Novel splice-affecting variants in CYP27A1 gene in two Chilean patients with Cerebrotendinous Xanthomatosis

Cerebrotendinous Xanthomatosis (CTX), a rare lipid storage disorder, is caused by recessive loss-of-function mutations of the 27-sterol hydroxylase (CYP27A1), producing an alteration of the synthesis of bile acids, with an accumulation of cholestanol. Clinical characteristics include juvenile cataracts, diarrhea, tendon xanthomas, cognitive impairment and other neurological manifestations. Early diagnosis is critical, because treatment with chenodeoxycholic acid may prevent neurological damage. We studied the CYP27A1 gene in two Chilean CTX patients by sequencing its nine exons, exon-intron boundaries, and cDNA from peripheral blood mononuclear cells. Patient 1 is a compound heterozygote for the novel substitution c.256-1G > T that causes exon 2 skipping, leading to a premature stop codon in exon 3, and for the previously-known pathogenic mutation c.1183C > T (p.Arg395Cys). Patient 2 is homozygous for the novel mutation c.1185-1G > A that causes exon 7 skipping and the generation of a premature stop codon in exon 8, leading to the loss of the crucial adrenoxin binding domain of CYP27A1

Rabdomiólisis metabólica: actualización

RESUMEN: La rabdomiólisis resulta de la destrucción del tejido muscular con liberación de sus componentes a la circulación sistémica, lo que puede ser potencialmente grave. Sus causas pueden ser adquiridas o hereditarias (genéticas-metabólicas), y según los mecanismos fisiopatológicos se han clasificado en causas metabólicas (falla en la producción de energía), estructurales (miopatías estructurales o distrofias), por alteración en la bomba de calcio y causas inflamatorias. Independiente de la causa de la rabdomiólisis, la vía final común es la injuria del sarcolema, ya sea por aumento del calcio intracelular o por falla de la producción de energía, lo que conduce a la necrosis de la fibra y, consecuentemente, la liberación a la circulación de electrolitos y proteínas intracelulares. Las anormalidades metabólicas más frecuentemente reportadas con rabdomiólisis son la deficiencia de Carnitina Palmitoil transferasa II (CPT II), defectos de glicólisis y recientemente se han descrito mutaciones en el gen de Lipina 1 (LPIN1). Ante un episodio de rabdomiólisis se deben descartar inicialmente trastornos adquiridos potencialmente tratables, para luego dar paso a estudios de miopatías estructurales o metabólicas. Respecto al manejo, en fase aguda tiene como objetivo preservar la función renal y restaurar anormalidades metabólicas, a través de un aporte precoz y adecuado de volumen, asegurando una adecuada diuresis, y en situaciones de acidosis o hiperkalemia extremas, debe considerarse la hemodiálisis o terapias de reemplazo renal continuas. Se debe tener en consideración, complicaciones graves en este cuadro clínico, como la coagulación intravascular diseminada y síndromes compartimentales que pueden requerir fasciotomías múltiples precoces. Específicamente, en mutaciones en gen de LPIN1, causantes de hasta el 50% de los episodios de rabdomiólisis en edad pediátrica, las estrategias terapéuticas deben ser dirigidas a la prevención y tratamiento precoz del catabolismo, a través del aporte de soluciones intravenosas con elevadas concentraciones de glucosa. ABSTRACT: Rhabdomyolysis results from the destruction of muscle tissue and the release of its components into the systemic circulation, which can be potentially serious. Causes can be acquired or hereditary (genetic-metabolic), and according to the pathophysiological mechanisms have been classified into metabolic causes (failure in the production of energy), structural (structural myopathies or dystrophies), by abnormalities in the calcium pump and inflammatory causes. Regardless of the cause of rhabdomyolysis, the common final mechanism is the sarcolemma injury, either by increased intracellular calcium or by failure of energy production, which leads to fiber necrosis and, consequently, the release to the circulation of electrolytes and intracellular proteins. Metabolic abnormalities most frequently reported with rhabdomyolysis are Carnitine palmitoyltransferase II deficiency (CPT II), glycolysis defects, and mutations in the Lipin 1 gene (LPIN1), which have been described recently. Under an episode of rhabdomyolysis, potentially treatable acquired disorders should be ruled out initially, and then studies of structural or metabolic myopathies should be carried out. Regarding management, in acute phase aims to preserve renal function and restore metabolic abnormalities, through an early and adequate volume, ensuring adequate diuresis, and in situations of extreme acidosis or hyperkalemia, should be considered hemodialysis or therapies of continuous renal replacement. Consideration should be given to serious complications in this clinical picture, such as disseminated intravascular coagulation and compartment syndromes that may require early multiple fasciotomies. Specifically, in mutations in the gene of LPIN1, which cause up to 50% of episodes of rhabdomyolysis in the pediatric age, therapeutic strategies should be directed to the prevention and early treatment of catabolism, through the use of intravenous solutions with high concentrations of glucose. Palabras clave: Miopatías metabólicas, rabdomiólisis, Keywords: Metabolic myopathies, rhabdomyolysi

Miopatías metabólicas

RESUMEN: Las miopatías metabólicas son enfermedades que afectan el músculo esquelético. Son causadas por deficiencias enzimáticas genéticamente determinadas, que afectan el metabolismo del glicógeno, de los lípidos, de la cadena respiratoria mitocondrial o de las purinas.Las manifestaciones clínicas son variables desde síntomas permanentes como la debilidad progresiva; síntomas episódicos como la intolerancia al ejercicio, mialgias y/o mioglobinuria; o en la combinación de síntomas episódicos y permanentes.En este espectro de síntomas, la insuficiencia respiratoria y la insuficiencia renal aguda producto de una rabdomiólisis masiva representan los cuadros de mayor severidad.El diagnóstico de este grupo heterogéneo de enfermedades se basa en la historia clínica, con la búsqueda dirigida de síntomas y potenciales desencadenantes de ellos, así como en la historia familiar en busca de consanguinidad y/o de síntomas relacionados en otros miembros de la familia.El examen clínico en busca de debilidad generalizada o localizada (compromiso selectivo de algunos grupos musculares), hipertrofia muscular, o anormalidades en la relajación del músculo pueden orientar, aunque la ausencia de hallazgos relevantes al examen no excluye la posibilidad de una miopatía metabólica.La caracterización de síntomas, antecedentes familiares y hallazgos del examen guía el estudio, el cual incluye exámenes básicos como al creatinkinasa, búsqueda de rabdomiólisis, así como estudios de compromiso sistémico finalizando habitualmente en estudio genético molecular.Desde el punto de vista terapéutico evitar desencadenantes, asegurar aporte de glucosa en situaciones de sobreexigencia metabólica al músculo, prevención y manejo e la insuficiencia renal asociada a rabdomiolisis y en algunos casos reemplazo de la enzima deficiente deben plantearse muy precozmente a fin de evitar mayor morbilidad. ABSTRACT: Metabolic myopathies are diseases that involve the skeletal muscle. They are caused by genetically determined enzymatic deficiencies that affect the metabolism of glycogen, lipids, mitochondrial respiratory chain or purines.The clinical manifestations are variable from permanent symptoms such as progressive weakness; episodic symptoms such as exercise intolerance, myalgia and/or myoglobinuria; or in the combination of episodic and permanent symptoms.In this spectrum of symptoms, respiratory failure and acute renal failure due to massive rhabdomyolysis represent the most severe cases.The diagnosis of this heterogeneous group of illness based on the clinical history, with the directed search of symptoms and potential triggers of them, as well as in the family history in search of consanguinity and/or of related symptoms in other members of the family.The clinical examination in search of generalized or localized weakness (selective involvement of some muscle groups), muscle hypertrophy, or abnormalities in muscle relaxation may help; although the absence of findings relevant to the examination does not exclude the possibility of a metabolic myopathy.The characterization of symptoms, family history and findings of the study guide the study, which includes basic tests such as creatinkinase, search for rhabdomyolysis, as well as systemic commitment studies usually ending in molecular genetic study.From the therapeutic point of view, avoid triggers, ensure glucose intake in situations of metabolic over-exertion to the muscle, prevention and management of renal failure associated with rhabdomyolysis and in some cases replacement of the deficient enzyme should be considered very early in order to avoid greater morbidity. Palabras clave: Miopatías metabólicas, trastornos de metabolismo del glicógeno, trastornos del metabolismo de los lípidos, miopatías mitocondriales, Keywords: Metabolic myopathies, glycogen storage disease, lipid metabolism diseases, mitochondrial myopathie

Trace Elements Induce Predominance among Methanogenic Activity in Anaerobic Digestion

Trace elements play an essential role in all organisms due to their functions in enzyme complexes. In anaerobic digesters, control and supplementation of trace elements lead to stable and more efficient methane production processes while trace element deficits cause process imbalances. However, the underlying metabolic mechanisms and the adaptation of the affected microbial communities to such deficits are not yet fully understood. Here, we investigated the microbial community dynamics and resulting process changes induced by trace element deprivation. Two identical lab-scale continuous stirred tank reactors fed with distiller’s grains and supplemented with trace elements (cobalt, molybdenum, nickel, tungsten) and a commercial iron additive were operated in parallel. After 72 weeks of identical operation, the feeding regime of one reactor was changed by omitting trace element supplements and reducing the amount of iron additive. Both reactors were operated for further 21 weeks. Various process parameters (biogas production and composition, total solids and volatile solids, trace element concentration, volatile fatty acids, total ammonium nitrogen, total organic acids/alkalinity ratio, and pH) and the composition and activity of the microbial communities were monitored over the total experimental time. While the methane yield remained stable, the concentrations of hydrogen sulfide, total ammonia nitrogen, and acetate increased in the trace element-depleted reactor compared to the well-supplied control reactor. Methanosarcina and Methanoculleus dominated the methanogenic communities in both reactors. However, the activity ratio of these two genera was shown to depend on trace element supplementation explainable by different trace element requirements of their energy conservation systems. Methanosarcina dominated the well-supplied anaerobic digester, pointing to acetoclastic methanogenesis as the dominant methanogenic pathway. Under trace element deprivation, Methanoculleus and thus hydrogenotrophic methanogenesis was favored although Methanosarcina was not overgrown by Methanoculleus. Multivariate statistics revealed that the decline of nickel, cobalt, molybdenum, tungsten, and manganese most strongly influenced the balance of mcrA transcripts from both genera. Hydrogenotrophic methanogens seem to be favored under nickel- and cobalt-deficient conditions as their metabolism requires less nickel-dependent enzymes and corrinoid cofactors than the acetoclastic and methylotrophic pathways. Thus, trace element supply is critical to sustain the activity of the versatile high-performance methanogen Methanosarcina

Transaminases increase: A manifestation of Duchenne's muscular dystrophy Aumento de transaminasas: Una manifestación de distrofia muscular de Duchenne

Commonly used in clinical practice, glutamic oxalacetic (GOT) and glutamic piruvic (GPT) transaminases are produced in various body tissues, including striated muscle, so their blood elevation is not due exclusively to liver disease. The objective of this study is to demonstrate the correlation between elevated creatinkinase (CK) and transaminases in patients with diagnosis of Duchenne muscular dystrophy (DMD), the most frequent neuromuscular disease in children. Patients and Method: Assessment in 61 children with diagnosis of DMD of CK, AST and ALT levels, and their correlation. Results: All patients had increase of CK (x̄ = 13.363 IU/L), AST (x̄ = 203 IU/L) and ALT (x̄ = 194 IU/L) above normal values. The increase of transaminases related directly with the increase of CK. Conclusion: Patients with DMD have increased transaminases, so it is necessary to include this diagnostic possibility in a child with hypertransaminemia, prior to performing liver biopsy

Transaminases increase: a manifestation of Duchenne’s muscular dystrophy

Los autores de este artículo pretenden demostrar la correlación entre el alza de la creatinkinasa (cK) y transaminasas en pacientes con el diagnóstico de distrofia muscular de Duchenne (DMD), la enfermedad neuromuscular más frecuente en niños

Management of pediatric status epilepticus Revisión del estado epileptic convulsivo pediátrico y su manejo antiepiléptico

© 2016, Sociedad Medica de Santiago. All right reserved.Pediatric Status Epilepticus (SE) is an emergency situation with high morbidity and mortality that requires early and aggressive management. The minimum time criterion to define SE was reduced from 30 to 5 minutes, defined as continuous seizure activity or rapidly recurrent seizures without resumption of consciousness for more than 5 minutes. This definition considers that seizures that persist for > 5 minutes are likely to do so for more than 30 min. Those that persist for more than 30 minutes are more difficult to treat. Refractory SE is the condition that extends beyond 60-120 minutes and requires anesthetic management. Super-refractory SE is the state of no response to anesthetic management or relapse during withdrawal of these drugs. The aim of this review is to provide and update on convulsive SE concepts, pathophysiology, etiology, available antiepileptic treatment and propose a rational management scheme. A literature sea

Novel splice-affecting variants in CYP27A1 gene in two Chilean patients with Cerebrotendinous Xanthomatosis

Artículo de publicación ISICerebrotendinous Xanthomatosis (CTX), a rare lipid storage disorder, is caused by recessive loss-of-function mutations of the 27-sterol hydroxylase (CYP27A1), producing an alteration of the synthesis of bile acids, with an accumulation of cholestanol. Clinical characteristics include juvenile cataracts, diarrhea, tendon xanthomas, cognitive impairment and other neurological manifestations. Early diagnosis is critical, because treatment with chenodeoxycholic acid may prevent neurological damage. We studied the CYP27A1 gene in two Chilean CTX patients by sequencing its nine exons, exon-intron boundaries, and cDNA from peripheral blood mononuclear cells. Patient 1 is a compound heterozygote for the novel substitution c.256-1G > T that causes exon 2 skipping, leading to a premature stop codon in exon 3, and for the previously-known pathogenic mutation c.1183C > T (p.Arg395Cys). Patient 2 is homozygous for the novel mutation c.1185-1G > A that causes exon 7 skipping and the generation of a premature stop codon in exon 8, leading to the loss of the crucial adrenoxin binding domain of CYP27A1