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Hipocolesterolemias: síndrome de Smith-Lemli-Opitz, uma revisão narrativa
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| Projeto de pós-graduação_42290 | 1.22 MB | Adobe PDF |
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Abstract(s)
As hipocolesterolemias, contrariamente às hipercolesterolemias, constituem um grupo heterogéneo de patologias ainda pouco conhecido associado a uma elevada morbilidade, sendo, por conseguinte, necessário aprofundar o seu estudo para que o respetivo diagnóstico e tratamento possam ser melhorados. Nos doentes com comprometimento da biossíntese do colesterol, há um desenvolvimento embrionário anormal, o qual leva ao aparecimento de diversas características fenotípicas ainda no período pré-natal, uma vez que a passagem do colesterol através da barreira placentária é limitada. O processo patológico subjacente à carência em colesterol decorre como consequência do bloqueio da via metabólica responsável pela sua síntese.
Apesar de pouco conhecidas, estão presentemente descritas dez doenças genéticas afetando a parte distal da via metabólica da biossíntese deste esterol, a mais frequente das quais é a síndrome de Smith-Lemli-Opitz (SLOS), causada pelo défice da enzima 7-dehidrocolesterol redutase, que catalisa a conversão de 7-dehidrocolesterol a colesterol. O espetro fenotípico da SLOS é muito amplo, variando desde uma doença leve com problemas comportamentais e de aprendizagem a uma síndrome de malformações letais, sendo que as características clínicas mais frequentes são sindactilia do segundo e terceiro dedos dos pés, microcefalia, retrognatismo, narinas antevertidas, entre outras.
Este trabalho tem como objetivos uma revisão bibliográfica atual sobre as hipocolesterolemias, tendo como foco principal a SLOS, a importância do diagnóstico dos défices da biossíntese do colesterol e os potenciais tratamentos.
Este estudo permitiu comprovar que o diagnóstico ainda é um desafio, por existirem outras síndromes que compartilham algumas características clínicas da SLOS. No entanto, a sindactilia do segundo e terceiro dedos em forma de Y, presente na maioria dos indivíduos com SLOS, raramente é observada noutros distúrbios. Concluiu-se que atualmente não há tratamento comprovadamente eficaz para pacientes com SLOS; a suplementação dietética de colesterol e a terapia com estatinas são discutidas de forma controversa. O ácido cólico pode ser benéfico por melhorar a absorção de colesterol, mas não é suficiente para reverter a patologia.
A utilização de miglustato (aprovado pela FDA como Zavesca®), um fármaco de iminoaçúcar que inibe a glucosilceramida sintase, tem sido considerada como terapia, pelo potencial de tratar anormalidades associadas ao sistema nervoso central presentes na SLOS. A suplementação com antioxidantes, como a vitamina E, demonstrou igualmente inibir a formação de oxiesterois derivados de 7-dehidrocolesterol em fibroblastos de pacientes com SLOS, alguns dos quais são altamente tóxicos para as células e podem contribuir para a fisiopatologia da doença. Contudo, é crucial a continuidade da investigação científica sobre os benefícios dos tratamentos.
Hypocholesterolemias, unlike hypercholesterolemias, are a heterogeneous group of pathologies that are still poorly understood and associated with high morbidity. It is, therefore, necessary to study them further in order to improve their diagnosis and treatment. In patients with impaired cholesterol biosynthesis, there is an abnormal embryonic development, which leads to the appearance of several phenotypic characteristics even in the prenatal period, since the passage of cholesterol through the placental barrier is limited. The pathological process underlying cholesterol deficiency occurs as a result of the blockage of the metabolic pathway responsible for its synthesis. Although little known, ten genetic diseases affecting the distal part of the metabolic pathway of this sterol biosynthesis are currently described, the most common of which is Smith-Lemli-Opitz syndrome (SLOS), caused by a deficit of the enzyme 7-dehydrocholesterol reductase, which catalyzes the conversion of 7-dehydrocholesterol to cholesterol. The phenotypic spectrum of SLOS is very broad, ranging from a mild illness with behavioral and learning problems to a syndrome of lethal malformations. The most frequent clinical features are syndactyly of the second and third toes, microcephaly, retrognathism, anteverted nares, among others. The aim of this study is to review the current literature on hypocholesterolemia, focusing mainly on SLOS, the importance of diagnosing deficits in cholesterol biosynthesis, and potential treatments. This study showed that diagnosis is still a challenge, as there are other syndromes that share some of the clinical characteristics of SLOS. However, the Y-shaped syndactyly of the second and third fingers, present in most individuals with SLOS, is rarely observed in other disorders. It was concluded that there is currently no proven effective treatment for patients with SLOS; dietary cholesterol supplementation and statin therapy are controversially discussed. Cholic acid can be beneficial by improving cholesterol absorption, but it is not sufficient to reverse the pathology. The use of miglustat (FDA-approved as Zavesca®), an iminosugar drug that inhibits glucosylceramide synthase, has been considered as a therapy due to its potential to treat central nervous system-associated abnormalities present in SLOS. Supplementation with antioxidants such as vitamin E has also been shown to inhibit the formation of oxysterols derived from 7-dehydrocholesterol in fibroblasts from patients with SLOS, some of which are highly toxic to cells and may contribute to the pathophysiology of the disease. However, further scientific research into the benefits of treatments is crucial.
Hypocholesterolemias, unlike hypercholesterolemias, are a heterogeneous group of pathologies that are still poorly understood and associated with high morbidity. It is, therefore, necessary to study them further in order to improve their diagnosis and treatment. In patients with impaired cholesterol biosynthesis, there is an abnormal embryonic development, which leads to the appearance of several phenotypic characteristics even in the prenatal period, since the passage of cholesterol through the placental barrier is limited. The pathological process underlying cholesterol deficiency occurs as a result of the blockage of the metabolic pathway responsible for its synthesis. Although little known, ten genetic diseases affecting the distal part of the metabolic pathway of this sterol biosynthesis are currently described, the most common of which is Smith-Lemli-Opitz syndrome (SLOS), caused by a deficit of the enzyme 7-dehydrocholesterol reductase, which catalyzes the conversion of 7-dehydrocholesterol to cholesterol. The phenotypic spectrum of SLOS is very broad, ranging from a mild illness with behavioral and learning problems to a syndrome of lethal malformations. The most frequent clinical features are syndactyly of the second and third toes, microcephaly, retrognathism, anteverted nares, among others. The aim of this study is to review the current literature on hypocholesterolemia, focusing mainly on SLOS, the importance of diagnosing deficits in cholesterol biosynthesis, and potential treatments. This study showed that diagnosis is still a challenge, as there are other syndromes that share some of the clinical characteristics of SLOS. However, the Y-shaped syndactyly of the second and third fingers, present in most individuals with SLOS, is rarely observed in other disorders. It was concluded that there is currently no proven effective treatment for patients with SLOS; dietary cholesterol supplementation and statin therapy are controversially discussed. Cholic acid can be beneficial by improving cholesterol absorption, but it is not sufficient to reverse the pathology. The use of miglustat (FDA-approved as Zavesca®), an iminosugar drug that inhibits glucosylceramide synthase, has been considered as a therapy due to its potential to treat central nervous system-associated abnormalities present in SLOS. Supplementation with antioxidants such as vitamin E has also been shown to inhibit the formation of oxysterols derived from 7-dehydrocholesterol in fibroblasts from patients with SLOS, some of which are highly toxic to cells and may contribute to the pathophysiology of the disease. However, further scientific research into the benefits of treatments is crucial.
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Keywords
Síntese de colesterol Erro inato Hipocolesterolemias Défice enzimático Síndrome de Smith-Lemli-Opitz Cholesterol synthesis Inborn error Hypocholesterolemias Enzyme deficiency Smith-Lemli-Opitz syndrome