Abstract
Background The objective of this review is to unify the various genetic defects along with elaborating metabolic pathways in Familial Combined Hyperlipidemia(FCHL) and also to differentiate the phenotype of FCHL from metabolic syndrome. Methods PubMed and Cochrane’s library was searched for keyword “Familial combined hyperlipidemia” and latter with “Familial combined hyperlipidemia genes” to finally shortlist 23 articles. Further search with key words “molecular pathogenesis of familial combined hyperlipidemia” and “metabolic syndrome and familial combined hyperlipidemia” was carried out for finding molecular defects in FCHL, non-molecular findings distinguishing FCHL from metabolic syndrome and overlapping features between FCHL and metabolic syndrome. Results Major culprit regions identified included Chromosome-1q21-q24(USF1 and FOXA2) , Ch-11q (APOA5), Ch-16q24, Ch-20q12-q13.1, Ch.4q32.3 (rs6829588), and Ch-19q13.32 containing PVRL-2 gene (Also known as Nectin-2). The genetic and metabolic pathways linked to FCHL may involve: 1-Defective clearance of Apo-B containing lipoproteins, 2-Overproduction of Apo-B containing lipoprotein i.e., VLDL and 3-Adipose tissue dysfunction. FCHL phenotype showed close resemblance with metabolic syndrome clinical and biochemical features with slight differences. Conclusion The reviewed data suggested that FCHL phenotype is the resultant end outcome from multiple molecular defects and thus underlying genetic defect identification in the index case is important for personalized medicine and incoming gene therapy. Further research is warranted to explore specific genetic defects.
Highlights
[1] Apparently the available data on the subjects suggests the significantly heterogeneous Familial Combined Hyperlipidemia (FCHL) genetics, extremely high risk of premature coronary artery disease (CAD), hypertriglyceridemia related disorders, and relationship with other metabolic disorders like insulin resistance. [2, 3] Unmet need must be acknowledged on its impact on health economy in terms of this being the most frequent lipid disorder, loss of productive technical man hours, family crises emerging from premature morbidity and mortality and linkage or lead to newer metabolic disorders. [4]
The genetic and metabolic pathways linked to FCHL may involve: 1-Defective clearance of Apo-B containing lipoproteins, 2-Overproduction of ApoB containing lipoprotein i.e., VLDL and 3-Adipose tissue dysfunction
The reviewed data suggested that FCHL phenotype is the resultant end outcome from multiple molecular defects and underlying genetic defect identification in the index case is important for personalized medicine and incoming gene therapy
Summary
Familial Combined Hyperlipidemia (FCHL) supersedes most other genetic lipid and non-lipid disorders in most of the shared scientific evidence with disease prevalence ranging from 1% to 2.5% in different parts of the globe. [1] Apparently the available data on the subjects suggests the significantly heterogeneous FCHL genetics, extremely high risk of premature coronary artery disease (CAD), hypertriglyceridemia related disorders, and relationship with other metabolic disorders like insulin resistance. [2, 3] Unmet need must be acknowledged on its impact on health economy in terms of this being the most frequent lipid disorder, loss of productive technical man hours, family crises emerging from premature morbidity and mortality and linkage or lead to newer metabolic disorders. [4]FCHL is not a singular entity in pathology or a monogenic genetic disorder. [1] Apparently the available data on the subjects suggests the significantly heterogeneous FCHL genetics, extremely high risk of premature coronary artery disease (CAD), hypertriglyceridemia related disorders, and relationship with other metabolic disorders like insulin resistance. [7] literature search converges to a few common traits which may help elucidate a criteria for nominating a person with FCHL These criteria includes: 1- Strong family history (at least 2 members from one family), 2- Variable lipid abnormalities including combined hyperlipidemia or hypercholesterolemia or hypertriglyceridemia all shaping in different dimension over a person’s life, 3- Autosomal dominant pattern of inheritance with high penetrance, 4- Dermatological manifestations like xanthomas are rare unlike familial hypercholesterolemia and 5- Strong predisposition to early onset coronary artery disease (CAD). The objective of this review is to unify the various genetic defects along with elaborating metabolic pathways in Familial Combined Hyperlipidemia(FCHL) and to differentiate the phenotype of FCHL from metabolic syndrome
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