RESUMO
Lynch syndrome (LS) is an autosomal dominant cancer-susceptibility disease caused by inactivating germline mutations in mismatch repair (MMR) genes. Variants of unknown significance (VUS) are often detected in mutational analysis of MMR genes. Here we describe a large family fulfilling Amsterdam I criteria carrying two rare VUS in the MLH1 gene: c.121G > C (p.D41H) and c.2128A > G (p.N710D). Collection of clinico-pathological data, multifactorial analysis, in silico predictions, and functional analyses were used to elucidate the clinical significance of the identified MLH1 VUS. Only the c.121G > C variant cosegregated with LS-associated tumors in the family. Diagnosed colorectal tumors were microsatellite unstable although immunohistochemical staining revealed no loss of MMR proteins expression. Multifactorial likelihood analysis classified c.2128A > G as a non-pathogenic variant and c.121G > C as pathogenic. In vitro functional tests revealed impaired MMR activity and diminished expression of c.121G > C. Accordingly, the N710 residue is located in the unconserved MLH1 C-terminal domain, whereas D41 is highly conserved and located in the ATPase domain. The obtained results will enable adequate genetic counseling of c.121G > C and c.2128A > G variant carriers and their families. Furthermore, they exemplify how cumulative data and comprehensive analyses are mandatory to refine the classification of MMR variants.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Expressão Gênica , Variação Genética , Proteínas Nucleares/genética , Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Idade de Início , Substituição de Aminoácidos , Sítios de Ligação , Códon , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Família , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Proteína 1 Homóloga a MutL , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Linhagem , Conformação Proteica , Domínios e Motivos de Interação entre ProteínasRESUMO
El 15% de las personas mayores de 65 años sufre disfagiay la prevalencia en residencias geriátricas (RG) se estimaen un 40%. Objetivos: conocer la prevalencia de ancianoscon disfagia en RG de Barcelona y describir el estadofuncional (físico y psíquico), edad, sexo, patologías, fármacosque inciden en la posible aparición de la disfagia yvalorar las medidas dietéticas adoptadas por las RG parael manejo de la disfagia. Métodos: se han estudiado1.777 residentes de 66 RG valorados por la Unidad deAtención Domiciliaria Geriátrica (UADG) hasta septiembrede 2008. El estudio se realiza mediante un cuestionarioelaborado por la UADG asesorado por NestléNutrition. Resultados: el perfil de las personas con disfagiaes de mujeres mayores de 85 años con dependenciafísica importante y deterioro cognitivo severo. La mitadpresenta algún tipo de demencia. La prevalencia de disfagiaes del 5,40%. La disfagia a líquidos es del 88,52%. Lautilización de espesantes comerciales es reducida. La prevalenciade disfagias a texturas mixtas es del 76,03%. Ladieta triturada se da en el 79,16%. Utiliza dieta adecuadael 87,5%. La disfagia sólo consta en la historia clínica enel 13,54%. Conclusiones: la disfagia debe quedar reflejadaen la historia clínica. El personal de las RG necesitaformación para reconocer los signos de alerta indicativosde disfagia. Las medidas dietéticas son fundamentales (AU)
15% of people over 65 suffer dysphagia and prevalence ingeriatric residences (GR) is estimated at 40%. Objectives:to determine the prevalence of dysphagia in elderly in GRat Barcelona and to describe the functional status (physicaland mental), age, sex, diseases, drugs that affect the possibleoccurrence of dysphagia and to assess dietary measurestaken by the GR to management of dysphagia. Methods:we studied 1.777 residents of 66 GR, assessed by the GeriatricHome Care Unit (UADG) until September 2008.The study was conducted by questionnarie prepared by theUADG, advised by Nestlé Nutrition. Results: the profile ofpeople with dysphagia are women over age 85 with significantphysical dependence and severe cognitive impairment.Half have some form of dementia. The prevalence ofdysphagia is 5.40%. Dysphagia to liquids is 88.52%. Theuse of commercial thickeners is reduced. The prevalence ofmixed textures dysphagia is 76.03%. The crushed diet isgiven in 79.16%. They use proper diet 87.5%. Dysphagiais only recorded in history at 13.54%. Conclusions:dysphagia should be reflected in the history. The GR staffneed training to recognize the warning signs suggestive ofdysphagia. Dietary measures are essential (AU)