Variantes del gen GBA en el Suroccidente Colombiano / Variants of the GBA gene in the Southwest of Colombia

Introducción: La Enfermedad de Gaucher (EG) es un trastorno genético autosómico recesivo, causado por la deficiencia de la enzima B-Glucocerebrosidasa acida (GBA). En Colombia se ha estimado una prevalencia de 1:266.441 habitantes. Sin embargo, el país no cuenta con datos exactos sobre la incidencia, prevalencia y carga poblacional de esta enfermedad. Objetivo: Con el objetivo de caracterizar molecularmente las variantes encontradas en el gen GBA presentes en pacientes del Suroccidente Colombiano con enfermedad de Gaucher. Materiales y métodos: Se incluyeron 19 pacientes en el estudio, 57,8% de género masculino, con intérvalo de edad entre 4 y 71 años, diagnosticados clínica y enzimáticamente con EG. Se realizó un análisis molecular del gen GBA y posteriormente se buscaron las variantes en diferentes bases de datos poblacionales y clínicas; además se realizó análisis bioinformático para evaluar el posible impacto de las variantes de interés en la estructura y funcionalidad de la proteína. Resultados: Se encontraron 14/19 pacientes homocigotos; 4/19 heterocigotos compuestos y 1/19 heterocigotos). Se reportó la presencia de 7 variantes que codifican para 8 genotipos diferentes. El genotipo más frecuente es p.Asn409Ser/p.Asn409Ser (36%). De las 7 variantes encontradas, se reportó que específicamente p. Asn409Ser (10/23 alelos) y p.Leu483Pro (3/23 alelos) y p.Lys237Glu (3/23 alelos), están presentes en el 69,5% de los alelos. Todas las variantes presentaron una significancia clínica patogénica. Conclusiones: Este trabajo contribuye al establecimiento de las bases moleculares de la EG en los pacientes del Suroccidente Colombiano, permitiendo realizar una correlación genotipo-endotipo-fenotipo. Así mismo, se determina que los algoritmos de diagnóstico que incluyen análisis molecular y herramientas predictivas bioinformáticas permiten mejorar el diagnóstico, el tratamiento y el pronóstico de los pacientes afectados por EG, generando un impacto positivo en el seguimiento de los afectados, de la mano de una correcta consejería genética y estudios de portadores.

Introduction:Gaucher's disease (EG) is an autosomal recessive genetic disorder, caused by a deficiency of the acid B-Glucocerebrosidase (GBA) enzyme. In Colombia, a prevalence of 1: 266.441 inhabitants have been estimated. However, the country does not have exact data on the incidence, prevalence and population burden of this disease. Objective: molecularly characterize the variants found in the GBA gene present in patients from the Southwest of Colombia with Gaucher disease. Material and methods: 19 patients were included in the study, 57,8% male, with an age range between 4 and 71 years, clinically and enzymatically diagnosed with GD. A molecular analysis of the GBA gene was performed and the variants were subsequently searched in different population and clinical databases; In addition, a bioinformatic analysis was performed to evaluate the possible impact of the variants of interest on the structure and functionality of the protein. Results: 14/19 homozygous patients were found; 4/19 compound heterozygotes and 1/19 heterozygotes). The presence of 7 variants coding for 8 different genotypes was reported. The most frequent genotype was p.Asn409Ser/p.Asn409Ser (36%). Of the 7 variants found, it was reported that specifically p. Asn409Ser (10/23 alleles) and p.Leu483Pro (3/23 alleles) and p.Lys237Glu (3/23 alleles), are present in 69,5% of the alleles. All the variants presented a pathogenic clinical significance. Conclusion: This work contributes to the establishment of the molecular bases of GD in patients from the Southwest of Colombia, allowing a genotype-endotype-phenotype correlation to be carried out. Likewise, it is determined that diagnostic algorithms that include molecular analysis and bioinformatic predictive tools allow improving the diagnosis, treatment and prognosis of patients affected by GD, generating a positive impact on the follow-up of those affected, hand in hand with correct genetic counseling and carrier studies.

Glicogenoses: uma revisão geral / Glycogenoses: an overeview

Compreender o metabolismo dos diferentes tipos de glicogênio no organismo humano torna-se de suma importância, pois além da sua relevância no fornecimento energético e no controle da glicemia, o glicogênio pode estar relacionado com diversos tipos de doenças que comprometem a saúde do ser humano, especialmente pela deficiência em enzimas de vias anabólicas e catabólicas. Em um contexto de avanços no desenvolvimento de pesquisas relacionadas às áreas da saúde, uma série de estudos busca entender fisiologicamente os caminhos do glicogênio em situações de exercício, repouso, jejum, dentre outras, além de analisar os mais variados transtornos decorrentes da deficiência no metabolismo desse polissacarídeo. Um exemplo são as glicogenoses, doenças hereditárias, em sua maioria de caráter recessivo, relacionadas com o armazenamento de glicogênio. Dentre alguns dos treze tipos de glicogenoses podemos citar a glicogenose tipo 0, uma doença rara que se desenvolve na infância e implica na produção defeituosa da enzima glicogênio sintase; e a glicogenose tipo I, também conhecida como Doença de Von Gierke, que se caracteriza pela deficiência no complexo enzimático glicose-6-fosfatase, responsável pela catalisação da hidrólise de glicose-6-fosfato na metabolização do glicogênio. Apesar de todas essas doenças serem caracterizadas por glicogenoses, elas possuem diferenças quanto ao órgão afetado, à gravidade de suas manifestações, o perfil etário que cada uma atinge e no efeito enzimático. Por isso, a necessidade de estudos que correlacionam as principais causas e sintomas, e visam proporcionar uma visão global dessas desordens de hereditariedade.

The comprehension of the metabolism of different types of glycogen in the human organism becomes extremely important since, other than its relevance in providing energy and controlling glycemia, glycogen can be related to many types of diseases that compromise the human health, especially when it comes to the deficiency in enzyme anabolic and catabolic pathways. In the context of advances in the development of researches related of health area, many studies inquire a physiological understanding of the glycogen pathways exercising, resting, fasting and other conditions, as well as analyzing the most varied disorders arising from hereditary deficiencies in the carbohydrate metabolism, in polysaccharide specially. The glycogenoses are hereditary disorders, which present mainly recessive feature, related with the glycogen storage. Among the thirteen types of glycogenoses, type 0 is a rare disease that develops in early stages of life and implies in the production of defective glycogen synthase enzyme; and type I is characterized by the deficiency of the glucose-6-phosphatase enzyme complex, responsible for catalyzing the hydrolysis of glucose-6- phosphate in glycogen metabolism. Although all these diseases are characterized as being glycogenoses, they possess differences as to the organ affected, the gravity of their manifestations, the age it begins to manifest, and in which way it affects enzymatic properties. Therefore, there is a necessity of studies that correlates the main causes and symptoms, and aim to provide a global vision of these hereditary disorders.