RESUMEN
Previous work has shown that dietary treatments affect woody breast (WB) incidence differently, which indicates that gut conditions such as gut barrier function, inflammation, and oxidative stress are likely related to WB. In this study, dietary supplementation with antibiotics (bacitracin) or probiotics (Bacillus subtilis) was investigated for their effects on the expression of transcripts related to gut barrier function, inflammation, and oxidative stress in the mucus lining of the jejunum from broilers with or without WB. A split-plot experimental design was used in this study. The dietary treatments served as the main plot factor and the breast muscle condition was the subplot factor. On d 41, jejunum mucus was collected from 1 bird from each of 3 replicate pens in each 3 dietary treatment groups that exhibited WB and an additional bird that contained a normal breast (3 biological replicates/treatment/phenotype; 3 × 3 × 2, total N = 18). Total RNA was extracted using a commercial RNA extraction kit. The expression levels of CLDN1, MUC6, TLR2A, TLR2B, TLR4, IFN-γ, IL-1ß, IL-8L1, IL-10, NOS2, and SOD were determined using 2-step RT-qPCR analysis. The gene expression difference in ΔCt values was determined after normalizing with the chicken 18S rRNA gene. When the significant differences occurred between treatments, the relative fold change was calculated using the ΔΔCt method and the significance level was calculated. The PROC GLM procedure of SAS 9.4 was used, and the level of significance was set at P ≤ 0.05. There were no significant interactive effects between diet and the breast muscle condition on the expression of any of the genes tested. However, birds with WB exhibited higher MUC6 (P < 0.0001) gene expression levels than birds with normal breast muscles. In addition, the expression of SOD decreased in birds that were fed the antibiotic diet when compared to birds that were fed the probiotic diet (P = 0.014). In conclusion, WB identified in broilers tested in the current study is attributed to increased expression of mucin, indicating a correlation between WB incidence and gel-forming mucin secretion and pathogen signaling.
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Pollos , Enfermedades Musculares , Animales , Pollos/genética , Enfermedades Musculares/genética , Enfermedades Musculares/veterinaria , Moco , Antibacterianos , Inflamación/veterinaria , Mucinas , Expresión Génica , ARN , Superóxido DismutasaRESUMEN
BACKGROUND: Neutral lipid storage disease with myopathy (NLSD-M) is an autosomal recessive disease that manifests itself around the 3rd to 4th decade with chronic myopathy predominantly proximal in the shoulder girdle. Clinical myotonia is uncommon. We will report a rare case of association of pathogenic variants on PNPLA2 and CLCN1 genes with a mixed phenotype of NLSD-M and a subclinical form of Thomsen's congenital myotonia. CASE PRESENTATION: We describe a patient with chronic proximal myopathy, subtle clinical myotonia and electrical myotonia on electromyography (EMG). Serum laboratory analysis disclosure hyperCKemia (CK 1280 mg/dL). A blood smear analysis showed Jordan's anomaly, a hallmark of NLSD-M. A genetic panel was collected using next-generation sequencing (NGS) technique, which identified two pathogenic variants on genes supporting two different diagnosis: NLSD-M and Thomsen congenital myotonia, whose association has not been previously described. CONCLUSIONS: Although uncommon, it is important to remember the possibility of association of pathogenic variants to explain a specific neuromuscular disease phenotype. The use of a range of complementary methods, including myopathy genetic panels, may be essential to diagnostic definition in such cases.
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Enfermedades Musculares , Miotonía Congénita , Miotonía , Humanos , Aciltransferasas/genética , Canales de Cloruro/genética , Lipasa/genética , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/genética , Enfermedades Musculares/patología , Mutación/genética , Miotonía/genética , Miotonía Congénita/diagnóstico , Miotonía Congénita/genéticaRESUMEN
Chanarin-Dorfman syndrome (CDS) is a rare, autosomal recessive disorder of impaired triacylglycerol catabolism leading to cytoplasmic deposition of triglycerides in various cell types. We describe the case of an 8-month-old boy with cataracts, strabismus, motor delays, and an ichthyosiform rash since birth. Genetic testing revealed a pathogenic variant of the ABHD5 gene, suggestive of CDS, and further workup demonstrated hepatic steatosis and myopathy. His ichthyosis improved with initiation of a diet low in very long-chain fatty acids and medium-chain fatty acid supplementation.
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Catarata , Eritrodermia Ictiosiforme Congénita , Ictiosis Lamelar , Ictiosis , Errores Innatos del Metabolismo Lipídico , Enfermedades Musculares , Masculino , Humanos , Lactante , Eritrodermia Ictiosiforme Congénita/diagnóstico , Eritrodermia Ictiosiforme Congénita/genética , Ictiosis Lamelar/diagnóstico , Ictiosis Lamelar/genética , Ictiosis/diagnóstico , Ictiosis/genética , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/genética , Enfermedades Musculares/patología , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/genética , Errores Innatos del Metabolismo Lipídico/patología , Catarata/diagnóstico , 1-Acilglicerol-3-Fosfato O-Aciltransferasa/genéticaRESUMEN
We report the case of an individual with severe hypercholesterolemia who experienced rhabdomyolysis with high dose atorvastatin. Genetic testing was undertaken to evaluate for suspected familial hypercholesterolemia (FH) and for the presence of gene variants associated with susceptibility to statin associated muscle disease. Genetic testing identified the presence of a potentially damaging variant of the hepatic xenobiotic transporter pump SLCO1B1, a single nucleotide variant (SNV) (rs77271279, c.481+1G>T) that disrupts the canonical donor splice motif. Although this variant has not previously been reported as associated with rhabdomyolysis and thus requires validation in population studies, it likely played a role in this patient's susceptibility to rhabdomyolysis based on functional assessment of the effect of this variant on SLCO1B1 protein function and given the known role of this transporter in statin uptake by the liver. The presence of this gene variant reinforced our decision to treat the patient's hypercholesterolemia with non-statin alternatives (PCSK9 inhibitor and ezetimibe). Genetic testing also identified the presence of a second SLCO1B1 gene variant, c.1200C>G (p.Phe400Leu, rs59113707) and homozygosity for an intron variant of the apolipoprotein(a) (LPA) gene (c.2604.138G>A intron variant, rs9457951) associated with increased Lp(a), a risk factor for atherosclerotic cardiovascular disease. Notably, all three variants are rare in persons of European descent but more frequent in African-Americans. These findings underscore the role of disabling mutations of the SLCO1B1 gene in statin myopathy and the need to validate these and other gene variants associated with statin myopathy in a population of patients with statin-associated muscle disease.
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Inhibidores de Hidroximetilglutaril-CoA Reductasas , Hipercolesterolemia , Enfermedades Musculares , Rabdomiólisis , Atorvastatina/efectos adversos , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Hipercolesterolemia/tratamiento farmacológico , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Enfermedades Musculares/genética , Polimorfismo de Nucleótido Simple , Proproteína Convertasa 9/genética , Rabdomiólisis/tratamiento farmacológico , Rabdomiólisis/genéticaRESUMEN
SEPN1-related myopathy (SEPN1-RM) is a muscle disorder due to mutations of the SEPN1 gene, which is characterized by muscle weakness and fatigue leading to scoliosis and life-threatening respiratory failure. Core lesions, focal areas of mitochondria depletion in skeletal muscle fibers, are the most common histopathological lesion. SEPN1-RM underlying mechanisms and the precise role of SEPN1 in muscle remained incompletely understood, hindering the development of biomarkers and therapies for this untreatable disease. To investigate the pathophysiological pathways in SEPN1-RM, we performed metabolic studies, calcium and ATP measurements, super-resolution and electron microscopy on in vivo and in vitro models of SEPN1 deficiency as well as muscle biopsies from SEPN1-RM patients. Mouse models of SEPN1 deficiency showed marked alterations in mitochondrial physiology and energy metabolism, suggesting that SEPN1 controls mitochondrial bioenergetics. Moreover, we found that SEPN1 was enriched at the mitochondria-associated membranes (MAM), and was needed for calcium transients between ER and mitochondria, as well as for the integrity of ER-mitochondria contacts. Consistently, loss of SEPN1 in patients was associated with alterations in body composition which correlated with the severity of muscle weakness, and with impaired ER-mitochondria contacts and low ATP levels. Our results indicate a role of SEPN1 as a novel MAM protein involved in mitochondrial bioenergetics. They also identify a systemic bioenergetic component in SEPN1-RM and establish mitochondria as a novel therapeutic target. This role of SEPN1 contributes to explain the fatigue and core lesions in skeletal muscle as well as the body composition abnormalities identified as part of the SEPN1-RM phenotype. Finally, these results point out to an unrecognized interplay between mitochondrial bioenergetics and ER homeostasis in skeletal muscle. They could therefore pave the way to the identification of biomarkers and therapeutic drugs for SEPN1-RM and for other disorders in which muscle ER-mitochondria cross-talk are impaired.
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Retículo Endoplásmico/metabolismo , Mitocondrias/metabolismo , Proteínas Musculares/metabolismo , Enfermedades Musculares/metabolismo , Selenoproteínas/metabolismo , Adolescente , Adulto , Animales , Calcio/metabolismo , Niño , Retículo Endoplásmico/genética , Metabolismo Energético , Femenino , Homeostasis , Humanos , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patología , Proteínas Musculares/genética , Enfermedades Musculares/genética , Enfermedades Musculares/patología , Oxidación-Reducción , Selenoproteínas/genética , Adulto JovenRESUMEN
The nutrition management guideline for very-long chain acyl-CoA dehydrogenase deficiency (VLCAD) is the fourth in a series of web-based guidelines focusing on the diet treatment for inherited metabolic disorders and follows previous publication of guidelines for maple syrup urine disease (2014), phenylketonuria (2016) and propionic acidemia (2019). The purpose of this guideline is to establish harmonization in the treatment and monitoring of individuals with VLCAD of all ages in order to improve clinical outcomes. Six research questions were identified to support guideline development on: nutrition recommendations for the healthy individual, illness management, supplementation, monitoring, physical activity and management during pregnancy. This report describes the methodology used in its development including review, critical appraisal and abstraction of peer-reviewed studies and unpublished practice literature; expert input through two Delphi surveys and a nominal group process; and external review from metabolic physicians and dietitians. It includes the summary statements of the nutrition management recommendations for each research question, followed by a standardized rating based on the strength of the evidence. Online, open access of the full published guideline allows utilization by health care providers, researchers and collaborators who advise, advocate and care for individuals with VLCAD and their families and can be accessed from the Genetic Metabolic Dietitians International (https://GMDI.org) and Southeast Regional Genetics Network (https://southeastgenetics.org/ngp) websites.
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Acil-CoA Deshidrogenasa de Cadena Larga/genética , Síndromes Congénitos de Insuficiencia de la Médula Ósea/dietoterapia , Errores Innatos del Metabolismo Lipídico/dietoterapia , Enfermedades Mitocondriales/dietoterapia , Enfermedades Musculares/dietoterapia , Política Nutricional , Acil-CoA Deshidrogenasa de Cadena Larga/metabolismo , Síndromes Congénitos de Insuficiencia de la Médula Ósea/genética , Síndromes Congénitos de Insuficiencia de la Médula Ósea/metabolismo , Síndromes Congénitos de Insuficiencia de la Médula Ósea/patología , Femenino , Guías como Asunto , Humanos , Errores Innatos del Metabolismo Lipídico/genética , Errores Innatos del Metabolismo Lipídico/metabolismo , Errores Innatos del Metabolismo Lipídico/patología , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/metabolismo , Enfermedades Mitocondriales/patología , Enfermedades Musculares/genética , Enfermedades Musculares/metabolismo , Enfermedades Musculares/patología , Terapia Nutricional , EmbarazoRESUMEN
BACKGROUND: Primary carnitine deficiency due to mutations in the SLC22A5 gene is a rare but well-treatable metabolic disorder that puts patients at risk for metabolic decompensations, skeletal and cardiac myopathy and sudden cardiac death. RESULTS: We report on a 7-year-old boy diagnosed with primary carnitine deficiency 2 years after successful heart transplantation thanks his younger sister's having been identified via expanded newborn screening during a pilot study evaluating an extension of the German newborn screening panel. CONCLUSION: As L-carnitine supplementation can prevent and mostly reverse clinical symptoms of primary carnitine deficiency, all patients with cardiomyopathy should be investigated for primary carnitine deficiency even if newborn screening results were unremarkable.
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Cardiomiopatías , Trasplante de Corazón , Enfermedades Musculares , Cardiomiopatías/diagnóstico , Cardiomiopatías/genética , Carnitina/deficiencia , Niño , Humanos , Hiperamonemia , Recién Nacido , Masculino , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/genética , Proteínas de Transporte de Catión Orgánico/genética , Proyectos Piloto , Miembro 5 de la Familia 22 de Transportadores de SolutosRESUMEN
Atorvastatin (ATV) is frequently prescribed and generally well tolerated, but can lead to myotoxicity, especially at higher doses. A genome-wide association study of circulating levels of ATV, 2-hydroxy (2-OH) ATV, ATV lactone (ATV L), and 2-OH ATV L was performed in 590 patients who had been hospitalized with a non-ST elevation acute coronary syndrome 1 month earlier and were on high-dose ATV (80 mg or 40 mg daily). The UGT1A locus (lead single nucleotide polymorphism, rs887829) was strongly associated with both increased 2-OH ATV/ATV (P = 7.25 × 10-16 ) and 2-OH ATV L/ATV L (P = 3.95 × 10-15 ) metabolic ratios. Moreover, rs45446698, which tags CYP3A7*1C, was nominally associated with increased 2-OH ATV/ATV (P = 6.18 × 10-7 ), and SLCO1B1 rs4149056 with increased ATV (P = 2.21 × 10-6 ) and 2-OH ATV (P = 1.09 × 10-6 ) levels. In a subset of these patients whose levels of ATV and metabolites had also been measured at 12 months after hospitalization (n = 149), all of these associations remained, except for 2-OH ATV and rs4149056 (P = 0.057). Clinically, rs4149056 was associated with increased muscular symptoms (odds ratio (OR) 3.97; 95% confidence interval (CI) 1.29-12.27; P = 0.016) and ATV intolerance (OR 1.55; 95% CI 1.09-2.19; P = 0.014) in patients (n = 870) primarily discharged on high-dose ATV. In summary, both novel and recognized genetic associations have been identified with circulating levels of ATV and its major metabolites. Further study is warranted to determine the clinical utility of genotyping rs4149056 in patients on high-dose ATV.
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Atorvastatina/sangre , Inhibidores de Hidroximetilglutaril-CoA Reductasas/sangre , Variantes Farmacogenómicas , Polimorfismo de Nucleótido Simple , Atorvastatina/efectos adversos , Atorvastatina/análogos & derivados , Atorvastatina/farmacocinética , Biotransformación , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Femenino , Estudio de Asociación del Genoma Completo , Glucuronosiltransferasa/genética , Glucuronosiltransferasa/metabolismo , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Lactonas/sangre , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Masculino , Persona de Mediana Edad , Enfermedades Musculares/inducido químicamente , Enfermedades Musculares/genética , Farmacogenética , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , Reino UnidoRESUMEN
Anaplerotic odd-chain fatty acid supplementation has been suggested as an approach to replenish citric acid cycle intermediate (CACi) pools and facilitate adenosine triphosphate (ATP) production in subjects with long-chain fatty acid oxidation disorders, but the evidence that cellular CACi depletion exists and that repletion occurs following anaplerotic substrate supplementation is limited. We exercised very long-chain acyl-CoA dehydrogenase-deficient (VLCAD-/-) and wild-type (WT) mice to exhaustion and collected cardiac tissue for measurement of CACi by targeted metabolomics. In a second experimental group, VLCAD-/- and WT mice that had been fed chow prepared with either medium-chain triglyceride (MCT) oil or triheptanoin for 4 weeks were exercised for 60 minutes. VLCAD-/- mice exhibited lower succinate in cardiac muscle at exhaustion than WT mice suggesting lower CACi in VLCAD-/- with prolonged exercise. In mice fed either MCT or triheptanoin, succinate and malate were greater in VLCAD-/- mice fed triheptanoin compared to VLCAD-/- animals fed MCT but lower than WT mice fed triheptanoin. Long-chain odd acylcarnitines such as C19 were elevated in VLCAD-/- and WT mice fed triheptanoin suggesting some elongation of the heptanoate, but it is unknown what proportion of heptanoate was oxidized vs elongated. Prolonged exercise was associated with decreased cardiac muscle succinate in VLCAD-/- mice in comparison to WT mice. VLCAD-/- fed triheptanoin had increased succinate compared to VLCAD-/- mice fed MCT but lower than WT mice fed triheptanoin. Cardiac CACi were higher following dietary ingestion of an anaplerotic substrate, triheptanoin, in comparison to MCT.
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Acil-CoA Deshidrogenasa de Cadena Larga/deficiencia , Síndromes Congénitos de Insuficiencia de la Médula Ósea/dietoterapia , Síndromes Congénitos de Insuficiencia de la Médula Ósea/metabolismo , Errores Innatos del Metabolismo Lipídico/dietoterapia , Errores Innatos del Metabolismo Lipídico/metabolismo , Enfermedades Mitocondriales/dietoterapia , Enfermedades Mitocondriales/metabolismo , Enfermedades Musculares/dietoterapia , Enfermedades Musculares/metabolismo , Triglicéridos/administración & dosificación , Acil-CoA Deshidrogenasa de Cadena Larga/genética , Acil-CoA Deshidrogenasa de Cadena Larga/metabolismo , Animales , Ciclo del Ácido Cítrico , Síndromes Congénitos de Insuficiencia de la Médula Ósea/genética , Grasas de la Dieta/administración & dosificación , Ácidos Grasos/metabolismo , Femenino , Errores Innatos del Metabolismo Lipídico/genética , Hígado/metabolismo , Masculino , Ratones , Enfermedades Mitocondriales/genética , Enfermedades Musculares/genética , Miocardio/metabolismo , Oxidación-Reducción , Triglicéridos/químicaRESUMEN
OBJECTIVE: To study the prevalence, clinical and genetic characteristics of primary carnitine deficiency (PCD). METHODS: From January 2013 to December 2017, 720 667 newborns and their mothers were tested for PCD by tandem mass spectrometry. Potential mutations of carnitine transporter gene SLC22A5 among suspected PCD patients were analyzed. Dietary guidance and L-carnitine supplementation were provided to the parents. Growth and intelligence development were surveyed during follow-up. RESULTS: In total 21 neonates and 6 mothers were diagnosed with PCD, which yielded an incidence of 1 in 34 317. Eighteen SLC22A5 mutations were detected, which included 4 novel mutations, namely c.1484T>C, c.394-1G>T, c.431T>C and c.265-266insGGCTCGCCACC. Eighteen patients were found to carry compound heterozygous mutations and 3 have carried homozygous SLC22A5 mutations. Three mothers carried compound heterozygous mutations and 2 carried homozygous mutations. Common mutations included c.1400C>G (42.3%), c.760C>T (11.5%) and c.51C>G (7.7%). During the 8-42 month follow-up, neonates with PCD showed no clinical symptoms but normal growth. Blood level of free carnitine was raised in all mothers after the treatment. CONCLUSION: The incidence of neonatal PCD in Henan is 1 in 34 317, with the most common mutation being c.1400C>G. Above finding has enriched the spectrum of SLC22A5 gene mutations.
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Cardiomiopatías/genética , Carnitina/deficiencia , Hiperamonemia/genética , Enfermedades Musculares/genética , Miembro 5 de la Familia 22 de Transportadores de Solutos/genética , Cardiomiopatías/epidemiología , Carnitina/administración & dosificación , Carnitina/genética , China , Femenino , Humanos , Hiperamonemia/epidemiología , Recién Nacido , Enfermedades Musculares/epidemiología , Mutación , Tamizaje NeonatalRESUMEN
PURPOSE OF REVIEW: This article provides an overview of mitochondrial and metabolic biology, the genetic mechanisms causing mitochondrial diseases, the clinical features of mitochondrial diseases, lipid myopathies, and glycogen storage diseases, all with a focus on those syndromes and diseases associated with myopathy. Over the past decade, advances in genetic testing have revolutionized patient evaluation. The main goal of this review is to give the clinician the basic understanding to recognize patients at risk of these diseases using the standard history and physical examination. RECENT FINDINGS: Primary mitochondrial disease is the current designation for the illnesses resulting from genetic mutations in genes whose protein products are necessary for mitochondrial structure or function. In most circumstances, more than one organ system is involved in mitochondrial disease, and the value of the classic clinical features as originally described early in the history of mitochondrial diseases has reemerged as being important to identifying patients who may have a primary mitochondrial disease. The use of the genetic laboratory has become the most powerful tool for confirming a diagnosis, and nuances of using genetic results will be discussed in this article. Treatment for mitochondrial disease is symptomatic, with less emphasis on vitamin and supplement therapy than in the past. Clinical trials using pharmacologic agents are in progress, with the field attempting to define proper goals of treatment. Several standard accepted therapies exist for many of the metabolic myopathies. SUMMARY: Mitochondrial, lipid, and glycogen diseases are not uncommon causes of multisystem organ dysfunction, with the neurologic features, especially myopathy, occurring as a predominant feature. Early recognition requires basic knowledge of the varied clinical phenotypes before moving forward with a screening evaluation and possibly a genetic evaluation. Aside from a few specific diseases for which there are recommended interventions, treatment for the majority of these disorders remains symptomatic, with clinical trials currently in progress that will hopefully result in standard treatments.
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Enfermedad del Almacenamiento de Glucógeno , Trastornos del Metabolismo de los Lípidos , Enfermedades Mitocondriales , Enfermedades Musculares , Adolescente , Anciano , Femenino , Enfermedad del Almacenamiento de Glucógeno/diagnóstico , Enfermedad del Almacenamiento de Glucógeno/genética , Enfermedad del Almacenamiento de Glucógeno/fisiopatología , Humanos , Trastornos del Metabolismo de los Lípidos/diagnóstico , Trastornos del Metabolismo de los Lípidos/genética , Trastornos del Metabolismo de los Lípidos/fisiopatología , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/fisiopatología , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/genética , Enfermedades Musculares/metabolismo , Enfermedades Musculares/fisiopatologíaRESUMEN
BACKGROUND In this study, we investigated the clinical and pathological features of patients with lipid storage myopathy (LSM) complicated with hyperuricemia, to improve clinicians' understanding of metabolic multi-muscular disorder with metabolic disorders, and to reduce the risk of missed diagnosis of LSM. MATERIAL AND METHODS From January 2005 to December 2017, 8 patients underwent muscle biopsy and diagnosed by muscle pathology and genetic testing in our hospital. All 8 patients were in compliance with LSM diagnosis. We collected data on the patient's clinical performance, adjuvant examination, treatment, and outcomes to provide a comprehensive report and description of LSM patients with hyperuricemia. RESULTS All patients were diagnosed as having ETFDH gene mutations. The main clinical manifestations of patients were chronic limb and trunk weakness, limb numbness, and muscle pain. The serum creatine kinase (CK) values in all patients were higher than normal values. Electromyography showed 3 cases of simple myogenic damage and 3 cases of neurogenic injury. Hematuria metabolic screening showed that 2 patients had elevated glutaric aciduria, and 1 patient had elevated fatty acyl carnitine in the blood. All patients were given riboflavin treatment, and the clinical symptoms were significantly improved, and 3 patients returned to normal uric acid levels after treatment. Pathological staining showed an abnormal deposition of lipid droplets in muscle fibers. CONCLUSIONS If an adolescent hyperuricemia patient has abnormal limb weakness, exercise intolerance, and elevated serum CK values, clinicians need to be highly alert to the possibility of LSM. Early diagnosis and treatment of LSM should improve the clinical symptoms and quality of life and reduce complications.
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Hiperuricemia/fisiopatología , Errores Innatos del Metabolismo Lipídico/genética , Errores Innatos del Metabolismo Lipídico/fisiopatología , Distrofias Musculares/genética , Distrofias Musculares/fisiopatología , Adolescente , Adulto , Carnitina/análogos & derivados , Carnitina/metabolismo , Niño , China , Flavoproteínas Transportadoras de Electrones/genética , Flavoproteínas Transportadoras de Electrones/metabolismo , Femenino , Humanos , Hiperuricemia/metabolismo , Proteínas Hierro-Azufre/genética , Proteínas Hierro-Azufre/metabolismo , Errores Innatos del Metabolismo Lipídico/metabolismo , Masculino , Debilidad Muscular , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Enfermedades Musculares/genética , Distrofias Musculares/metabolismo , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/genética , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/metabolismo , Calidad de Vida , Riboflavina/metabolismo , Adulto JovenRESUMEN
OBJECTIVE: Exercise induced metabolic myopathy in German Hunting Terrier dogs is an autosomal-recessively inherited disorder, caused by a nonsense variant of the gene encoding for the very long-chain acyl-CoA-dehydrogenase (VLCAD) enzyme. Clinical signs include exercise- induced fatigue, muscle pain and weakness. In the present study, the long-term course of this disease was investigated over a period of 1 year in 9 affected German Hunting Terriers. The dogs were treated symptomatically with oral L-carnitine, coenzyme Q10 and a special diet characterized by a low content of long-chain fatty acids and a high proportion of carbohydrates. MATERIAL AND METHODS: In 9 affected dogs, the phenotype as well as clinical, laboratory parameters, and histopathological findings are described (time point 1) and compared to follow-up examinations 1 year later (time point 2). At both time points clinical and neurological examinations, complete blood cell count, clinical chemistry profile and the concentration of brain natriuretic peptide (NT-proBNP) were investigated. RESULTS: In the follow-up examinations, the same post-exercise clinical signs were present as in the initial presentation of the homozygous dogs. Dark-brownish discoloration of the urine, weakness, myalgia as well as stiff and tetraparetic gait were apparant. All hematological values and the concentration of NT-proBNP were within the relevant reference ranges. Plasma CK and ALT activities were compared between the first presentation and the follow- up examination and no significant differences were detected (pCK = 0.31, pALT = 0.64). Signs of myopathy remained unchanged throughout the examination period. CONCLUSION AND CLINICAL RELEVANCE: Oral supplementation with L-carnitine, coenzyme Q10 and the special dietary management did not result in any improvement of clinical signs or laboratory parameters. No progression of the disease was observed. The prognosis for affected dogs remains cautious as long-term observations of affected dogs over several years are lacking. Our findings provide further important information on inherited disorders of mitochondrial ß-oxidation in dogs, especially focused on the exercise induced metabolic myopathy in the German Hunting Terrier. This may provide new insights for novel treatment modalities in conjuntion with the development of improved breeding guidelines.
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Enfermedades de los Perros , Enfermedades Musculares , Condicionamiento Físico Animal/efectos adversos , Acil-CoA Deshidrogenasa de Cadena Larga/genética , Animales , Carnitina/uso terapéutico , Dieta , Enfermedades de los Perros/diagnóstico , Enfermedades de los Perros/genética , Enfermedades de los Perros/terapia , Perros , Estudios de Seguimiento , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/genética , Enfermedades Musculares/terapia , Enfermedades Musculares/veterinaria , Ubiquinona/análogos & derivados , Ubiquinona/uso terapéuticoRESUMEN
We report a case of sudden unexplained death in a young asymptomatic woman in whom postmortem genetic testing after a negative autopsy identified a homozygous pathogenic mutation in SLC22A5 which leads clinically to primary carnitine deficiency (PCD). Her brother was subsequently diagnosed clinically with short QT syndrome, received an implantable defibrillator, and was then found to carry the same pathogenic homozygous mutation and critically low levels of carnitine. His QT interval improved with the use of carnitine supplementation, highlighting the close relationship between electrophysiology and biochemistry, and the importance of postmortem genetic testing in the clinical management of surviving relatives.
Asunto(s)
Cardiomiopatías/genética , Carnitina/deficiencia , Muerte Súbita Cardíaca/etiología , Pruebas Genéticas/métodos , Hiperamonemia/genética , Síndrome de QT Prolongado/genética , Enfermedades Musculares/genética , Mutación , Miembro 5 de la Familia 22 de Transportadores de Solutos/genética , Adulto , Autopsia , Cardiomiopatías/complicaciones , Cardiomiopatías/metabolismo , Carnitina/genética , Carnitina/metabolismo , ADN/genética , Resultado Fatal , Femenino , Predisposición Genética a la Enfermedad , Humanos , Hiperamonemia/complicaciones , Hiperamonemia/metabolismo , Síndrome de QT Prolongado/etiología , Enfermedades Musculares/complicaciones , Enfermedades Musculares/metabolismo , Miembro 5 de la Familia 22 de Transportadores de Solutos/metabolismoRESUMEN
Primary carnitine deficiency (PCD) not treated with L-Carnitine can lead to sudden cardiac death. To our knowledge, it is unknown if asymptomatic patients treated with L-Carnitine suffer from myocardial scarring and thus be at greater risk of potentially serious arrhythmia. Cardiac evaluation of function and myocardial scarring is non-invasively best supported by cardiac magnetic resonance imaging (CMR) with late gadolinium enhancement (LGE). The study included 36 PCD patients, 17 carriers and 17 healthy subjects. A CMR cine stack in the short-axis plane were acquired to evaluate left ventricle (LV) systolic and diastolic function and a similar LGE stack to evaluate myocardial scarring and replacement fibrosis. LV volumes and ejection fraction were not different between PCD patients, carriers and healthy subjects. However, LV mass was higher in PCD patients with the severe homozygous mutation, c.95 A > G (p = 0.037; n = 17). Among homozygous PCD patients there were two cases of unexplained myocardial scarring and this is in contrast to no myocardial scarring in any of the other study participants (p = 0.10). LV mass was increased in PCD patients. L-carnitine supplementation is essential in order to prevent potentially lethal cardiac arrhythmia and serious adverse cardiac remodeling.
Asunto(s)
Carnitina/deficiencia , Cicatriz/epidemiología , Corazón/diagnóstico por imagen , Imagen por Resonancia Magnética , Enfermedades Musculares/diagnóstico por imagen , Miocardio/patología , Adulto , Carnitina/genética , Cicatriz/diagnóstico por imagen , Medios de Contraste , Femenino , Gadolinio , Heterocigoto , Homocigoto , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Musculares/genética , Enfermedades Musculares/patología , Mutación , Función VentricularRESUMEN
MEGF10 myopathy is a rare inherited muscle disease that is named after the causative gene, MEGF10. The classic phenotype, early onset myopathy, areflexia, respiratory distress and dysphagia, is severe and immediately life-threatening. There are no disease-modifying therapies. We performed a small molecule screen and follow-up studies to seek a novel therapy. A primary in vitro drug screen assessed cellular proliferation patterns in Megf10-deficient myoblasts. Secondary evaluations were performed on primary screen hits using myoblasts derived from Megf10-/- mice, induced pluripotent stem cell-derived myoblasts from MEGF10 myopathy patients, mutant Drosophila that are deficient in the homologue of MEGF10 (Drpr) and megf10 mutant zebrafish. The screen yielded two promising candidates that are both selective serotonin reuptake inhibitors (SSRIs), sertraline and escitalopram. In depth follow-up analyses demonstrated that sertraline was highly effective in alleviating abnormalities across multiple models of the disease including mouse myoblast, human myoblast, Drosophila and zebrafish models. Sertraline also restored deficiencies of Notch1 in disease models. We conclude that SSRIs show promise as potential therapeutic compounds for MEGF10 myopathy, especially sertraline. The mechanism of action may involve the Notch pathway.
Asunto(s)
Proteínas de la Membrana/genética , Enfermedades Musculares/tratamiento farmacológico , Mioblastos/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Sertralina/uso terapéutico , Animales , Línea Celular , Movimiento Celular , Proliferación Celular , Citalopram/farmacología , Citalopram/uso terapéutico , Drosophila/efectos de los fármacos , Drosophila/genética , Evaluación Preclínica de Medicamentos , Humanos , Ratones , Ratones Noqueados , Músculo Esquelético/metabolismo , Enfermedades Musculares/genética , Mutación , Mioblastos/metabolismo , Receptor Notch1/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Sertralina/farmacología , Transducción de Señal , Pez Cebra/genética , Pez Cebra/metabolismoRESUMEN
BACKGROUND: Maternofetal carnitine transport through the placenta is the main route of fetal carnitine uptake. Decreased free carnitine levels discovered by newborn screening has identified many asymptomatic adult women with systemic primary carnitine deficiency (PCD). Here, we presented amplitude integrated electroencephalogram (aEEG) and magnetic resonance imaging (MRI) findings from a neonate with epilepsy whose mother was carnitine deficient. CASE PRESENTATION: A one-day-old female newborn was admitted after experiencing seizures for half a day; status epilepticus was found on the continuous normal voltage background pattern with immature sleep-wake cycling during aEEG monitoring. On T1-weighted, T2-weighted, FLAIR, and DWI head MRI, there were various degrees of hyperintense signals and diffusion restrictions in the deep white matter of the right hemisphere. Tandem mass spectrometry discovered carnitine deficiency on the second day, which elevated to normal by the 9th day before L-carnitine supplementation was started. The patient was treated with phenobarbital after admission. No further seizures were noted by day 5. It was confirmed that the patient's mother had a low level of serum-free carnitine. Gene analyses revealed that the newborn had heterozygote mutations on c.1400C > G of the SLC22A5 gene, and her mother had homozygous mutations on c.1400C > G. The patient had a good outcome at the 8-month follow up. CONCLUSIONS: Maternal carnitine deficiency that occurs during the perinatal period may manifest as secondary epilepsy with cerebral injury in neonates. The short-term neurodevelopmental outcomes were good. Early diagnosis of asymptomatic PCD in female patients can provide guidance for future pregnancies.
Asunto(s)
Cardiomiopatías/complicaciones , Carnitina/deficiencia , Hiperamonemia/complicaciones , Enfermedades Musculares/complicaciones , Convulsiones/etiología , Encéfalo/diagnóstico por imagen , Cardiomiopatías/diagnóstico , Cardiomiopatías/genética , Carnitina/sangre , Carnitina/genética , Electroencefalografía , Femenino , Enfermedades Fetales/etiología , Humanos , Hiperamonemia/diagnóstico , Hiperamonemia/genética , Recién Nacido , Enfermedades del Recién Nacido/diagnóstico , Imagen por Resonancia Magnética , Madres , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/genética , MutaciónRESUMEN
WHAT IS KNOWN AND OBJECTIVE: SLCO1B1 T521>C variant carriers are susceptible to simvastatin-induced myopathy. We report a patient who developed rhabdomyolysis possibly triggered by a drug-drug and/or herb-drug interaction. CASE DESCRIPTION: A 69-year-old man presented with myalgia and weakness progressing to severe rhabdomyolysis. He had been taking 40 mg simvastatin daily for 10 years and recently consumed supplements, including Stevia rebaudiana and linagliptin. Genotyping revealed he carried one copy of SLCO1B1 T521>C and two copies of ABCG2 C421>A. WHAT IS NEW AND CONCLUSION: Despite apparent long-term safe administration, co-ingestion of simvastatin and other CYP3A4 inhibitors may result in severe myopathy in those at increased genetic risk.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Linagliptina/administración & dosificación , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Enfermedades Musculares/inducido químicamente , Enfermedades Musculares/genética , Polimorfismo de Nucleótido Simple/genética , Simvastatina/efectos adversos , Anciano , Inhibidores del Citocromo P-450 CYP3A/administración & dosificación , Interacciones Farmacológicas/genética , Interacciones de Hierba-Droga/genética , Humanos , Masculino , SteviaRESUMEN
3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are extremely well tolerated but are associated with a range of mild-to-moderate statin-associated muscle symptoms (SAMS). Estimates of SAMS incidence vary from <1% in industry-funded clinical trials to 10-25% in nonindustry-funded clinical trials and â¼60% in some observational studies. SAMS are important because they result in dose reduction or discontinuation of these life-saving medications, accompanied by higher healthcare costs and cardiac events. The mechanisms that produce SAMS are not clearly defined. Statins block the production of farnesyl pyrophosphate, an intermediate in the mevalonate pathway, which is responsible for the production of coenzyme Q10 (CoQ10). This knowledge has prompted the hypothesis that reductions in plasma CoQ10 concentrations contribute to SAMS. Consequently, CoQ10 is popular as a form of adjuvant therapy for the treatment of SAMS. However, the data evaluating the efficacy of CoQ10 supplementation has been equivocal, with some, but not all, studies suggesting that CoQ10 supplementation mitigates muscular complaints. This review discusses the rationale for using CoQ10 in SAMS, the results of CoQ10 clinical trials, the suggested management of SAMS, and the lessons learned about CoQ10 treatment of this problem.
Asunto(s)
Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Enfermedades Musculares/inducido químicamente , Enfermedades Musculares/tratamiento farmacológico , Ubiquinona/análogos & derivados , Suplementos Dietéticos , Metabolismo Energético/fisiología , Humanos , Músculo Esquelético/química , Enfermedades Musculares/genética , Mialgia/inducido químicamente , Mialgia/tratamiento farmacológico , Fosfatos de Poliisoprenilo/antagonistas & inhibidores , Polimorfismo de Nucleótido Simple , Sesquiterpenos/antagonistas & inhibidores , Ubiquinona/deficiencia , Ubiquinona/fisiología , Ubiquinona/uso terapéuticoRESUMEN
A detrimental consequence of hypermethylation is hyperhomocysteinemia (HHcy), that causes oxidative stress, inflammation, and matrix degradation, which leads to multi-pathology in different organs. Although, it is well known that hypermethylation leads to overall gene silencing and hypomethylation leads to overall gene activation, the role of such process in skeletal muscle dysfunction during HHcy condition is unclear. In this study, we emphasized the multiple mechanisms including epigenetic alteration by which HHcy causes skeletal muscle myopathy. This review also highlights possible role of methylation, histone modification, and RNA interference in skeletal muscle dysfunction during HHcy condition and potential therapeutic molecules, putative challenges, and methodologies to deal with HHcy mediated skeletal muscle dysfunction. We also highlighted that B vitamins (mainly B12 and B6), with folic acid supplementation, could be useful as an adjuvant therapy to reverse these consequences associated with this HHcy conditions in skeletal muscle. However, we would recommend to further study involving long-term trials could help to assess efficacy of the use of these therapeutic agents. J. Cell. Biochem. 118: 2108-2117, 2017. © 2017 Wiley Periodicals, Inc.