaline myopathies: a current view

Nemaline myopathies are a heterogenous group of congenital myopathies caused by de novo, dominantly or recessively inherited mutations in at least twelve genes. The genes encoding skeletal α-actin (ACTA1) and nebulin (NEB) are the commonest genetic cause. Most patients have congenital onset characterized by muscle weakness and hypotonia, but the spectrum of clinical phenotypes is broad, ranging from severe neonatal presentations to onset of a milder disorder in childhood. Most patients with adult onset have an autoimmune-related myopathy with a progressive course. The wide application of massively parallel sequencing methods is increasing the number of known causative genes and broadening the range of clinical phenotypes. Nemaline myopathies are identified by the presence of structures that are rod-like or ovoid in shape with electron microscopy, and with light microscopy stain red with the modified Gömöri trichrome technique. These rods or nemaline bodies are derived from Z lines (also known as Z discs or Z disks) and have a similar lattice structure and protein content. Their shape in patients with mutations in KLHL40 and LMOD3 is distinctive and can be useful for diagnosis. The number and distribution of nemaline bodies varies between fibres and different muscles but does not correlate with severity or prognosis. Additional pathological features such as caps, cores and fibre type disproportion are associated with the same genes as those known to cause the presence of rods. Animal models are advancing the understanding of the effects of various mutations in different genes and paving the way for the development of therapies, which at present only manage symptoms and are aimed at maintaining muscle strength, joint mobility, ambulation, respiration and independence in the activities of daily living.

Clinical and molecular-genetic profiles of patients with morphological indications of congenital multicore myopathy

Congenital core myopathies are a clinically and genetically heterogenous group of congenital myopathies that share a specific histopathological feature: areas of reduced oxidative activity in muscle fibers. The relationship between clinical, genetic and morphological characteristics of this group of disorders remains understudied. The aim of this work was to compare clinical presentations and morphological phenotypes of patients with congenital myopathies/myodystrophy to the data yielded by massively parallel exome sequencing. Eight children were included in the study: 2 boys and 6 girls aged 3 to 14 years. Their biopsy material was analyzed by light and electron microscopy. Sequencing was performed on HiSeq2500. Mutations were detected in 7 (87.5%) of 8 participants. Six children had 8 mutations in the genes associated with congenital core myopathies; one patient had 2 mutations in the LAMA2 gene implicated in merosin-deficient muscular dystrophy. The proportions of patients with mutations in RYR1 and SEPN1 were equal (42.86%). Of 10 detected mutations, 3 had not been previously described, including c.7561G&gt;A in RYR1, c.485C&gt;A in SEPN1 and p.Cys1136Arg in LAMA2. The clinical and morphological features of core myopathies suggest that genetic causes of this group of disorders should not be limited to RYR1 and SEPN1 genes only. This necessitates the search for and the study of other genes implicated in congenital myopathies or myodystrophy using state-of-the-art molecular genetic tools.

Assessment of skeletal muscle early myopathy with contrast-enhanced ultrasound in rabbit model of diabetes mellitus

Objective To evaluate early skeletal muscle myopathy with contrast-enhanced ultrasound (CEUS) in diabetic rabbits. Methods Alloxan (100 mg/kg) was given intravenously to 11 New Zealand white rabbits. Another 5 age-matched normal rabbits were used as controls.CEUS was performed at baseline and 1, 2, 3 months after the establishment of diabetes, respectively. Then, skeletal muscle samples were obtained for pathological observation. Additionally, the diabetic rabbits were divided into 3 groups according to their pathologic findings: mild, moderate, and severe myopathy group. Micro-perfusion parameters, including artery-to-vein transit time (A-VTT), muscle tissue mean transit time (M-MTT) and muscle tissue peak intensity (M-PI) were calculated. Results The diabetic rabbits exhibited a lower body weight increase and a decrease of muscle thickness.Plasma levels of triglyceride, cholesterol and creatinine were significantly higher in diabetic group than those in control group (P<0.05). The A-VTT and M-MTT values of the diabetic rabbits significantly increased over time (all P<0.05), whereas M-PI value significantly decreased compared with that in control group (P=0.013). Besides, the A-VTT value was significantly higher in severe myopathy group than that in mild group (P=0.001). The M-MTT values in both moderate and severe groups were significantly higher when compared to that in mild group (all P<0.05). The A-VTT and M-MTT values were correlated with the severity of diabetic myopathy(ρ=0.898, P<0.001; ρ=0.527, P=0.01). Conclusions Diabetic rabbits have defective skeletal muscle micro-perfusion in the early stage. CEUS can quantify impaire muscle microcirculation, and is a valuable tool for assessment of diabetic myopathy. Key words: Contrast-enhanced ultrasound; Diabetes mellitus; Myopathy; Microcirculation

Allele-Specific CRISPR/Cas9 Correction of a Heterozygous DNM2 Mutation Rescues Centronuclear Myopathy Cell Phenotypes

Genome editing with the CRISPR/Cas9 technology has emerged recently as a potential strategy for therapy in genetic diseases. For dominant mutations linked to gain-of-function effects, allele-specific correction may be the most suitable approach. In this study, we tested allele-specific inactivation or correction of a heterozygous mutation in the Dynamin 2 (DNM2) gene that causes the autosomal dominant form of centronuclear myopathies (CNMs), a rare muscle disorder belonging to the large group of congenital myopathies. Truncated single-guide RNAs targeting specifically the mutated allele were tested on cells derived from a mouse model and patients. The mutated allele was successfully targeted in patient fibroblasts and Dnm2R465W/+ mouse myoblasts, and clones were obtained with precise genome correction or inactivation. Dnm2R465W/+ myoblasts showed an alteration in transferrin uptake and autophagy. Specific inactivation or correction of the mutated allele rescued these phenotypes. These findings illustrate the potential of CRISPR/Cas9 to target and correct in an allele-specific manner heterozygous point mutations leading to a gain-of-function effect, and to rescue autosomal dominant CNM-related phenotypes. This strategy may be suitable for a large number of diseases caused by germline or somatic mutations resulting in a gain-of-function mechanism.

Comparative transcriptome analysis of skeletal muscle in ADSSL1 myopathy

ADSSL1 myopathy was recently identified as the cause of muscular disorders in Korean patients with distal myopathy. We generated transcriptome profiles of muscles from control subjects and patients with ADSSL1 myopathy. In the present study, RNA sequencing was conducted with seven vastus lateralis muscle samples from four patients with ADSSL1 myopathy and three control subjects. The hierarchical clustering result revealed a separation between myopathy and control groups. A total of 1,260 transcripts were significantly differentially expressed (|fold change| ≥ 2, p < 0.05), with 740 upregulated transcripts and 520 downregulated transcripts in myopathy group. Eighteen transcripts that mapped to purine metabolism pathway were significantly differentially expressed between the two groups, with ten downregulated transcripts and eight upregulated transcripts in myopathy group. In particular, three genes involved in purine nucleotide cycle (ADSSL1, ADSL, and AMPD1) were significantly downregulated in myopathy group. Ten transcripts in glycolysis/gluconeogenesis pathway were also significantly differentially expressed. This is the first study on the altered expression of transcripts in muscle tissues from patients with ADSSL1 myopathy. Our results provide new insights into the pathogenesis of ADSSL1 myopathy.

Myopathies featuring non-caseating granulomas: Sarcoidosis, inclusion body myositis and an unfolding overlap

Granulomatous myopathies are etiologically heterogeneous myopathies, pathologically characterized by the presence of intramuscular granulomas. Treatment outcomes are variable. We aimed to identify prognostic factors of treatment outcomes in myopathies featuring non-caseating granulomas. Sixteen patients were identified (9 sarcoid myopathy, 6 inclusion body myositis, and 1 granulomatous myopathy of indeterminate cause) over a 21-year period. The median age at diagnosis was 67 years in sarcoid myopathy group, and 64 years in inclusion body myositis group. Three inclusion body myositis patients were initially diagnosed with sarcoid myopathy based on the presence of systemic features of sarcoidosis and findings on muscle biopsies, but subsequent biopsies performed because of treatment refractoriness, showed all canonical pathologic features of inclusion body myositis. We identified sarcoplasmic congophilic inclusions in 6 sarcoid myopathy patients without associated rimmed vacuoles or typical weakness pattern of inclusion body myositis. Four inclusion body myositis and 4 of 5 sarcoid myopathy patients with congophilic inclusions were refractory to immunotherapy. Our study portrays the overlapping clinical and pathological features of sarcoid myopathy and inclusion body myositis. The presence of sarcoplasmic congophilic inclusions in sarcoid myopathy may predict an unfavorable outcome of immunosuppressive therapy, but a larger prospective study is required to further validate this observation.

Peculiar clinicopathological features of immune-mediated necrotizing myopathies.

In the past decade, immune-mediated necrotizing myopathies have emerged as a separate entity in the heterogenous group of autoimmune myopathies. This group is characterized by clinical manifestations restricted to the muscle tissue, and until recently, the definition was based on muscular pathological features. It was shown that they are the most severe autoimmune myopathies in term of muscle damages. They have been associated with two myositis-specific antibodies: either anti-signal recognition particle (anti-SRP) or anti-hydroxy-3-methylglutaryl-CoA reductase (anti-HMGCR) antibodies. These two antibodies are now considered as immune-mediated necrotizing myopathy (IMNM) diagnostic criteria. Each antibody delineates a homogenous subgroup of IMNM patients in terms of severity and IMNM without myositis-specific antibodies have a high risk of malignancy. In addition, pathological observations as well as in-vitro experiments suggest the pathogenic role of anti-SRP and anti-HMGCR antibodies. IMNM are muscle-specific autoimmune diseases associated with a severe weakness and a risk poor muscle strength recovery. Anti-SRP and anti-HMGCR antibodies are specifically associated with this condition and are crucial for the diagnosis and the prognosis. The muscle biopsy remains necessary for IMNM diagnosis in absence of myositis-specific antibodies.

Centronuclear myopathies under attack: A plethora of therapeutic targets.

Centronuclear myopathies are a group of congenital myopathies characterized by severe muscle weakness, genetic heterogeneity, and defects in the structural organization of muscle fibers. Their names are derived from the central position of nuclei on biopsies, while they are at the fiber periphery under normal conditions. No specific therapy exists yet for these debilitating diseases. Mutations in the myotubularin phosphoinositides phosphatase, the GTPase dynamin 2, or amphiphysin 2 have been identified to cause respectively X-linked centronuclear myopathies (also called myotubular myopathy) or autosomal dominant and recessive forms. Mutations in additional genes, as RYR1, TTN, SPEG or CACNA1S, were linked to phenotypes that can overlap with centronuclear myopathies. Numerous animal models of centronuclear myopathies have been studied over the last 15 years, ranging from invertebrate to large mammalian models. Their characterization led to a partial understanding of the pathomechanisms of these diseases and allowed the recent validation of therapeutic proof-of-concepts. Here, we review the different therapeutic strategies that have been tested so far for centronuclear myopathies, some of which may be translated to patients.

MYOFIBRILLAR AND DISTAL MYOPATHIES: P.250The clinical, myopathological characteristics of a Chinese cohort of myofibrillar myopathy: a retrospective study

Myofibrillar myopathy is a group of hereditary myopathies characterized by myofibrillar dissolution and abnormal intramuscular accumulation of proteins. Here we present 14 Chinese patients with pathologically diagnosed myofibrillar myopathy. Our patients show a male predominance (2.5:1), and the age of onset ranges from childhood to senior (5yr to 67yr) with a median age of 41yr. On physical evaluation, 57.1% patients demonstrate a mixed proximal and distal weakness, 28.6% a predominantly proximal involvement and 14.3% distal. Other common clinical features include joint contracture (35.8%), respiratory insufficiency (28.6%) and paresthesia/hypesthesia (28.6%). Of the 13 patients who underwent electrophysiological evaluation, all show myopathic changes and 78.6% have variable neurogenic changes, the majority of which is consistent with an axonal polyneuropathy with a preferential motor nerve involvement. Next generation sequencing was performed on 13 patients, and 12 were identified to harbor pathogenic mutations in genes including DES, BAG3, FLNC, FHL1 and TTN. Four novel mutations were found in DES, FLNC and FHL1. On muscle pathology, eosinophilic bodies were present in all patients with mutations in DES, BAG3, FHL1 and TTN, but not in the two cases with FLNC mutations. In contrast, patients associated with FLNC tend to demonstrate more rimmed vacuoles than others. The patients with the most rubbed-out fibers were the ones with DES mutations, while those with FLNC mutations did not show any. Abnormal accumulation of desmin was present in all patients, except the ones with FLNC, to a variable extent. It seems that patients with FLNC have a distinctive myopathological picture, ie. the presence of more rimmed vacuoles without eosinophilic bodies. These, together with the absence of abnormal desmin accumulation, make it tantalizing to propose that the patients with FLNC mutations do not share a common etiology with other myofibrillar myopathy cases.

NEXT GENERATION SEQUENCING AND EXPERIMENTAL MYOLOGY: P.372Next generation sequencing: new phenotype-genotype correlations

Congenital myopathies and muscular dystrophies are clinically and genetically heterogeneous diseases with broadly overlapping features. Next generation sequencing (NGS) techniques represent a powerful tool to identify genetic variants in these disorders in contrast to classic time consuming gene by gene approach. We describe the results obtained in an extensive study of 150 genetically undiagnosed patients. The patients were classified, according to their clinical phenotype, as affected by congenital myopathy (CM), congenital muscular dystrophy (CMD), limb girdle muscle dystrophy (LGMD), distal myopathies (DM) and exercise intolerance. All the patients were followed at the French South-West Reference Center of neuromuscular disorders. The causing gene mutations could be identified in 46% of the patients. In most of the cases the variants were localized in genes classically implicated in each phenotype group (RYR1, ACTA1, NEB mutations in congenital myopathy group for example). However, one key finding from our study was the identification of new phenotype-genotype correlations in 10% of the cases. Two FLNC gene mutations in patients with congenital myopathy and severe cardiopathy; NEB variants in three patients with adult onset pure distal myopathy; ACTA1 neomutation in a patient with asymptomatic elevation of creatin kinase; 11 GCG repeats expansions in PABPN1 in a patient with predominant axial myopathy without ptosis. Of special interest is the emerging role of TTN gene mutations in muscular disease. We found clear pathogenic variants (compound heterozygous or homozygous stop codon, frameshift or splicing) in seven patients with quite heterogeneous clinical picture from congenital centronuclear myopathy to congenital distal arthrogryposis or limb girdle muscular weakness with cardiopathy The aim of the work is to present the global results of the study and more particularly the new phenotype-genotype correlations.

Impact of pharmacogenetics on statin-induced myopathy in South-Indian subjects

ObjectivesStatins are the most commonly prescribed medications for the treatment of atherosclerotic cardiovascular disease. Statin-associated adverse effects occur in ∼10% of patients and are associated with polymorphisms in several key genes coding for transporters and metabolizing enzymes that affect statin pharmacokinetics. In the present study, we examine the association between cytochrome P450 3A5*3 (CYP3A5*3) T>C (rs776746), COQ G>C (rs4693075), and SLCO1B1 T>C (rs4149056) genetic variants with the risk of myopathy in South Indian patients on statin therapy. MethodsA total of 202 patients on atorvastatin or rosuvastatin therapy for 12 years were recruited in the study. Genotyping of drug metabolic CYP3A5*3 gene variant and drug transporter genes COQ G>C (rs4693075) and SLCO1B1 T>C (rs4149056) was analyzed by Sanger's sequencing. ResultsIn our study subjects, the percentage of patients diagnosed to have statin-induced myopathy was 18%. The majority of the patients were on 10 mg/day dose of either atorvastatin or rosuvastatin. The homozygous nonexpressors genotype CYP3A5*3/3 frequency of the CYP3A5 polymorphism was higher in patients with myopathy. But we could not find association of CYP3A5, COQ, and SLCO1B1 gene polymorphisms with either rosuvastatin or atorvastatin. ConclusionOur results clearly demonstrate that the frequency of CYP3A5*3 splicing variant is higher in myopathy group than in the tolerant group. We did not find significant association of genetic polymorphisms in CYP3A5, COQ, and SLCO1B1 with atorvastatin- or rosuvastatin-induced myopathy.

Association of Statin Exposure With Histologically Confirmed Idiopathic Inflammatory Myositis in an Australian Population

Statin medications are widely prescribed for cardiovascular risk reduction. Myalgia and rhabdomyolysis are well-recognized adverse effects of statins, and they resolve with the cessation of statin therapy. Idiopathic inflammatory myositis (IIM) is a heterogeneous group of autoimmune myopathies that may also be associated with statin use. Recently, statin-associated autoimmune myopathy has been recognized as a distinct entity with the presence of specific autoantibodies against hydroxymethylglutaryl-coenzyme A reductase, which results in a necrotizing myositis that does not resolve with cessation of statin therapy and requires treatment with immunosuppressive agents. To examine the association between histologically confirmed IIM and current exposure to statin medications. Population-based case-control study using the South Australian Myositis Database of all histologically confirmed cases of IIM diagnosed between 1990 and 2014 in patients 40 years or older (n = 221) and population-based controls from the North West Adelaide Health Study (n = 662), matched by age and sex in a 3:1 ratio of controls to cases. Data analysis using conditional logistic regression was performed from June 1, 2016, to July 14, 2017. Current statin medication use. Unadjusted and adjusted (for diabetes and cardiovascular disease) odds ratios and 95% CIs for likelihood of inflammatory myositis. A total of 221 IIM cases met the inclusion criteria with a mean (SD) age of 62.2 (10.8) years, and 132 (59.7%) were female. Statin exposure at the time of IIM diagnosis was 68 of 221 patients (30.8%) and 142 of 662 matched controls (21.5%) (P = .005). There was an almost 2-fold increased likelihood of statin exposure in patients with IIM compared with controls (adjusted odds ratio, 1.79; 95% CI, 1.23-2.60; P = .001). Similar results were observed when patients with necrotizing myositis were excluded from the analysis (adjusted odds ratio, 1.92; 95% CI, 1.29-2.86; P = .001). In this large population-based study, statin exposure was significantly associated with histologically confirmed IIM. Given the increased use of statins worldwide and the severity of IIM, increased awareness and recognition of this potentially rare adverse effect of statin exposure is needed.