Discuss about the Autosomal Recessive Familial Hypercholesterolemia.
Familial hypercholesterolemia is a genetically acquired disease that is characterized by elevated levels of serum cholesterol although in most cases, triglyceride levels are within the normal range(Tada et al., 2015). Cholesterol is a fat-like and waxy substance that can be obtained from exogenous sources such as foods products from animals mainly meat, dairy products, egg yolks, and fish (Pusey, 2006). However, due to endogenous mechanisms, the body produces cholesterol through the gastrointestinal food metabolism (Clifton et al., 2014). Cholesterol plays a significant role in the body’s physiology and anatomy. It is essential in the processing of several hormones, building cell membranes, and producing compounds that facilitate lipolysis (Sherwood, 2015). In contrast, extreme elevation of cholesterol in the bloodstream contributes to the elevation of low-density lipoprotein cholesterol (LDL-C) commonly known as bad cholesterol. Consequently, high levels of LDL-C is attributed to the deposition of cholesterol on the arterial walls particularly the coronary arteries thus increasing the risk for accelerated atherosclerosis and cardiovascular disease (CVD)(Alallaf et al., 2017). In addition, inherited hypercholesterolemia causes excess systemic cholesterol buildup. For instance, tendon xanthomas result from the accumulation of cholesterol in the tendons while cholesterol deposits under the eyelids skin and in the cornea result in xanthelasmata and arcus cornealis respectively(Tada et al., 2015). This defects show the grave importance of analyzing the pathophysiology of familial hypercholesterolemia.
As a primary cause of inherited high cholesterol, familial hypercholesterolemia results from the mutation of the LDLR gene which is responsible for the synthesis of the low-density lipoprotein receptor (Di Taranto et al., 2015) .The latter plays a vital role in the clearance of cholesterol from the bloodstream since the receptor binds to the low-density lipoproteins (LDLs) which serve as cholesterol carriers (Tada et al., 2015). Ultimately, the removal of the LDLs from the blood acts as a homeostatic mechanism for the apparent regulation of cholesterol level. However, as previously stated, mutations in the LDLR genes lower the number of LDL receptors as well as disrupt the process of LDL removal from the bloodstream leading to the accumulation of cholesterol (Santos et al, 2016).Besides LDLR, other gene mutations that have implicated in familial hypercholesterolemia include alteration in the low-density lipoprotein receptor adaptor protein 1(LDLRAP1). Also, Apolipoprotein B (APOB) and Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) genes leading to the broader classification of the inherited hypercholesterolemia disorders(Santos et al, 2016) .Autosomal recessive hypercholesterolemia (ARH) is a rare defect where a person is born with two muted copies of the LDLRAP1 gene in each cell. LDLRAP1 is a gene that encodes Apolipoprotein A (APOA), a specific clathrin adaptor protein(Tada et al., 2015) .However, patients with ARH carry two defective alleles of the gene resulting in the inability to internalize the LDL receptor(Alallaf et al., 2017).
Globally, autosomal recessive hypercholesterolemia has rarely occurred in comparison to the autosomal dominant familial hypercholesterolemia (Gidding et al., 2015). The latter is relatively common since heterozygous carriers of the defective genes are clinically affected with an estimate of the two-fold increase in average levels of serum cholesterol with ranges of 250-450 mg/dL or 6.5-11.6 mmol/L(Alallaf et al., 2017).On the other hand, autosomal recessive hypercholesterolemia has severe clinical manifestations with an approximate four-to-fivefold elevation of normal cholesterol to above 400mg/dL(Tada et al., 2015) .Due to its severity, ARH has been highlighted as the significant contributor to the emerging cases of aortic valve stenosis, coronary artery disease, and cutaneous xanthoma in childhood(Tada et al., 2015) .Statistically, autosomal dominant hypercholesterolemia affects approximately in 1:250 to 1:500 individuals while autosomal recessive hypercholesterolemia has an estimated prevalence ratio of 1:1,000,000 live births(Kosmas, 2017).Research findings indicate that up to date, not more than 10,000 cases of ARH have been reported with the affected geographical populations being the Mexicans, Lebanese, Indians, Italian, Turkish, and the Syrians(Kosmas, 2017). In addition, current literature indicates that only 36 families with 14 different mutations have been reported worldwide(Kosmas, 2017).However, the clinical similarities between ARH and the autosomal dominant hypercholesterolemia among populations necessitate the implementation of statins as lipid-lowering treatment in addition to the conventional dietary monitoring strategies during patient management(Alallaf et al., 2017).
Familial hypercholesterolemia is among the leading causes of premature cardiovascular disease in Saudi Arabia(Alallaf et al., 2017). Familial hypercholesterolemia has been reported to be a dominant genetic disease of potential morbidity and mortality (Henneman et al, 2015). According to the International Familial Hypercholesterolemia Foundation, the cases of familial hypercholesterolemia are often undiagnosed or misdiagnosed in Saudi Arabia. Although no evidence in literature provides the exact frequency of familial hypercholesterolemia in Saudi Arabia, the figures in developed countries are used to give the country’s estimates(Alallaf et al., 2017). Based on the 2015 population census report, in the United States, the prevalence of the disease was approximately 1 case per 500 people (Batais et al., 2017) .With the overall population of 25,795, 938 in Saudi Arabia, the prevalence in the latter would be estimated as 51,591 autosomal dominant cases. On the other hand, with the 1: 300,000-600,000 ratios of autosomal recessive hypercholesterolemia, the expected examples of ARH in Saudi Arabia would be 56 to 106 (see fig.1)(Alallaf et al., 2017).The high prevalence in the country is attributed to the culture of consanguineous marriages which increase the chances of the transfer of mutated genes along the family pedigree. However, unavailability of data for the statistical analysis of familial hypercholesterolemia in Saudi Arabia is mainly due to the lack of genetic screening and national registries for the disease(Alallaf et al., 2017).Research indicates that currently, more than eighty molecularly and clinically confirmed cases of homozygous familial hypercholesterolemia are undergoing LDL-apheresis treatment after every two weeks in a single center located in Riyadh, the capital city of Saudi Arabia(Alallaf et al., 2017).Moreover, the increasing rates of the wrongdiagnosis have been attributed to the substantial deficit in the knowledge, awareness, and detection of familial hypercholesterolemia among practicing clinicians in Saudi Arabia(Batais et al., 2017).
The estimated prevalence of Familial Hypercholesterolemia in Saudi Arabia. A. Expected Heterozygous Familial Hypercholesterolemia (HeFH) cases. B. Expected Homozygous Familial Hypercholesterolemia (HoFH) cases; (Alallaf et al, 2017). The Spectrum of Familial Hypercholesterolemia (FH) in Saudi Arabia: Prime Time for Patient FH Registry. The open cardiovascular medicine journal, 11, pp.66-75.
The diagnosis of autosomal recessive familial hypercholesterolemia not only depends on biochemistry tests but mainly on the clinical and molecular analyses(Alallaf et al., 2017). Conventionally, biochemistry screening tests that analyze the lipid profile to determine cholesterol levels are considered insufficient to make a diagnosis for familial hypercholesterolemia conclusively. Mainly because of factors such as age, gender, certain drugs, ethnicity, pathological and physiological conditions which contribute to the variation of the results, ultimately leading to false negative or false positive values(Alallaf et al., 2017).The clinical criteria is to integrate the reports of repeated measurements of very high LDL-C or total cholesterol levels with the presence of xanthomas as well as considering family histories of signs and symptoms of dyslipidemia in making the diagnosis(Alallaf et al., 2017).Based on the clinical criteria, there exist conventional diagnostic systems that are applied in the determination of familial hypercholesterolemia(Alallaf et al., 2017).They include the Make Early Diagnosis to Prevent Early Deaths (MEDPED) criteria (USA), the Simon Broome Register Group (United Kingdom) released by the European Atherosclerosis Society, and the Dutch Lipid Clinic Network (DLCN) (Alallaf et al., 2017). Molecular genetic tests for autosomal recessive familial hypercholesterolemia include targeted variant analysis through the capillary method and sequence analysis of the entire coding region using the high-throughput next-generation sequencing (NGS)-based strategy(Alallaf et al., 2017).Conversely, after discovering causative mutation, it is always necessary to carry out cascade screening in first degree relatives such as parents to determine the underlying dominant patterns of inheritance.
The LDLRAP1 gene is located at position 36.11 on the short arm of chromosome 1 in humans. Thus, its cytogenic location is denoted as 1p36.11 (see fig 2). The gene has alternative mRNA variants which include four validated alternative polyadenylation sites and six on overlapping exons. The gene’s mRNAs differ by the alignment of the 3′ end, the truncation of the 5′ end, the presence or absence of the 11 cassette exons, and the highlighted overlapping exons. Mutations in the various axons determine the varying phenotypic characteristics.
Discrepancies in the response of patients with autosomal dominant inherited forms of familial hypercholesterolemia probed the research into the underlying causes of the rarity. Research studies in the family pedigree of several patients indicated lack of mutation in the contemporary genes that were inclined as causative agents of autosomal dominant familial hypercholesterolemia(Tada et al., 2015).The genes that were tested included LDLR, Apolipoprotein B (APOB) and Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9)(Tada et al., 2015).Moreover, a study that was conducted on Lebanese family with four offspring who were presented with large tendon xanthomas, and biochemistry analysis indicated severe hypercholesterolemia(Tada et al., 2015). It was hypothesized that the family had autosomal dominant hypercholesterolemia, but the cascade screening was slightly different since it identified the mode of inheritance to be the recessive form(Tada et al., 2015). The findings led to the first demonstration of autosomal recessive familial hypercholesterolemia in the year 1973(Tada et al., 2015).Later on, familial investigations probed the discovery of the LDLRAP1 mutation and its role in as a causative factor for the autosomal recessive form of familial hypercholesterolemia(Tada et al., 2015).Since then, there was a shift from the classical LDLR genes to the inclusion of LDLRAP 1 in the future research to provide data which will aid in the management of familial hypercholesterolemia. Fourteen different mutations in the LDLRAP 1 gene have been reported among the 36 autosomal recessive hypercholesterolemia families, mostly in the Sardinia island where the frequency for the heterozygous mutation carrier states of the gene is estimated to be high, rated as 1 per 143 individuals(Tada et al., 2015).
Typically, the LDLRAP 1 gene encodes for the LDLRAP 1 protein(Cuchel et al., 2014) .The protein is characterized as cytosolic, and it contains a phosphotyrosine binding domain (PTD) that interacts with the tail of the LDL receptor in the cell’s cytoplasm(Kosmas, 2017).Consequently, the interaction of the gene and the LDL receptor facilitates the endocytosis process of the receptor through the clathrin-coated pit machinery (see fig 3)(Kosmas, 2017).Through endocytosis, the LDL receptors releases cholesterol in the cells for further use in the body’s structural development, for storage or the removal of excess through liver metabolism(Kosmas, 2017).
Reported mutations in the gene include the lack of phosphotyrosine-binding domain which plays a critical role in the genes function(Tada et al., 2015).These mutations inhibit the synthesis of the LDLRAP 1 protein leading to the production of nonfunctional protein versions, abnormally small proteins or complete lack synthesized proteins(Tada et al., 2015).Without the LDLRAP1, the clearance of LDL-C from the bloodstream is by the LDL receptors is ineffective leading to the elevation of LDLs in the bloodstream(Tada et al., 2015).Therefore, since low-density lipoproteins are main cholesterol carriers in the blood, theinadequate clearance in reported LDLRAPI mutation results in very high levels of blood cholesterol(Tada et al., 2015).The abnormal deposition of the excess cholesterol in tissues such as the tendons, arteries, and skin increase the risk for anomalies such as xanthomata and coronary heart disease which are the characteristic features of autosomal recessive familial hypercholesterolemia as stipulated in the introductory section(Kosmas, 2017).
Family and twin studies have significantly impacted the field of research in the heterogeneity and the genetic flow of the mutated form in autosomal recessive hypercholesterolemia. In most cases, the effects of consanguinity have been investigated(Tada et al., 2015).The consanguineous culture entails marriages between relatives leading to the predominance of homozygous gene knockouts. According to the Mendelian genetics, natural gene knockouts in most consanguineous populations, the introduction of premature nonsense codons increases chances for genetic shifts(Tada et al., 2015).Therefore, if the ancestry line consists of missense mutations, there is a high probability that the allele in the offspring will be inactivated or completely dysfunctional(Kosmas, 2017).Besides, family studies have indicated substantial genotypic and phenotypic correlations between affected offspring’s and the first-pedigree relatives, mostly the parents(Henderson et al., 2016) .For instance, a patient diagnosed with ARH was screened, and it was highlighted that the father had an internalized mutant while the mother had a binding mutant consequently leading to the allelic mutations(Henderson et al., 2016). It was argued that the allelic mutations at the specific structural locus for the LDL receptor resulted in the homozygosity of the underlying effect and the ultimate manifestation of the rare genetic defect of autosomal recessive familial hypercholesterolemia (Tada et al., 2015) .
Similar to the inheritance of other recessive disorders, twin studies play a vital role in the understanding of autosomal recessive familial hypercholesterolemia. With the heterozygous parental carriers of LDLRAP1, the probability of each of the monozygous or identical twin inheriting the gene is 1 thus both have an equal chance of expressing similar phenotypic and genotypic features of autosomal recessive familial hypercholesterolemia. On the contrary fraternal twins, like other offsprings have a ¼ probability of inheriting recessive genes from their parents. Due to the lower discordance for autosomal recessive disorders in fraternal twins, chances of inheriting the disorders are minimal(Kathiresan, 2017).For instance, a study on 53-year-old male monozygous twins with familial hypercholesterolemia indicated similarities in serum lipoprotein profile, and other clinical manifestations like blood pressure and obesity(Kathiresan, 2017).However, there were slight differences in the atherosclerotic coronary artery grade. The differences allude to the contributions of epigenetic factors like environmental differences in genetic expression of autosomal recessive disorders (Nguyen et al., 2014).
The treatment regimens for ARH include the use of statins as a first-line of treatment which reduces the risk of cardiovascular disease and the manifestations of associated atherosclerosis in early childhood(Alallaf et al., 2017). Statins, lipid-lowering drugs are included in the management of affected adults to increase the efficacy of drug therapy and the improved prognosis. Current lipid-lowering treatment includes ezetimibe which reduces cholesterol absorption and bile salt sequestrates which increases the activity and elevates the clearance of low-density lipoprotein-cholesterol cascade from the circulation(Alallaf et al., 2017). In severe cases, low-density lipoprotein apheresis is recommended. This procedure aids in filtering the LDL particles from the circulations using heparin or dextran sulfate extracorporeal binding, consequently contributing a large percentage of LDL and cholesterol clearance. Currently biweekly or weekly LDL-C apheresis is the recommended treatment plan for patients with autosomal recessive hypercholesterolemia(Alallaf et al., 2017).Despite its high efficacy, LDL-C apheresis is associated with adverse side effects which include nausea, hypotension, chest pain, headache, blood loss, anemia and arrhythmias. Liver transplantations and other surgical procedures such as portacaval shunt surgery are applicable in severe cases to minimize cholesterol absorption and increase the loss of bile salts respectively.
Conclusion
Familial hypercholesterolemia is an inherited disorder that has been in the limelight for causing the majority of reported cardiovascular diseases(Henderson et al., 2016).Statistically, the increase in the mortality and morbidity cases across different age groups necessitates the urgency for addressing this health menace. As indicated in the paper, a dearth of literature analyzes the familial hypercholesterolemia while little is known about the rare autosomal recessive form. It is evident that mutation of the LDLRAP1 results in the inability of the liver cells (hepatocytes) to internalize the LDL-C ligand-receptor cascade and the subsequent inhibition of endocytosis leading to elevation of low-density lipoprotein and cholesterol levels in the blood. The management of ARH patients entails treatment regimens such as statins, lipid-treatment therapies, and LDL-C apheresis. However, there is need for advancement and development of new treatments to minimize the reported side effects associated with the preferred LDL-C apheresis. Moreover, within geographical populations where the prevalence of the disease is high such as the in Saudi Arabia, there is need for improved awareness of the disease through advocacy, advanced molecular diagnosis, and organization of patient registries. An in-depth analysis of autosomal recessive familial hypercholesterolemia through future research will be a prerequisite for the reduction in the alarming cardiovascular diseases and improved patient care as depicted in the millennium development goals.
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