Autosomal Recessive Familial Hypercholesterolemia

This article provides a detailed background to Autosomal Recessive Familial Hypercholesterolemia including its characterization and manifestation. It highlights the prevalence of the disease in highly endemic regions like Saudi Arabia and the worldwide epidemiological impact of the condition. The relevance of LDLRAP1 gene in determining the discourse of familial hypercholesterolemia is analyzed, along with the cytogenic properties of the gene, its discovery, and its specific role in the pathophysiology of autosomal recessive familial hypercholesterolemia. The diagnosis and treatment of the disease are also described.

[Type text]
Autosomal Recessive Familial Hypercholesterolemia
By: Faten AlQahtani
1801412

Autosomal recessive familial hypercholesterolemia
Table of contents
Table of Abbreviation ………………………………………………………….…………………2
Table of figures …………………………………………………………………………………...3
Abstract……………………………………………………………………………………………4
Introduction………………………………………………………………..………………………5
Prevalence in the World…………………………………………………..…………… …………6
Prevalence of Familial Hypercholesterolemia in Saudi Arabia…...………………………………7
Diagnosis…………………………………………………………………………………………..9
Low-density Lipoprotein Receptor Adaptor Protein 1(LDLRAP1)………………………..……10
Family study and twins study in ARH………………………………………………...…………13
Treatment…………………………………………………………………………………..…….14
Conclusion…………………………………………...…………………………………………..15
References………………………………………………………………………………………..17
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Autosomal recessive familial hypercholesterolemia
Table of Abbreviation
LDLRAP1 Low-Density Lipoprotein Receptor Adaptor Protein 1
LDL-C Low-Density Lipoprotein Cholesterol
CVD Cardiovascular Disease
LDLR Low-Density Lipoprotein Receptor
LDLs Low-Density Lipoproteins
APOB Apolipoprotein B
PCSK9 Proprotein Convertase Subtilisin/Kexin Type 9
ARH Autosomal Recessive Hypercholesterolemia
APOA Apolipoprotein A
HeFH Heterozygous Familial Hypercholesterolemia
HoFH Homozygous Familial Hypercholesterolemia
FH Familial Hypercholesterolemia
MEDPED Make Early Diagnosis to Prevent Early Deaths
DLCN Dutch Lipid Clinic Network
NGS Next-Generation Sequencing
PTD Phosphotyrosine Binding Domain
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Autosomal recessive familial hypercholesterolemia
Table of figures
Fig 1. 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.
Fig.2 LDLRAP1 gene. a.CytogenicLocation of LDLRAP1gene on the short (p) arm of
chromosome 1 at position 36.11. b. Represented exons. c. Mutations seen in
LDLRAP1 (Henderson et al, 2016). The genetics and screening of familial
hypercholesterolemia. Journal of biomedical science, 23(1), p.39.
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Autosomal recessive familial hypercholesterolemia
Abstract
Autosomal recessive familial hypercholesterolemia is a rare genetic disease that poses an
incremental risk to the general health. This paper aims at providing a detailed background to the
condition including its characterization and manifestation. The article further focuses on
highlighting the prevalence of the disease in highly endemic regions like Saudi Arabia
andtheworldwide epidemiological impact of the condition. In addition to dealing with the
relevance of LDLRAP1 gene in determining the discourse of familial hypercholesterolemia, this
assignment will focus on analyzing the cytogenic properties of the gene, its discovery and its
specific role in the pathophysiology of autosomal recessive familial hypercholesterolemia. The
overall purpose of family and twin studies will also be integrated into the paper to provide an
emphasis on the genetic baselines of the disease under discussion. Finally, the treatment will be
described as well as a conclusive summary of the disease under discussion.
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Autosomal recessive familial hypercholesterolemia
Introduction
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
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Autosomal recessive familial hypercholesterolemia
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).
Prevalence in the World
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
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Autosomal recessive familial hypercholesterolemia
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).
Prevalence of Familial Hypercholesterolemia in Saudi Arabia
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
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Autosomal recessive familial hypercholesterolemia
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).
Fig 1. 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.
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Autosomal recessive familial hypercholesterolemia
Diagnosis
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.
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Fig. 5 LDLRAP1 gene. a. Location of the LDLRAP1 gene on the short (p) arm of chromosome 1 at position 36.11. b. Numbered vertical bars represent
the exons. c. 39 mutations seen in LDLRAP1 and each exon mutation produces various phenotypic effects, for example, a mutation in exon 6 will be more
responsive to lipid-lowering therapeutics Data extracted from –Partially adapted from
Autosomal recessive familial hypercholesterolemia
Low-density Lipoprotein Receptor Adaptor Protein 1(LDLRAP1)
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.
Fig.2LDLRAP1gene. a. CytogenicLocation of LDLRAP1gene on the short (p) arm of
chromosome 1 at position 36.11. b. Represented exons. c. Mutations seen in LDLRAP1
(Henderson et al, 2016). The genetics and screening of familial hypercholesterolemia. Journal of
biomedical science, 23(1), p.39.
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Autosomal recessive familial hypercholesterolemia
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,
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Autosomal recessive familial hypercholesterolemia
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).
Fig 3. Role of LDLRAP1 in the Metabolic Pathway of LDL; (Tada et al, 2015).
Autosomal recessive hypercholesterolemia: a mild phenotype of familial
hypercholesterolemia: insight from the kinetic study using stable isotope and animal
studies. Journal of atherosclerosis and thrombosis, 22(1), pp.1-9.
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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 study and twins study in ARH
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-
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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).
Treatment
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
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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
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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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References
ALALLAF, F., FA, H. N., ALNEFAIE, M., ALMAYMUNI, A., RASHIDI, O. M., ALHABIB, K., ALNOURI,
F., ALAMA, M. N., ATHAR, M. & AWAN, Z. 2017. The Spectrum of Familial
Hypercholesterolemia (FH) in Saudi Arabia: Prime Time for Patient FH Registry. The open
cardiovascular medicine journal, 11, 66-75.
BATAIS, M. A., ALMIGBAL, T. H., BIN ABDULHAK, A. A., ALTARADI, H. B. & ALHABIB, K. F. 2017.
Assessment of physicians' awareness and knowledge of familial hypercholesterolemia in
Saudi Arabia: Is there a gap? PloS one, 12.
CLIFTON, P. M., GALBRAITH, C. & COLES, L. 2014. Effect of a low dose whey/guar preload on
glycemic control in people with type 2 diabetes--a randomised controlled trial. Nutr J,
13, 103.
CUCHEL, M., BRUCKERT, E., GINSBERG, H. N., RAAL, F. J., SANTOS, R. D., HEGELE, R. A.,
KUIVENHOVEN, J. A., NORDESTGAARD, B. G., DESCAMPS, O. S., STEINHAGEN-THIESSEN,
E., TYBJAERG-HANSEN, A., WATTS, G. F., AVERNA, M., BOILEAU, C., BOREN, J.,
CATAPANO, A. L., DEFESCHE, J. C., HOVINGH, G. K., HUMPHRIES, S. E., KOVANEN, P. T.,
MASANA, L., PAJUKANTA, P., PARHOFER, K. G., RAY, K. K., STALENHOEF, A. F., STROES,
E., TASKINEN, M. R., WIEGMAN, A., WIKLUND, O. & CHAPMAN, M. J. 2014. Homozygous
familial hypercholesterolaemia: new insights and guidance for clinicians to improve
detection and clinical management. A position paper from the Consensus Panel on
Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J, 35,
2146-57.
DI TARANTO, M. D., D'AGOSTINO, M. N. & FORTUNATO, G. 2015. Functional characterization of
mutant genes associated with autosomal dominant familial hypercholesterolemia:
integration and evolution of genetic diagnosis. Nutr Metab Cardiovasc Dis, 25, 979-87.
GIDDING, S. S., CHAMPAGNE, M. A., DE FERRANTI, S. D., DEFESCHE, J., ITO, M. K., KNOWLES, J.
W., MCCRINDLE, B., RAAL, F., RADER, D., SANTOS, R. D., LOPES-VIRELLA, M., WATTS, G.
F. & WIERZBICKI, A. S. 2015. The Agenda for Familial Hypercholesterolemia: A Scientific
Statement From the American Heart Association. Circulation, 132, 2167-92.
17 | P a g e

Autosomal recessive familial hypercholesterolemia
HENDERSON, R., O’KANE, M., MCGILLIGAN, V. & WATTERSON, S. 2016. The genetics and
screening of familial hypercholesterolaemia. Journal of Biomedical Science, 23, 39.
KATHIRESAN, K. G. A. A. S. 2017. Genetics of Coronary Atherosclerosis. Chronin Coronary Artery
Disease: A Companion to Braunwald's Heart Disease James de Lemos, Torbjørn Omland.
KOSMAS, C. E. 2017. Autosomal Recessive Hypercholesterolemia: A Rare Cause of Familial
Hypercholesterolemia. BJSTR Biomedical Journal of Scientific & Technical Research, 1.
Pusey, B. A. S. (2006). You Are What You Eat: Nutrition for the Beginner. Xlibris Corporation.
Sherwood, L. (2015). Human physiology: from cells to systems. Cengage learning.
NGUYEN, G. H., TANG, W., ROBLES, A. I., BEYER, R. P., GRAY, L. T., WELSH, J. A., SCHETTER, A. J.,
KUMAMOTO, K., WANG, X. W., HICKSON, I. D., MAIZELS, N., MONNAT, R. J., JR. &
HARRIS, C. C. 2014. Regulation of gene expression by the BLM helicase correlates with
the presence of G-quadruplex DNA motifs. Proc Natl Acad Sci U S A, 111, 9905-10.
TADA, H., KAWASHIRI, M. A., NOHARA, A., INAZU, A., KOBAYASHI, J., MABUCHI, H. &
YAMAGISHI, M. 2015. Autosomal recessive hypercholesterolemia: a mild phenotype of
familial hypercholesterolemia: insight from the kinetic study using stable isotope and
animal studies. J Atheroscler Thromb, 22, 1-9.
Santos, R. D., Gidding, S. S., Hegele, R. A., Cuchel, M. A., Barter, P. J., Watts, G. F., ... &
Folco, E. (2016). Defining severe familial hypercholesterolaemia and the implications for
clinical management: a consensus statement from the International Atherosclerosis
Society Severe Familial Hypercholesterolemia Panel. The Lancet Diabetes &
Endocrinology, 4(10), 850-861
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