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O impacto das variações genéticas no diagnóstico e tratamento da hipercolesterolemia familiar
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A hipercolesterolemia familiar (HF) é uma doença monogénica com uma prevalência de cerca de 1 em cada 311 indivíduos, que resulta em níveis plasmáticos de colesterol de lipoproteínas de baixa densidade (LDL) elevados ao longo da vida e com risco acrescido de doença cardiovascular aterosclerótica prematura (DCVA). Apesar desta prevalência a doença tem uma taxa de diagnóstico de 2.1% na infância ou adolescência, o que leva a HF não diagnosticada e que pode ser responsável por 1 em cada 10 enfartes do miocárdio antes dos 50 anos (Dharmayat et al., 2024).
Este estudo visa rever as principais mutações do gene LDLR e outras alterações genéticas associadas à hipercolesterolemia familiar, analisando terapêuticas atuais e emergentes, e identificando potenciais marcadores para um diagnóstico mais preciso.
A HF é causada por mutações nos genes que codificam o recetor LDL (LDLR), a apolipoproteína B (APOB), e a proproteína convertase subtilisina/kexina tipo 9 (PCSK9) (Beheshti et al., 2020).
Na HF, os indivíduos homozigóticos (HoHF), apesar de ser uma doença Autossómica Dominante, existe uma forma rara de hereditariedade Autossómica Recessiva em indivíduos que têm a mutação no gene LDLRAP1, no qual a mutação deste afeta a capacidade de ligação da LDLRAP1 e em que impede a síntese do LDLR (McGowan et al., 2019). No entanto, os indivíduos heterozigóticos em HF (HeHF) têm maior prevalência, o que o que a torna uma das doenças hereditárias mais prevalentes e subdiagnosticadas (Abifadel &; Boileau, 2023).
Atualmente, o diagnóstico consiste, em grande parte, questionar os doentes se tem antecedentes familiares que apresentam valores elevados de colesterol (Timoshchenko et al., 2024). O diagnóstico mais correto seria fazer uma análise ao perfil genético, ainda pouco implementado ou apenas usado em casos específicos.
O estudo evidenciou a necessidade de reformular a abordagem ao diagnóstico da HF, promovendo uma maior implementação de testes genéticos e do diagnóstico em cascata, de modo a identificar mutações associadas, otimizar o tratamento e reduzir custos em saúde.
Familial hypercholesterolemia (HF) is a monogenic disease with a prevalence of 1 in every 311 individuals, which results in high levels of low-density lipoproteins cholesterol (LDL) throughout the lifespan with the increased risk of developing premature atherosclerotic cardiovascular disease (DVCA). Despite of this prevalence the disease has a diagnosis rate about 2.1% in childhood or adolescence, which takes to undiagnosed HF and can be responsible for 1 in 10 myocardial infarctions before the age of 50 (Dharmayat et al., 2024). The objective of this study is to revise the literature about low density lipoprotein receptor (LDLR) gene mutations and other familial hypercholesterolemia (HF) genetic alterations. HF mutations are caused in genes that code LDL receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9) (Beheshti et al., 2020). Homozygotic individuals in HF (HoHF), although being a Dominant Autosomal Disease, there is a rare hereditary Recessive Autosomal form in individuals with LDLRAP1 gene mutation, in which this mutation affects the binding capacity of LDLRAP1 and prevents LDLR synthesis (McGowan et al., 2019). However, heterozygotic individuals in HF (HeHF) have higher prevalence, which makes one of the most underdiagnosed common hereditary diseases (Abifadel & Boileau, 2023a). Now, the diagnosis consists of, at the majority, in questioning patients about family backgrounds with high levels of cholesterol (Timoshchenko et al., 2024). The best approach would be genetic profile analysis, something that has a low implementation or is used in specific cases. This study has shown that it is necessary to change the approach to diagnosing HF, by implementing more widespread genetic testing and subsequently cascade diagnostics, to identify mutations in HF and to achieve effective health savings and appropriate treatment for the patient.
Familial hypercholesterolemia (HF) is a monogenic disease with a prevalence of 1 in every 311 individuals, which results in high levels of low-density lipoproteins cholesterol (LDL) throughout the lifespan with the increased risk of developing premature atherosclerotic cardiovascular disease (DVCA). Despite of this prevalence the disease has a diagnosis rate about 2.1% in childhood or adolescence, which takes to undiagnosed HF and can be responsible for 1 in 10 myocardial infarctions before the age of 50 (Dharmayat et al., 2024). The objective of this study is to revise the literature about low density lipoprotein receptor (LDLR) gene mutations and other familial hypercholesterolemia (HF) genetic alterations. HF mutations are caused in genes that code LDL receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9) (Beheshti et al., 2020). Homozygotic individuals in HF (HoHF), although being a Dominant Autosomal Disease, there is a rare hereditary Recessive Autosomal form in individuals with LDLRAP1 gene mutation, in which this mutation affects the binding capacity of LDLRAP1 and prevents LDLR synthesis (McGowan et al., 2019). However, heterozygotic individuals in HF (HeHF) have higher prevalence, which makes one of the most underdiagnosed common hereditary diseases (Abifadel & Boileau, 2023a). Now, the diagnosis consists of, at the majority, in questioning patients about family backgrounds with high levels of cholesterol (Timoshchenko et al., 2024). The best approach would be genetic profile analysis, something that has a low implementation or is used in specific cases. This study has shown that it is necessary to change the approach to diagnosing HF, by implementing more widespread genetic testing and subsequently cascade diagnostics, to identify mutations in HF and to achieve effective health savings and appropriate treatment for the patient.
Descrição
Dissertação para obtenção do grau de Mestre no Instituto Universitário Egas Moniz
Palavras-chave
Hipercolesterolemia familiar Recetor LDL APOB PCSK9 Aterosclerose HF Homozigótica HF Heterozigótica