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1.
Pharmacogenet Genomics ; 30(9): 208-211, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32453264

RESUMO

The most common adverse drug reaction from statins are statin-associated muscle symptoms (SAMS), characterized by myopathy (weakness), myalgia (muscle pain), and commonly elevation in serum creatine kinase. All statins are substrates of the organic anion transporter 1B1 (OATP1B1; gene: SLCO1B1), albeit to different degrees. A genetic polymorphism in SLCO1B1, c.521T>C (rs4149056), markedly decreases OATP1B1 function. The literature is currently unclear as to whether SLCO1B1 c.521T>C is significantly associated with discontinuation of atorvastatin specifically due to SAMS. Our hypothesis was that individuals carrying the SLCO1B1 decreased function 521C allele are more likely to discontinue atorvastatin due to SAMS. This was a retrospective analysis of survey data from 379 Caucasians genotyped for rs4149056 and treated with atorvastatin for at least 12 months. Crude and multivariable logistic regression, adjusted for established risk factors for SAMS, determined the association of SLCO1B1 c.521T>C with discontinuation of atorvastatin due to SAMS (SLCO1B1 521T-homozygotes vs. 521C-carriers). The sample was 51% male, with a mean age of 57 years (SD = 11). Sixty-one percent of participants reported discontinuing atorvastatin due to SAMS, and 32% overall carried the 521C allele. SLCO1B1 521C-carrier status was not a significant predictor of atorvastatin discontinuation in any model: crude OR = 1.07; 95% CI, 0.68-1.66; P = 0.78 and adjusted OR = 1.07; 95% CI, 0.68-1.69; P = 0.76. The results were similar in a sub-group of participants treated with higher doses of atorvastatin (>20 mg). In summary, SLCO1B1 c.521T>C was not significantly associated with discontinuation of atorvastatin therapy due to SAMS.


Assuntos
Atorvastatina/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Doenças Musculares/genética , Doenças Musculares/patologia , Polimorfismo de Nucleotídeo Único , Suspensão de Tratamento/estatística & dados numéricos , Feminino , Seguimentos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Musculares/induzido quimicamente , Prognóstico , Estudos Retrospectivos
2.
Muscle Nerve ; 59(5): 537-543, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30549046

RESUMO

INTRODUCTION: Statins reduce cardiovascular disease risk and are generally well tolerated, yet up to 0.5% of statin-treated patients develop incapacitating muscle symptoms including rhabdomyolysis. Our objective was to identify clinical factors related to statin-associated muscle symptoms (SAMS). METHODS: Clinical and laboratory characteristics were evaluated in 748 statin-treated Caucasians (634 with SAMS and 114 statin-tolerant controls). Information was collected on statin type, concomitant drug therapies, muscle symptom history, comorbidities, and family history. Logistic regression was used to identify associations. RESULTS: Individuals with SAMS were 3.6 times (odds ratio [OR] 3.60, 95% confidence interval [CI] 2.08-6.22) more likely than statin-tolerant controls to have a family history of heart disease. Additional associations included obesity (OR 3.08, 95% CI 1.18, 8.05), hypertension (OR 2.24, 95% CI 1.33, 3.77), smoking (OR 2.08, 95% CI 1.16, 3.74), and statin type. DISCUSSION: Careful medical monitoring of statin-treated patients with the associated coexisting conditions may ultimately reduce muscle symptoms and lead to improved compliance. Muscle Nerve 59:537-537, 2019.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Debilidade Muscular/induzido quimicamente , Mialgia/induzido quimicamente , Rabdomiólise/induzido quimicamente , Idoso , Atorvastatina/efeitos adversos , Feminino , Cardiopatias , Humanos , Hipertensão/epidemiologia , Modelos Logísticos , Lovastatina/efeitos adversos , Masculino , Anamnese , Pessoa de Meia-Idade , Debilidade Muscular/epidemiologia , Doenças Musculares/induzido quimicamente , Doenças Musculares/epidemiologia , Mialgia/epidemiologia , Obesidade/epidemiologia , Razão de Chances , Pravastatina/efeitos adversos , Estudos Retrospectivos , Rabdomiólise/epidemiologia , Fatores de Risco , Rosuvastatina Cálcica/efeitos adversos , Sinvastatina/efeitos adversos , Fumar/epidemiologia , População Branca
3.
Eur Heart J ; 39(27): 2526-2539, 2018 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-29718253

RESUMO

Aims: To objectively appraise evidence for possible adverse effects of long-term statin therapy on glucose homeostasis, cognitive, renal and hepatic function, and risk for haemorrhagic stroke or cataract. Methods and results: A literature search covering 2000-2017 was performed. The Panel critically appraised the data and agreed by consensus on the categorization of reported adverse effects. Randomized controlled trials (RCTs) and genetic studies show that statin therapy is associated with a modest increase in the risk of new-onset diabetes mellitus (about one per thousand patient-years), generally defined by laboratory findings (glycated haemoglobin ≥6.5); this risk is significantly higher in the metabolic syndrome or prediabetes. Statin treatment does not adversely affect cognitive function, even at very low levels of low-density lipoprotein cholesterol and is not associated with clinically significant deterioration of renal function, or development of cataract. Transient increases in liver enzymes occur in 0.5-2% of patients taking statins but are not clinically relevant; idiosyncratic liver injury due to statins is very rare and causality difficult to prove. The evidence base does not support an increased risk of haemorrhagic stroke in individuals without cerebrovascular disease; a small increase in risk was suggested by the Stroke Prevention by Aggressive Reduction of Cholesterol Levels study in subjects with prior stroke but has not been confirmed in the substantive evidence base of RCTs, cohort studies and case-control studies. Conclusion: Long-term statin treatment is remarkably safe with a low risk of clinically relevant adverse effects as defined above; statin-associated muscle symptoms were discussed in a previous Consensus Statement. Importantly, the established cardiovascular benefits of statin therapy far outweigh the risk of adverse effects.


Assuntos
Catarata/induzido quimicamente , Hemorragia Cerebral/induzido quimicamente , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Transtornos Cognitivos/induzido quimicamente , Glucose/fisiologia , Homeostase/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Nefropatias/induzido quimicamente , Acidente Vascular Cerebral/induzido quimicamente , Humanos
4.
Eur Heart J ; 36(17): 1012-22, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25694464

RESUMO

Statin-associated muscle symptoms (SAMS) are one of the principal reasons for statin non-adherence and/or discontinuation, contributing to adverse cardiovascular outcomes. This European Atherosclerosis Society (EAS) Consensus Panel overviews current understanding of the pathophysiology of statin-associated myopathy, and provides guidance for diagnosis and management of SAMS. Statin-associated myopathy, with significant elevation of serum creatine kinase (CK), is a rare but serious side effect of statins, affecting 1 per 1000 to 1 per 10 000 people on standard statin doses. Statin-associated muscle symptoms cover a broader range of clinical presentations, usually with normal or minimally elevated CK levels, with a prevalence of 7-29% in registries and observational studies. Preclinical studies show that statins decrease mitochondrial function, attenuate energy production, and alter muscle protein degradation, thereby providing a potential link between statins and muscle symptoms; controlled mechanistic and genetic studies in humans are necessary to further understanding. The Panel proposes to identify SAMS by symptoms typical of statin myalgia (i.e. muscle pain or aching) and their temporal association with discontinuation and response to repetitive statin re-challenge. In people with SAMS, the Panel recommends the use of a maximally tolerated statin dose combined with non-statin lipid-lowering therapies to attain recommended low-density lipoprotein cholesterol targets. The Panel recommends a structured work-up to identify individuals with clinically relevant SAMS generally to at least three different statins, so that they can be offered therapeutic regimens to satisfactorily address their cardiovascular risk. Further research into the underlying pathophysiological mechanisms may offer future therapeutic potential.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Doenças Musculares/induzido quimicamente , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Terapias Complementares , Consenso , Creatina Quinase/metabolismo , Dieta , Predisposição Genética para Doença/etiologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Hipolipemiantes/uso terapêutico , Mitocôndrias Musculares , Doenças Mitocondriais/complicações , Doenças Musculares/diagnóstico , Doenças Musculares/terapia , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/antagonistas & inibidores , Fatores de Risco , Serina Endopeptidases
5.
Muscle Nerve ; 47(2): 224-9, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23169530

RESUMO

INTRODUCTION: Twenty-six patients with clinical symptoms of adult onset carnitine palmitoyltransferase II (CPTII) deficiency were examined. All patients had skeletal muscle CPTII enzyme activity levels indicative of heterozygosity for CPT2 mutations, however sequence analysis identified no pathogenic mutations within the CPT2 gene. METHODS: Because the reaction product of CPTII is the substrate for very long-chain acyl-CoA dehydrogenase (VLCAD), we examined the ACADVL gene in these patients by sequence analysis. RESULTS: Missense mutations within the ACADVL gene were identified in 3 of the patients. CONCLUSIONS: The locations of the altered amino acid residues within the crystal structure of VLCAD are on the surface of the molecule and may be involved in interactions with neighboring molecules. These findings support the importance of considering that mutations may be present in the ACADVL gene when a significant partial deficiency is found in CPTII activity, but no mutations in the CPT2 gene can be identified.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/genética , Erros Inatos do Metabolismo Lipídico/genética , Doenças Mitocondriais/genética , Músculo Esquelético/enzimologia , Doenças Musculares/genética , Mutação de Sentido Incorreto , Acil-CoA Desidrogenase de Cadeia Longa/metabolismo , Adolescente , Adulto , Carnitina O-Palmitoiltransferase/deficiência , Carnitina O-Palmitoiltransferase/genética , Criança , Pré-Escolar , Feminino , Humanos , Erros Inatos do Metabolismo Lipídico/enzimologia , Erros Inatos do Metabolismo Lipídico/patologia , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/enzimologia , Doenças Mitocondriais/patologia , Músculo Esquelético/patologia , Doenças Musculares/enzimologia , Doenças Musculares/patologia , Análise de Sequência de DNA
6.
Anesth Analg ; 116(5): 1078-1086, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23558838

RESUMO

BACKGROUND: Mutations in the ryanodine receptor type 1 gene (RYR1) that encodes the skeletal muscle-specific intracellular calcium (Ca(2+)) release channel are a cause of malignant hyperthermia (MH). In this study, we examined RYR1 mutations in a large number of North American MH-susceptible (MHS) subjects without prior genetic diagnosis. METHODS: RYR1 was examined in 120 unrelated MHS subjects from the United States in a tiered manner. The α-1 subunit of the dihydropyridine receptor gene (CACNA1S) was screened for 4 variants in subjects in whom no abnormality was found in ≥ 100 exons of RYR1. RESULTS: Ten known causative MH mutations were found in 26 subjects. Variants of uncertain significance in RYR1 were found in 36 subjects, 16 of which are novel. Novel variants in both RYR1 and CACNA1S were found in the 1 subject who died of MH. Two RYR1 variants were found in 4 subjects. Variants of uncertain significance were found outside and inside the hotspots of RYR1. Maximal contractures in the caffeine-halothane contracture test were greater in those who had a known MH mutation or variant of uncertain significance in RYR1 than in those who did not. CONCLUSIONS: The identification of novel RYR1 variants and previously observed RYR1 variants of uncertain significance in independent MHS families is necessary for demonstrating the significance of these variants for MH susceptibility and supports the need for functional studies of these variants. Continued reporting of the clinical phenotypes of MH is necessary for interpretation of genetic findings, especially because the pathogenicity of most of these genetic variants associated with MHS remains to be elucidated.


Assuntos
Hipertermia Maligna/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Anestésicos Inalatórios/efeitos adversos , Anestésicos Inalatórios/farmacologia , Canais de Cálcio/genética , Canais de Cálcio Tipo L , DNA/química , DNA/genética , Éxons/genética , Variação Genética , Halotano/efeitos adversos , Halotano/farmacologia , Heterozigoto , Humanos , Hipertermia Maligna/epidemiologia , Contração Muscular/efeitos dos fármacos , Mutação/genética , Polimorfismo de Nucleotídeo Único , Estados Unidos/epidemiologia
7.
Future Cardiol ; 18(6): 461-470, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35297269

RESUMO

Aim: To determine the association of coenzyme Q10 (CoQ10) use with the resolution of statin-associated muscle symptoms (SAMS). Patients & methods: Retrospective analysis of a large, multicenter survey study of SAMS (total n = 511; n = 64 CoQ10 users). Univariate and multivariate logistic regression models assessed the association between CoQ10 use and the resolution of SAMS. Results: The frequency of SAMS resolution was similar between CoQ10 users and non-users (25% vs 31%, respectively; unadjusted odds ratio [OR]: 0.75 [95% CI: 0.41-1.38]; p = 0.357). Similarly, CoQ10 use was not significantly associated with the resolution of SAMS in multivariable models adjusted for SAMS risk factors (OR: 0.84 [95% CI: 0.45-1.55]; p = 0.568) or adjusted for significant differences among CoQ10 users and non-users (OR: 0.82 [95% CI: 0.45-1.51]; p = 0.522). Conclusion: CoQ10 was not significantly associated with the resolution of SAMS.


Statins are medications that help lower cholesterol and treat cardiovascular disease, but muscle pain is the most common side effect of statins. Statins decrease the body's levels of coenzyme Q10 (CoQ10), and thus taking CoQ10 supplements (which are widely available over the counter in pharmacies) may help treat the muscle side effects from statins. However, the results of previous studies are not clear whether CoQ10 is effective for treating statin-associated muscle symptoms. Therefore, the purpose of this study was to analyze whether the use of CoQ10 supplements improved statin-associated muscle side effects in a large group of individuals. When the authors compared the survey responses of 64 CoQ10 users versus those of 447 non-CoQ10 users with statin-associated muscle symptoms, CoQ10 supplements did not improve their muscle symptoms.


Assuntos
Suplementos Nutricionais , Inibidores de Hidroximetilglutaril-CoA Redutases , Doenças Musculares , Ubiquinona , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Músculos , Doenças Musculares/induzido quimicamente , Doenças Musculares/tratamento farmacológico , Estudos Retrospectivos , Ubiquinona/análogos & derivados , Ubiquinona/uso terapêutico
8.
Genet Med ; 13(9): 794-9, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21633293

RESUMO

PURPOSE: The diagnosis of a mitochondrial disorder relies heavily on the enzymatic analysis of mitochondrial respiratory chain complexes in muscle or other tissues. However, considerable differences exist between clinical laboratories in the protocols or particular tests used for evaluation. In addition, laboratories can encounter difficulties in consistent technique, as well as procurement of adequate positive or negative controls. Currently, there is no external quality assurance for respiratory chain complex assays. In this study, we explored the use of Caenorhabditis elegans mitochondria as a potential aid to diagnostic centers that perform respiratory chain complex assays. METHOD: Five diagnostic test centers in the United States and one from Australia comparatively analyzed enzyme activities of mitochondria from C. elegans. The first survey consisted of three open-labeled samples including one normal control and two mutants; the second survey consisted of one open-labeled normal control and two blinded samples. RESULTS: There was very good concordance among laboratories in detecting the majority of the defects present in the mutant specimens. Despite the ability to detect respiratory chain complex defects, the scatter between centers for certain enzymatic assays, particularly I + III, II, III, and IV, led to different diagnostic interpretations between the centers. CONCLUSION: The data strongly support the need for comparative testing of mitochondrial enzyme assays between multiple laboratories. Our overall results are encouraging for the use of nematode mitochondria as a tool that might provide a virtually inexhaustible supply of mitochondria with defined defects for development of assays and as a potential source of control specimens.


Assuntos
Caenorhabditis elegans/metabolismo , Técnicas de Laboratório Clínico/métodos , Ensaios Enzimáticos/métodos , Mitocôndrias/enzimologia , Doenças Mitocondriais/diagnóstico , Complexos Multienzimáticos/análise , Animais , Caenorhabditis elegans/genética , Transporte de Elétrons , Doenças Mitocondriais/enzimologia , Complexos Multienzimáticos/metabolismo , Mutação , Controle de Qualidade
9.
Mol Genet Metab ; 104(1-2): 167-73, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21795085

RESUMO

Malignant hyperthermia (MH) is a pharmacogenetic, autosomal dominantly inherited disorder of skeletal muscle triggered by volatile anesthetics and infrequently by extreme exertion and heat exposure. MH has variable penetrance with an incidence ranging from 1 in 5000 to 1 in 50,000-100,000 anesthesias. Mutations in the ryanodine receptor gene, RYR1, are found in 50-70% of cases. We hypothesized that a portion of patients with drug-induced muscle diseases, unrelated to anesthesia, such as severe statin myopathy, have underlying genetic liability that may include RYR1 gene mutations. DNA samples were collected from 885 patients in 4 groups: severe statin myopathy (n=197), mild statin myopathy (n=163), statin-tolerant controls (n=133), and non-drug-induced myopathies of unknown etiology characterized by exercise-induced muscle pain and weakness (n=392). Samples were screened for 105 mutations and variants in 26 genes associated with 7 categories of muscle disease including 34 mutations and variants in the RYR1 gene. Disease-causing mutations or variants in RYR1 were present in 3 severe statin myopathy cases, 1 mild statin myopathy case, 8 patients with non-drug-induced myopathy, and none in controls. These results suggest that disease-causing mutations and certain variants in the RYR1 gene may contribute to underlying genetic risk for non-anesthesia-induced myopathies and should be included in genetic susceptibility screening in patients with severe statin myopathy and in patients with non-statin-induced myopathies of unknown etiology.


Assuntos
Anestesia , Predisposição Genética para Doença , Hipertermia Maligna/complicações , Hipertermia Maligna/genética , Doenças Musculares/complicações , Doenças Musculares/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Análise de Sequência com Séries de Oligonucleotídeos , Fatores de Risco , Canal de Liberação de Cálcio do Receptor de Rianodina/genética
10.
Muscle Nerve ; 44(4): 531-8, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21826682

RESUMO

INTRODUCTION: Of the nearly 38 million people in the USA who receive statin therapy, 0.1-0.5% experience severe or life-threatening myopathic side effects. METHODS: We performed a genome-wide association study (GWAS) in a group of patients with severe statin myopathy versus a statin-tolerant group to identify genetic susceptibility loci. RESULTS: Replication studies in independent groups of severe statin myopathy (n = 190) and statin-tolerant controls (n = 130) resulted in the identification of three single-nucleotide polymorphisms (SNPs), rs9342288, rs1337512, and rs3857532, in the eyes shut homolog (EYS) on chromosome 6 suggestive of an association with risk for severe statin myopathy (P = 0.0003-0.0008). Analysis of EYS cDNA demonstrated that EYS gene products are complex and expressed with relative abundance in the spinal cord as well as in the retina. CONCLUSION: Structural similarities of these EYS gene products to members of the Notch signaling pathway and to agrin suggest a possible functional role in the maintenance and regeneration of the structural integrity of skeletal muscle.


Assuntos
Proteínas do Olho/genética , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Doenças Musculares/induzido quimicamente , Doenças Musculares/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 6/genética , Biologia Computacional , Éxons/genética , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Doenças Musculares/patologia , Adulto Jovem
11.
Neurol Genet ; 6(2): e402, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32337332

RESUMO

OBJECTIVE: To describe clinical, biochemical, and genetic features of participants with mitochondrial diseases (MtDs) enrolled in the North American Mitochondrial Disease Consortium (NAMDC) Registry. METHODS: This cross-sectional, multicenter, retrospective database analysis evaluates the phenotypic and molecular characteristics of participants enrolled in the NAMDC Registry from September 2011 to December 2018. The NAMDC is a network of 17 centers with expertise in MtDs and includes both adult and pediatric specialists. RESULTS: One thousand four hundred ten of 1,553 participants had sufficient clinical data for analysis. For this study, we included only participants with molecular genetic diagnoses (n = 666). Age at onset ranged from infancy to adulthood. The most common diagnosis was multisystemic disorder (113 participants), and only a minority of participants were diagnosed with a classical mitochondrial syndrome. The most frequent classical syndromes were Leigh syndrome (97 individuals) and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (71 individuals). Pathogenic variants in the mitochondrial DNA were more frequently observed (414 participants) than pathogenic nuclear gene variants (252 participants). Pathogenic variants in 65 nuclear genes were identified, with POLG1 and PDHA1 being the most commonly affected. Pathogenic variants in 38 genes were reported only in single participants. CONCLUSIONS: The NAMDC Registry data confirm the high variability of clinical, biochemical, and genetic features of participants with MtDs. This study serves as an important resource for future enhancement of MtD research and clinical care by providing the first comprehensive description of participant with MtD in North America.

12.
Anesth Analg ; 109(4): 1070-2, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19762733

RESUMO

We describe a child who developed a malignant hyperthermia-like syndrome after exposure to succinylcholine and halothane. Many features of a typical malignant hyperthermia episode were present, including tachydysrhythmia, tachypnea, and fever in association with metabolic acidosis, hyperCKemia, myglobinemia, and rapid recovery without residual effects upon administration of dantrolene, sodium bicarbonate, and active cooling. Muscle rigidity, hypercarbia, and hyperkalemia were not observed. The patient was found to be heterozygous for a mutation in the carnitine palmitoyltransferase II gene (CPT2) encoding an arginine to cysteine substitution at amino acid 503 (R503C) with reduced activity of the enzyme.


Assuntos
Anestésicos Inalatórios/efeitos adversos , Carnitina O-Palmitoiltransferase/genética , Halotano/efeitos adversos , Hipertermia Maligna/etiologia , Erros Inatos do Metabolismo/complicações , Fármacos Neuromusculares Despolarizantes/efeitos adversos , Succinilcolina/efeitos adversos , Substituição de Aminoácidos , Arginina , Carnitina O-Palmitoiltransferase/deficiência , Pré-Escolar , Cisteína , Feminino , Predisposição Genética para Doença , Heterozigoto , Humanos , Hipertermia Maligna/genética , Hipertermia Maligna/terapia , Erros Inatos do Metabolismo/enzimologia , Erros Inatos do Metabolismo/genética , Mutação , Fatores de Risco , Síndrome
13.
Curr Opin Rheumatol ; 20(6): 648-55, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18946323

RESUMO

PURPOSE OF REVIEW: Genetic predisposition to statin myopathy is a rapidly expanding area of investigation. This review summarizes the latest information on genetic risk factors associated with statin-induced myopathy. Genetic determinants involved in both pharmacokinetics of statins and metabolic muscle diseases are discussed. Data are provided on the prevalence of statin use in the United States; incidence of associated myopathy; terminology relating to statin myopathy and genetic susceptibility; and common myths surrounding this disorder. RECENT FINDINGS: Technological advances now make it possible to identify genetic variation in the human genome that reveals disease-causing mutations and single nucleotide polymorphisms associated with disease. More than 30,000 individuals in the United States suffer from severe life-threatening symptoms of statin-induced myopathy that may, in some cases, persist long after the cessation of therapy. Genes of interest include those involved in the pharmacokinetics of the statin response, muscle atrophy, exercise intolerance, pain perception, and mitochondrial energy metabolism. SUMMARY: Genetic analysis for variants and disease-causing mutations relevant to statin myopathy will provide predisposition testing for this and other drug-induced disorders. This testing will become an integral part of personalized medicine that will contribute to the safe and informed use of selected drugs and improved compliance.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Doenças Musculares/induzido quimicamente , Doenças Musculares/genética , Carnitina O-Palmitoiltransferase/deficiência , Carnitina O-Palmitoiltransferase/genética , Creatina Quinase/sangue , Expressão Gênica , Predisposição Genética para Doença , Doença de Depósito de Glicogênio Tipo V/complicações , Doença de Depósito de Glicogênio Tipo V/genética , Humanos , Doenças Musculares/diagnóstico , Doenças Musculares/epidemiologia , Farmacogenética , Rabdomiólise/induzido quimicamente , Rabdomiólise/diagnóstico , Rabdomiólise/genética , Fatores de Risco , Ubiquinona/análogos & derivados , Ubiquinona/deficiência , Estados Unidos/epidemiologia
14.
Mol Genet Metab ; 94(4): 422-427, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18550408

RESUMO

Three distinct clinical manifestations of carnitine palmitoyltransferase II (CPT II) deficiency have been defined including a mild adult onset myopathy, a severe infantile disorder and a lethal neonatal form. In this study we have examined the genomic DNA of five patients, 3 with the lethal neonatal form and 2 with the severe infantile form of the disease and identified two disease-causing mutations in the CPT2 gene for each patient, three of which are novel. In addition, based on currently available structural, biochemical and clinical data, we have classified all 64 known disease-causing mutations into groups with different predicted phenotypes depending on their CPT2 allelic counterparts.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/enzimologia , Carnitina O-Palmitoiltransferase/deficiência , Carnitina O-Palmitoiltransferase/genética , Erros Inatos do Metabolismo/genética , Mutação , Erros Inatos do Metabolismo dos Aminoácidos/genética , Sequência de Aminoácidos , Substituição de Aminoácidos , Sequência de Bases , Carnitina O-Palmitoiltransferase/química , Evolução Fatal , Feminino , Humanos , Recém-Nascido , Masculino , Erros Inatos do Metabolismo/enzimologia , Doenças Musculares/enzimologia , Doenças Musculares/genética , Fenótipo
15.
Eur J Pediatr ; 167(7): 771-6, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17891417

RESUMO

A 6-week-old child presented with hypotonia, myopathy, and a rapidly worsening dilated cardiomyopathy with severe atrial and ventricular arrhythmias and pulmonary hypertension, which proved fatal at age 3 months. Biochemical analysis showed a combined deficiency of the enzymatic activities of complexes I and IV and molecular studies identified a T14709C mutation in the mitochondrial tRNA glutamic acid gene. A review of symptomatology in patients with this mutation shows that it mainly presents in childhood or young adults with mild myopathy and diabetes mellitus. Infants with a high, nearly homoplasmic mutant load can present with more severe symptoms including cardiomyopathy. Families with this mitochondrial DNA mutation should be aware that increased mutant load in a subsequent generation may result in severe and often fatal cardiac symptoms.


Assuntos
Cardiomiopatias/etiologia , Doenças Mitocondriais/genética , RNA de Transferência de Ácido Glutâmico/genética , Cardiomiopatias/fisiopatologia , Evolução Fatal , Feminino , Humanos , Lactente , Mutação
16.
Pharmacogenomics ; 19(16): 1235-1249, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30325262

RESUMO

AIM: To examine the genetic differences between subjects with statin-associated muscle symptoms and statin-tolerant controls. MATERIALS & METHODS: Next-generation sequencing was used to characterize the exomes of 76 subjects with severe statin-associated muscle symptoms and 50 statin-tolerant controls. RESULTS: 12 probably pathogenic variants were found within the RYR1 and CACNA1S genes in 16% of cases with severe statin-induced myopathy representing a fourfold increase over variants found in statin-tolerant controls. Subjects with probably pathogenic RYR1 or CACNA1S variants had plasma CK 5X to more than 400X the upper limit of normal in addition to having muscle symptoms. CONCLUSIONS: Genetic variants within the RYR1 and CACNA1S genes are likely to be a major contributor to the susceptibility to statin-associated muscle symptoms.


Assuntos
Canais de Cálcio/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Doenças Musculares/induzido quimicamente , Doenças Musculares/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Canais de Cálcio Tipo L , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
18.
J Neuromuscul Dis ; 4(1): 77-87, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28269789

RESUMO

BACKGROUND: Statins have well-known benefits in the prevention of cardiovascular disease, however, 7-29% of patients develop muscle side effects and up to 0.5% develop severe symptoms. Mitochondrial dysfunction has been associated with severe statin-induced myopathy (SM); however, there is a paucity of systematic studies in affected individuals. OBJECTIVES: The goal of this study was to combine clinical and laboratory features with quantitative biochemical and histopathologic studies of skeletal muscle biopsies from SM cases to determine what proportion could be attributed to mitochondrial dysfunction and how many of these had primary respiratory chain defects. METHODS: A retrospective analysis was performed on patient records derived from 279 SM patients whose muscle biopsies were referred to our clinical diagnostic laboratory for analysis. Clinical, histopathologic and biochemical features were compared with two myopathic control groups unexposed to statins: individuals with idiopathic mitochondrial myopathy (MMP; n = 94) and with unknown metabolic myopathy (UMP; n = 86); normal controls were unavailable for this record review study. RESULTS: More SM patients had significantly elevated plasma CK than in the other two groups (p < 0.01). A subset of SM patients (67 of 279; 24%) had histopathologic and/or electron microscopic (EM) evidence for mitochondrial dysfunction in skeletal muscle; more cases were identified by EM than by histochemical analysis. Of 279 cases, 29 (10%) were confirmed to have respiratory chain defects by biochemical analysis; 4 of these had mitochondrial abnormalities by EM. An additional 20 cases had mitochondrial abnormalities by EM without a biochemical diagnosis. CONCLUSIONS: Both primary and secondary mitochondrial dysfunction was found in subsets of SM patients. The fact that respiratory chain defects were not found in most cases with histopathologic mitochondrial abnormalities does not rule out primary mitochondrial disease in these cases, however, it is more likely that secondary effects on mitochondrial structure and function have occurred; molecular analysis may be helpful only in a small number of cases.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Doenças Mitocondriais/metabolismo , Músculo Esquelético/patologia , Doenças Musculares/induzido quimicamente , Adulto , Idoso , Estudos de Casos e Controles , Creatina Quinase/metabolismo , Eletromiografia , Feminino , Humanos , Masculino , Microscopia Eletrônica , Pessoa de Meia-Idade , Doenças Mitocondriais/complicações , Doenças Mitocondriais/patologia , Miopatias Mitocondriais/metabolismo , Miopatias Mitocondriais/patologia , Músculo Esquelético/ultraestrutura , Doenças Musculares/complicações , Doenças Musculares/metabolismo , Doenças Musculares/patologia , Estudos Retrospectivos , Índice de Gravidade de Doença
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