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Sitosterolemia is a rare autosomal recessive disease that lead to an increase in the intestinal absorption and decreased biliary excretion plant sterols. It is caused by mutations in ABCG5 and ABCG8 genes, encoring sterolin-1 and sterolin-2 protein. The main clinical manifestations are xanthomas, premature atherosclerosis, arthralgia and, of note, hematological alterations. As in many other systemic diseases, hematological manifestations may be the only notable finding, for this reason we want to highlight the importance of multidisciplinary work and raise awareness of this rare disease that can lead to serious consequences if not treated prematurely. Here we present a case of this disease as well as its entire diagnostic process developed from a simple analytical alteration., (© 2024 John Wiley & Sons Ltd.)

Background: Sitosterolemia is a rare inherited lipid metabolic disorder characterized by increased levels of plant sterols and accelerated atherosclerosis. Although early detection is beneficial for the prevention of disease progression, it is largely underdiagnosed by routine screening based on conventional lipid profiles., Materials and Methods: A gas chromatography-mass spectrometry (GC-MS)-based profiling has been developed and validated to measure the levels of biologically active free sterols, including five endogenous sterols and three plant sterols (sitosterol, campesterol, and stigmasterol) in dried blood spot (DBS)., Results: Within- and between-run precisions were 1.4-11.1 % and 2.2-14.1 %, respectively, while the accuracies were all 86.3 ∼ 121.9 % with the correlation coefficients (r 2 ) > 0.988 for all the sterols. In the patients (four girls and two boys, 6.5 ± 2.8 years), sitosterol levels were significantly increased, with an optimal cut-off value of 2.5 µg/mL distinguishing them from ninety-three age-matched healthy children. A cut-off value of 31.9 µg/mL differentiated the patients from six ABCG5/ABCG8 heterozygous carriers. In addition, the molecular ratios of sitosterol to cholesterol, desmosterol, and 7-dehydrocholesterol provided excellent cut-off values of 26.3, 67.6, and 21.6, respectively, to distinguish patients from both healthy controls and heterozygous carriers., Conclusions: The novel DBS-based GC-MS profiling of free sterols accurately identified patients with sitosterolemia, with a performance comparable to that of a serum assay. The DBS profiling could be more feasible method in clinical practice as well as population screening programs, and it can provide diagnostic cut-off values for individual plant sterols., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Sitosterolemia is a rare inherited disorder caused by mutations in the ABCG5/ABCG8 genes. These genes encode proteins involved in the transport of plant sterols. Mutations in these genes lead to decreased excretion of phytosterols, which can accumulate in the body and lead to a variety of health problems, including premature coronary artery disease. We conducted the first genome-wide association study (GWAS) in the Middle East/North Africa population to identify genetic determinants of plant sterol levels in Qatari people. GWAS was performed on serum levels of β-sitosterol and campesterol using the Metabolon platform from Qatar Biobank (QBB) and genome sequence data provided by Qatar Genome Program. A trans-ancestry meta-analysis of data from our Qatari cohort with summary statistics from a previously published large cohort (9758 subjects) of European ancestry was conducted. Using conditional analysis, we identified two independent single nucleotide polymorphisms associated with β-sitosterol (rs145164937 and rs4299376), and two others with campesterol (rs7598542 and rs75901165) in the Qatari population in addition to previously reported variants. All of them map to the ABCG5/8 locus except rs75901165 which is located within the Intraflagellar Transport 43 (IFT43) gene. The meta-analysis replicated most of the reported variants, and our study provided significant support for the association of variants in SCARB1 and ABO with sitosterolemia. Evaluation of a polygenic risk score devised from European GWAS data showed moderate performance when applied to QBB (adjusted-R 2  = 0.082). These findings provide new insights into the genetic architecture of phytosterol metabolism while showing the importance including under-represented populations in future GWAS studies., (© 2024. The Author(s).)

Background: Sitosterolemia, an autosomal recessive condition, is characterized by impaired metabolism of plant sterols. Clinical symptoms include skin xanthoma, premature atherosclerotic disease, arthritis, and unexplained hematological abnormalities. However, there is a dearth of studies on sitosterolemia-related brain damage., Methods: This study focused on the family of two sitosterolemia patients who presented with severe hypercholesterolemia and xanthoma. Radiological examinations, biopsies, whole-exome sequencing (WES), and plant sterol tests were conducted., Results: The index patient, a 66-year-old female, initially exhibited weakness in both lower limbs and later developed urinary and fecal incontinence. Neuroimaging showed that the falx of the brain had irregular fusiform thickening. Significant tissue edema was observed around the lesions in the bilateral frontal-parietal lobes. Pathological analysis of the biopsied brain lesion revealed extensive cholesterol crystal deposition and lymphocyte infiltration in the matrix. The index patient who experienced cerebral impairment and her sister both carried two compound heterozygous variants in ATP binding cassette transporter G5 (ABCG5). These included the nonsense variants NM_022436: c.751 C > T (p.Q251X) in exon 6 and NM_022436: c.1336 C > T (p.R446X) in exon 10. A notable increase in plant sterol levels was observed in the younger sister of the index patient., Conclusion: This study highlights a previously unreported neurological aspect of sitosterolemia. Imaging and pathology findings suggest that cholesterol crystals may be deposited in connective tissues such as the cerebral falx and pia mater through blood circulation., (© 2024. The Author(s).)

Sitosterolemia is an autosomal recessive and very rare disease. Its main characteristic is that there is a greater absorption and a decrease in the excretion of sterols, which leads to them being deposited in tissues. It is given by mutations in the ABCG5 or ABCG8 genes found on chromosome 2p21. In this clinical note, we describe the first two patients with familial sitosterolemia described in Colombia, brothers, one of them with xanthomas in extremities as the only symptom, and the other, completely asymptomatic. Genetic studies were performed as a diagnostic test in both patients, where a pathogenic homozygous variant could be identified in the ABCG8 gene in the first case (symptomatic), and a heterozygous variant in the ABCG8 gene in the second case (asymptomatic); the first patient has responded to treatment with ezetimibe. In conclusion, xanthomas should be studied in depth in pediatric age as they may be the only visible sign of such complex and hereditary diseases as familial sitosterolemia, which can be controlled and prevent cardiovascular complications of the disease., (Copyright © 2024 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.)

Abstract: Sitosterolemia is a rare autosomal recessive genetic disorder in which patients develop hypercholesterolemia and may exhibit abnormal hematologic and/or liver test results. In this disease, dysfunction of either ABCG5 or ABCG8 results in the intestinal hyperabsorption of all sterols, including cholesterol and, more specifically, plant sterols or xenosterols, as well as in the impaired ability to excrete xenosterols into the bile. It remains unknown how and why some patients develop hematologic abnormalities. Only a few unrelated patients with hematologic abnormalities at the time of diagnosis have been reported. Here, we report on 2 unrelated pedigrees who were believed to have chronic immune thrombocytopenia as their most prominent feature. Both consanguineous families showed recessive gene variants in ABCG5, which were associated with the disease by in silico protein structure analysis and clinical segregation. Hepatosplenomegaly was absent. Thrombopoietin levels and megakaryocyte numbers in the bone marrow were normal. Metabolic analysis confirmed the presence of strongly elevated plasma levels of xenosterols. Potential platelet proteomic aberrations were longitudinally assessed following dietary restrictions combined with administration of the sterol absorption inhibitor ezetimibe. No significant effects on platelet protein content before and after the onset of treatment were demonstrated. Although we cannot exclude that lipotoxicity has a direct and platelet-specific impact in patients with sitosterolemia, our data suggest that thrombocytopenia is neither caused by a lack of megakaryocytes nor driven by proteomic aberrations in the platelets themselves., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Objective: To enhance the detection, management and monitoring of Chinese children afflicted with sitosterolemia by examining the physical characteristics and genetic makeup of pediatric patients., Methods: In this group, 26 children were diagnosed with sitosterolemia, 24 of whom underwent genetic analysis. Patient family medical history, physical symptoms, tests for liver function, lipid levels, standard blood tests, phytosterol levels, cardiac/carotid artery ultrasounds, fundus examinations, and treatment were collected., Results: The majority (19, 73.1%) of the 26 patients exhibited xanthomas as the most prevalent manifestation. The second most common symptoms were joint pain (7, 26.9%) and stunted growth (4, 15.4%). Among the 24 (92.3%) patients whose genetics were analyzed, 16 (66.7%) harbored ABCG5 variants (type 2 sitosterolemia), and nearly one-third (8, 33.3%) harbored ABCG8 variants (type 1 sitosterolemia). Additionally, the most common pathogenic ABCG5 variant was c.1166G > A (p.Arg389His), which was found in 10 patients (66.7%). Further analysis did not indicate any significant differences in pathological traits among those carrying ABCG5 and ABCG8 variations (P > 0.05). Interestingly, there was a greater abundance of nonsense variations in ABCG5 than in ABCG8 (P = 0.09), and a greater frequency of splicing variations in ABCG8 than ABCG5 (P = 0.01). Following a change in diet or a combination of ezetimibe, the levels of cholesterol and low-density lipoprotein were markedly decreased compared to the levels reported before treatment., Conclusion: Sitosterolemia should be considered for individuals presenting with xanthomas and increased cholesterol levels. Phytosterol testing and genetic analysis are important for early detection. Managing one's diet and taking ezetimibe can well control blood lipids., (© 2024. The Author(s).)

Background: Sitosterolemia, also known as phytosterolemia, is a rare recessive genetic disorder characterized by accumulation of sitosterol from vegetable oils, nuts, and other plant-based foods in the body. In those with sitosterolemia, there is an increase of fatty deposits in the arteries (atherosclerosis), which may occur in early childhood, impeding blood flow and increasing the risk of a heart attack, stroke, or sudden death at a very early age. Visual signs of sitosterolemia may include small yellowish xanthomas beginning in early childhood. Xanthomas are accumulated lipids that develop in the heels, elbows, and buttocks., Case: A clinical case study of a patient with sitosterolemia with slow healing surgical wound from coronary artery bypass surgery is described. Treatment of sitosterolemia is aimed at lowering plasma plant sterol levels with dietary restriction intake of both animal- and plant-based sterols. However, plant-based products (collagen, chitosan, etc) are also used for wound dressings, so alternative wound dressings were selected to decrease the possibility of systemic absorption., Conclusion: This case study describes a young adult male with sitosterolemia who presented with a slow healing surgical incision following coronary artery bypass surgery. Sitosterolemia is often characterized by atherosclerosis of the coronary arteries that occurs in children and early adulthood, especially affecting men. Treatment is aimed at lowering plasma sterol levels with the restriction of animal and plant sterols. There is considerable interest today in natural versus synthetic wound care products. Dressings containing chitosan, cellulose, collagen, etc, to be avoided to decrease the chance of systemic absorption., Competing Interests: The author has no conflicts of interest to declare., (Copyright © 2024 by the Wound, Ostomy and Continence Nurses Society.)

This article focuses on a case study of sitosterolemia in a child who initially presented with hemolytic anemia and thrombocytopenia. Sitosterolemia is a rare autosomal recessive lipid metabolism disorder, difficult to diagnose due to its non-typical clinical manifestations. The 8-year-old patient was initially misdiagnosed with pyruvate kinase deficiency. Comprehensive biochemical and molecular biology analyses, including gene sequencing, eventually led to the correct diagnosis of sitosterolemia. This case highlights the complexity and diagnostic challenges of sitosterolemia, emphasizing the need for increased awareness and accurate diagnosis in patients presenting with similar symptoms.

Sitosterolemia is a rare genetic lipid disorder, mainly characterized by the accumulation of dietary xenosterols in plasma and tissues. It is caused by inactivating mutations in either ABCG5 or ABCG8 subunits, a subfamily-G ATP-binding cassette (ABCG) transporters. ABCG5/G8 encodes a pair of ABC half transporters that form a heterodimer (G5G8). This heterodimeric ATP-binding cassette (ABC) sterol transporter, ABCG5/G8, is responsible for the hepatobiliary and transintestinal secretion of cholesterol and dietary plant sterols to the surface of hepatocytes and enterocytes, promoting the secretion of cholesterol and xenosterols into the bile and the intestinal lumen. In this way, ABCG5/G8 function in the reverse cholesterol transport pathway and mediate the efflux of cholesterol and xenosterols to high-density lipoprotein and bile salt micelles, respectively. Here, we review the biological characteristics and function of ABCG5/G8, and how the mutations of ABCG5/G8 can cause sitosterolemia, a loss-of-function disorder characterized by plant sterol accumulation and premature atherosclerosis, among other features., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Background: Short-term clinical trials have shown the cholesterol-lowering potentials of phytosterols, but their impacts on cardiovascular disease (CVD) remain controversial. This study used the Mendelian randomization (MR) to investigate the relationships between genetic predisposition to blood sitosterol concentration and 11 CVD endpoints, along with the potential mediating effects of blood lipids and hematological traits., Methods: Random-effect inverse-variance weighted method was used as the main analysis of MR. Genetic instruments of sitosterol (seven SNPs, F = 253, and R 2  = 15.4 %) were derived from an Icelandic cohort. Summary-level data of the 11 CVDs were obtained from UK Biobank, FinnGen, and publicly available genome-wide association study results., Results: Genetically predicted one unit increment in log-transformed blood total sitosterol was significantly associated with a higher risk of coronary atherosclerosis (OR: 1.52; 95 % CI: 1.41, 1.65; n = 667,551), myocardial infarction (OR: 1.40; 95 % CI: 1.25, 1.56; n = 596,436), all coronary heart disease (OR: 1.33; 95 % CI: 1.22, 1.46; n = 766,053), intracerebral hemorrhage (OR: 1.68; 95 % CI: 1.24, 2.27; n = 659,181), heart failure (OR: 1.16; 95 % CI: 1.08, 1.25; n = 1,195,531), and aortic aneurysm (OR: 1.74; 95 % CI: 1.42, 2.13; n = 665,714). Suggestive associations were observed for an increased risk of ischemic stroke (OR: 1.06; 95 % CI: 1.01, 1.12; n = 2,021,995) and peripheral artery disease (OR: 1.20; 95 % CI: 1.05, 1.37; n = 660,791). Notably, blood non-high-density lipoprotein cholesterol (nonHDL-C) and apolipoprotein B mediated about 38-47 %, 46-60 %, and 43-58 % of the associations between sitosterol and coronary atherosclerosis, myocardial infarction, and coronary heart disease, respectively. However, the associations between sitosterol and CVDs were less likely to depend on hematological traits., Conclusion: The study suggests that genetic predisposition to higher blood total sitosterol is linked to a greater risk of major CVDs. Moreover, blood nonHDL-C and apolipoprotein B might mediate a significant proportion of the associations between sitosterol and coronary diseases., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Sitosterolemia is a rare autosomal recessive hereditary disease caused by loss-of-function genetic mutations in either ATP-binding cassette subfamily G member 5 or member 8 (ABCG5 or ABCG8). Here, we investigate novel variants in ABCG5 and ABCG8 that are associated with the sitosterolemia phenotype. We describe a 32-year-old woman with hypercholesterolemia, tendon and hip xanthomas, autoimmune hemolytic anemia and macrothrombocytopenia from early life, which make us highly suspicious of the possibility of sitosterolemia. A novel homozygous variant in ABCG5 (c.1769C>A, p.S590X) was identified by genomic sequencing. We also examined the lipid profile, especially plant sterols levels, using gas chromatography-mass spectrometry. Functional studies, including western blotting and immunofluorescence staining, showed that the nonsense mutation ABCG5 1769C>A hinders the formation of ABCG5 and ABCG8 heterodimers and the function of transporting sterols. Our study expands the knowledge of variants in sitosterolemia and provides diagnosis and treatment recommendations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Lipid injectable emulsions have been in clinical use for over 60 years. The first product launched was Intralipid, which consisted of an emulsion of soybean oil in water for intravenous administration. It was a key source of essential fatty acids and an alternative source of energy for patients with gastrointestinal dysfunction requiring long-term parenteral nutrition. With clinical experience, a condition known as parenteral nutrition-associated liver disease (PNALD), or intestinal failure-associated liver disease (IFALD), was observed, with a focus on carbohydrate and fat energy. Modifying the daily doses and infusion rates had some salutary effects, but PNALD persisted. Subsequently, on closer inspection of the fatty acids profile and phytosterol concentrations, degradation products arising from chemical and physical stability issues of the available lipid injectable emulsions were implicated. Recently, the US Food and Drug Administration convened an online workshop entitled "The Role of Phytosterols in PNALD/IFALD," with an emphasis on (1) the multifactorial pathophysiology of PNALD/IFALD, (2) risk associated with phytosterols, and (3) regulatory history. The scope of this review includes the multifactorial pathophysiology of PNALD/IFALD as it relates to the pharmaceutical aspects of the various lipid injectable emulsions on the market, with respect to potential proinflammatory components, as well as physical and chemical stability issues that may also affect products' safe intravenous administration to patients., (© 2023 American Society for Parenteral and Enteral Nutrition.)

Scope: Phytosterols (PS) and sterol oxidation products are key dietary factors influencing atherosclerosis besides cholesterol, although the mechanisms remain elusive. Recently, single-cell RNA sequencing (scRNA-seq) has revealed the heterogeneity of multiple cell types associated with complex pathogenesis in atherosclerosis development., Methods and Results: Here, scRNA-seq is performed to investigate the alterations in the aortic cells from ApoE -/- mice induced by diet-derived PS or two sterol oxidation products, phytosterols oxidation products (POPs), and cholesterol oxidation products (COPs). The study identifies four fibroblast subpopulations with different functions, and immunofluorescence demonstrates their spatial heterogeneity, providing evidence that suggests the transformation of smooth muscle cells (SMCs) and fibroblasts in atherosclerosis. The composition and gene expression profiles of aortic cells change broadly in response to PS/COPs/POPs exposure. Notably, PS exhibits an atheroprotective effect where different gene expressions are mainly found in B cells. Exposure to COPs accelerates atherosclerosis and results in marked alternations in myofibroblast subpopulations and T cells, while POPs only alter fibroblast subpopulations and B cells., Conclusion: The data elucidate the effects of dietary PS/COPs/POPs on aortic cells during atherosclerosis development, especially on the newly identified fibroblast subpopulations., (© 2023 Wiley-VCH GmbH.)

Purpose of Review: The purpose of this review was to summarize important and updated information on sitosterolemia. Sitosterolemia is an inherited lipid disorder consisting of high levels of plasma plant sterols. This sterol storage condition is caused by biallelic loss-of-function genetic variants in either ABCG5 or ABCG8, leading to increased intestinal absorption and decreased hepatic excretion of plant sterols. Clinically, patients with sitosterolemia usually exhibit xanthomatosis, high levels of plasma cholesterol, and premature atherosclerotic disease, but presentation can be highly heterogeneous. Therefore, recognition of this condition requires a high level of suspicion, with confirmation upon genetic diagnosis or through measurement of plasma phytosterols. Treatment of sitosterolemia with both a plant sterol-restricted diet and the intestinal cholesterol absorption inhibitor ezetimibe can reduce efficiently the levels of plasma plant sterols, consisting in the first-line therapy for this disease., Recent Findings: Since hypercholesterolemia is often present in individuals with sitosterolemia, it is important to search for genetic variants in ABCG5 and ABCG8 in patients with clinical criteria for familial hypercholesterolemia (FH), but no variants in FH implicated genes. Indeed, recent studies have suggested that genetic variants in ABCG5/ABCG8 can mimic FH, and even when in heterozygosis, they may potentially exacerbate the phenotype of patients with severe dyslipidemia. Sitosterolemia is a genetic lipid disorder characterized by increased circulating levels of plant sterols and clinically manifested by xanthomatosis, hematologic disorders, and early atherosclerosis. Awareness about this condition, a rare, but commonly underdiagnosed and yet treatable cause of premature atherosclerotic disease, is imperative., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose of Review: The aim of this study was to assess the potential value of the measurement of plasma xenosterols (or phytosterols) concentrations in clinical practice., Recent Findings: Recent genetic studies suggest that individuals with elevated plasma phytosterol concentrations due to monogenic and polygenic variants are at an increased risk of coronary artery disease. This supports early observations that elevated plasma phytosterol concentrations are per se atherogenic., Summary: Measurement of plasma phytosterols can identify individuals with xenosterolemia (or phytosterolemia). This may be clinically useful in four ways: Establishing a diagnosis and informing management of patients with homozygous phytosterolemia; Providing a comprehensive differential diagnosis for familial hypercholesterolemia; Providing an index of cholesterol absorption that may inform personalized pharmacotherapy; and Informing more precise assessment of risk of cardiovascular disease., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Sitosterolemia (STSL) is an extremely rare genetic disease. Xanthomas as the first symptom are frequently misinterpreted as familial hypercholesterolemia (FH) in children. Inappropriate treatment may deteriorate the condition of STSL., Objectives: To present the clinical and laboratory characteristics of xanthomatous children diagnosed with sitosterolemia in comparison with childhood FH with xanthomas., Methods: We summarized and compared the clinical characteristics of STSL and FH patients with xanthomas as the first manifestations and investigated the different indicators between the STSL and FH groups, as well as their diagnostic values for STSL., Results: Two tertiary pediatric endocrinology departments contributed ten STSL cases. Five of the STSL patients (50%) experienced mild anemia, whereas two (20%) had vascular complications. The xanthomas of the STSL group displayed morphologies comparable to those of the FH group. There were ten cases of homozygous FH (HoFH) with xanthomas as the predominant symptom of the control group who had no anemia. The serum cholesterol (Chol) levels of the STSL and FH groups were 12.57 (9.55 ~ 14.62) mmol/L and 17.45 (16.04 ~ 21.47) mmol/L, respectively (p value 0.002). The serum low-density lipoprotein cholesterol (LDL-c) levels of the STSL and FH groups were 9.26 ± 2.71 mmol/L and 14.58 ± 4.08 mmol/L, respectively (p value 0.003). Meanwhile, the mean platelet volume (MPV) levels of the STSL and FH groups were 11.00 (9.79 ~ 12.53) fl. and 8.95 (8.88 ~ 12.28) fl., respectively (p value 0.009). The anemia proportions of the STSL and FH groups were 50% and 0%, respectively (p value 0.033). The AUC values of Chol, LDL-c, MPV, hemoglobin (Hb) for the diagnosis of STSL were 0.910, 0.886, 0.869, 0.879, respectively. Chol ≤ 15.41 mmol/L, LDL-c ≤ 13.22 mmol/L, MPV ≥ 9.05 fl., or Hb≤120 g/L were the best thresholds for diagnosing STSL with childhood xanthomas., Conclusion: The xanthoma morphology of STSL patients resembles that of FH patients. Xanthomas as the initial symptom of a child with Chol ≤ 15.41 mmol/L, LDL-c≤13.22 mmol/L, MPV ≥ 9.05 fl., or Hb≤120 g/L, he was most likely to have STSL., (© 2022. The Author(s).)

Abstract: We report a noteworthy case of a 10-year-old girl who presented with papular and nodular lesions on the skin that were clinically and histologically mistaken for progressive nodular histiocytosis. During the clinical management of the patient, the high lipid levels raised the suspicion of lipid metabolism disease and helped us to make the correct diagnosis of sitosterolemia. In sitosterolemia, proper management such as restriction of plant sterol intake and administration of cholesterol absorption inhibitor can improve prognosis., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Gallstones are increasingly common in children. Genetic analyses of adult cohorts demonstrated that the sterol transporter ABCG8 p.D19H and Gilbert UGT1A1*28 variants enhance the odds of developing gallstones. The genetic background of common lithiasis in children remains unknown., Methods: Overall, 214 children with gallstone disease (1 month-17 years, 107 boys) were inclueded. The control cohorts comprised 214 children (age 6-17 years, 115 boys) and 172 adults (age 40-92 years, 70 men) without gallstones. The ABCG8 p.D19H and UGT1A1*28 polymorphisms as well as ABCB4 (c.504C>T rs1202283, c.711A>T rs2109505) and NPC1L1 variants (p.V1296V rs217434, c.-18C>A rs41279633) were genotyped using TaqMan assays. Serum concentrations of plant sterols and cholesterol precursors were measured by gas chromatography/mass spectrometry., Results: The ABCG8 risk allele was associated with an increased risk of stones (OR = 1.82, p = .03). Children carrying the p.19H allele presented with lower serum concentrations of surrogate markers of intestinal cholesterol absorption and decreased ratios of phytosterols to the cholesterol precursor desmosterol. Carriers of the common NPC1L1 rs217434 allele had an increased gallstone risk compared with stone-free adults (OR 1.90, p < .01). This variant also affected the ratio of phytosterols to cholesterol precursors (p = .03). Other tested variants were not associated with gallstone risk., Conclusions: The p.D19H ABCG8 and, to a lesser extent, NPC1L1 rs217434 variants increase the risk of early-onset gallstone formation. These results point to the presence of a common lithogenic pathway in children and adults., (© 2022 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background: Sitosterolemia is a rare autosomal recessive disorder caused by homozygous or compound heterozygous variants in ABCG5/ABCG8 . The disease is characterized by increased plasma plant sterols. Small case series suggest that patients with sitosterolemia have wide phenotypic heterogeneity with great variability on either plasma cholesterol levels or development of atherosclerotic cardiovascular disease. The present study aims to characterize the prevalence and clinical features of sitosterolemia participating in a familial hypercholesterolemia genetic cascade screening program., Methods: From 443 familial hypercholesterolemia index cases, 260 were negative for familial hypercholesterolemia genes and were sequenced for the ABCG5/8 genes. Clinical and laboratory characteristics of affected individuals were determined., Results: Eight (3.1%) index cases were found to be homozygous or compound heterozygous variant for ABCG5/ABCG8 genes, confirming the genetic diagnosis of sitosterolemia. Screening their relatives led to the identification of 6 additional confirmed sitosterolemia cases (3 homozygous and 3 compound heterozygous variant) and 18 carriers (heterozygous). The mean age of identified sitosterolemia cases (n=14) was 37.2±19.8 years, 50% were females, and 78.6% (all adults) presented either clinical or subclinical atherosclerotic cardiovascular disease. As expected, affected individuals presented elevated plasma plant sterol levels (mean β-Sitosterol and campesterol, respectively, 160.3±107.1 and 32.0±19.6 µg/mL) and the highest plasma LDL (low-density lipoprotein)-cholesterol was 269.0±120.0 mg/dL (range: 122-521 mg/dL). LDL-cholesterol mean reduction with therapy among cases was 65%. Eighty-three percent (83%) of identified sitosterolemia patients presented hematologic abnormalities., Conclusions: Testing genes associated with sitosterolemia in the molecular routine workflow of a familial hypercholesterolemia cascade screening program allowed the precise diagnosis of sitosterolemia in a substantial number of patients with varying LDL-C levels and high incidence of early atherosclerotic cardiovascular disease and hematologic abnormalities.

Background and Aim: Clinical manifestations and genetic backgrounds of Japanese patients with sitosterolemia have been unclear., Materials and Methods: We searched PubMed for studies using the keywords "sitosterolemia" or "phytosterolemia" and "Japan". Moreover, we added information from the members of the Committee on Primary Dyslipidemia under the Research Program on Rare and Intractable Disease of the Ministry of Health, Labour and Welfare (MHLW) of Japan., Results: We identified 36 patients with sitosterolemia caused by biallelic pathogenic mutations in the ATP-binding cassette subfamily G member 5 (ABCG5) or ATP-binding cassette subfamily G member 8 (ABCG8) from 31 families in Japan. The diagnosed age ranged from 0 to 64 years (median 13 years). The median sitosterol and LDL cholesterol levels were 100 μg/ml (IQR: 50-183), and 193 mg/dl (IQR: 108-295), respectively. All the patients exhibited cutaneous and/or tendon xanthomas, up to 9 (25%) patients exhibited premature coronary artery disease, 5 (16%) patients exhibited arthritis, and 8 (22%) patients exhibited blood abnormalities. Ezetimibe was administered to all the patients, including infantile cases, while statins, colestimide, evolocumab, probucol, and LDL apheresis were also used., Conclusion: We are providing a demographic overview of the clinical and genetic backgrounds of Japanese patients with sitosterolemia., (Copyright © 2022 Elsevier B.V. All rights reserved.)

A 17-year-old boy with acute coronary syndrome was admitted to our hospital. He had xanthomas over his elbow and Achilles tendon and a high level of low-density lipoprotein cholesterol; therefore, his initial diagnosis was familial hypercholesterolemia. However, a genetic analysis revealed a compound heterozygous mutation in the ABCG5 gene with a high serum level of sitosterol, leading to the diagnosis of sitosterolemia. After lipid-lowering treatment, percutaneous coronary intervention was performed. Furthermore, a persistently high C-reactive protein level and images of large arteries led to a diagnosis of Takayasu arteritis. To our knowledge, this is the first case of sitosterolemia complicated by Takayasu arteritis.

Background: Sitosterolemia, also known as phytosterolemia, results from increased intestinal absorption of plant sterols and decreased intestinal and biliary excretion of sterols, resulting in increased levels of plant sterols in the plasma. The most common symptoms include xanthomas, premature atherosclerosis, hemolytic anemia and macrothrombocytopenia, however delayed diagnosis or misdiagnosis also occur., Patient and Methods: Clinical exome sequencing was performed on a 10-year-old boy whom we followed up with signs of pancytopenia accompanied by macrothrombocytopenia and stomatocytosis. In addition, the blood sterol levels of the patient and his family were studied., Results: A novel homozygous c.904 + 5G > C intronic variant was detected in ABCG5 gene in index case. The mother and father were identified as carriers. The blood plant sterol levels of the patient and his family were studied, and the levels in the patient confirmed Sitosterolemia. Sitosterol levels decreased dramatically with restricted diet and ezetimibe treatment., Conclusion: In children, signs of Sitosterolemia may be subtle and the only symptom may be hematological. Therefore, Sitosterolemia should be kept in mind in children with stomatocytosis and macrothrombocytopenia., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Sitosterolemia is a rare inherited condition in which plant sterols are stored and deposited in the tissues. Described in 1974 by Battacharyya and Connor, it is characterized by tendon and tuberous xanthomas and a propensity to premature coronary atherosclerosis. We present the first reported case of the disease being manifest in the periorbital region. A 44-year-old man presented with a six-month history of swelling below the left eyebrow overlying the orbital rim, but without displacement of the globe. Magnetic resonance imaging identified a soft tissue mass within the orbit, with subsequent biopsy confirming a xanthogranulomatous process consistent with the diagnosis of sitosterolemia. Management of sitosterolemia aims to reduce plasma plant sterol concentrations which subsequently lowers serum cholesterol reducing the xanthomas and atherosclerotic cardiovascular diseases. This report highlights a rare, under-recognised condition (and indeed the first reporting periocular disease), and the potential dangers if misdiagnosed as hypercholesterolemia.

Background: Sitosterolemia is a lipid disorder characterized by the accumulation of phytosterols in plasma and organs, caused by mutations in the ABCG5 and/or ABCG8 genes. The disease is frequently misdiagnosed and mistreated as familial hypercholesterolemia (FH). To gain a better understanding of the disease, the current status of diagnosis and treatment of Chinese patients with sitosterolemia was reviewed and summarized., Method: Literature search was performed. The clinical features and molecular characteristics of Chinese patients with sitosterolemia were analysed. Four children with sitosterolemia and the treatment experience were described., Results: Fifty-five patients with sitosterolemia have been reported in China. These patients were aged from 3 months to 67 years at diagnosis, and the median was 8 years of age. Several complications, such as xanthomas in 47 patients (85%), thrombocytopenia in 17 patients (31%), anemia in 14 patients (25%), and cardiovascular damage in 12 patients (22%), were observed. Thirty-nine patients (71%) exhibited mutations in the ABCG5 gene, 15 patients (27%) showed mutations in ABCG8, and variations in both genes occurred in one patient (2%). A patient with two clinically rare diseases, namely, sitosterolemia and glycogen storage disease type VI (GSD VI)), is reported here for the first time. The four reported patients were treated with low cholesterol and phytosterol-limited diet alone or combined with cholestyramine. Even though decreases were observed for total plasma cholesterol (TC) and low-density-lipoprotein cholesterol (LDL-C), and these levels were as low as normal in some patients, the levels of plant sterols remained above the normal range. However, TC, LDL-C and plant sterol levels remained at high levels in patients treated with a control diet control only., Conclusions: The analysis reveals that different from Caucasians carrying mainly variations in ABCG8, most Chinese patients have mutations in the ABCG5 gene, and Arg446Ter, Gln251Ter, anArg389His might be hot-spot mutations in Chinese patients. The current survey provides clinical data to enable the development of a standardized protocol for the diagnosis and treatment of sitosterolemia in China., (© 2022. The Author(s).)

Background: Clinical reports show a positive correlation between phytosterol concentrations and severity of cholestatic liver disease markers in infants during long-term administration of parenteral lipid emulsions. Establishing a causal link between phytosterols and cholestasis has been complicated by confounding factors of lipid emulsion load, fatty acid composition, and vitamin E in many of these studies. The goal of this study is to determine whether altering the phytosterol concentration within a common soybean oil-based emulsion will alter the onset and severity of cholestasis in parenterally fed preterm piglets., Methods: Preterm piglets were administered, for 21 days, either enteral nutrition (ENT) or parenteral nutrition (PN) prepared from a soybean oil-based emulsion containing either 24.0% (depleted [DEP]), 100% (Intralipid; normal phytosterol [NP] concentration), or 144% (enriched [ENR]) total phytosterol concentration., Results: At the end of the study, plasma and liver phytosterol concentrations were highest in the ENR group, followed by NP and then DEP and ENT. Serum direct bilirubin, serum bile acids, and γ-glutamyltransferase were higher in the ENR and NP groups compared with either DEP or ENT groups. All PN lipid groups showed evidence of mild hepatic steatosis but no change in hepatic expression of proinflammatory cytokines or Farnesoid X receptor target genes., Conclusion: The increase in serum direct bilirubin was lower in the DEP group vs the lipid emulsions with normal or ENR phytosterols. Our results provide additional evidence that phytosterols are linked to an increase in serum markers of cholestasis in preterm PN-fed pigs., (© 2021 American Society for Parenteral and Enteral Nutrition.)

Sitosterolemia is an inherited metabolic disorder characterized by increased levels of plant sterols, such as sitosterol. This disease is caused by loss-of-function genetic mutations in the ATP-binding cassette (ABC) subfamily G member 5 or member 8 (ABCG5 or ABCG8, respectively), both of which play important roles in the selective excretion of plant sterols from the liver and intestine, leading to a failure to excrete plant sterols. Sitosterolemia, which is currently considered a rare genetic disorder, has been described as a phenocopy of homozygous familial hypercholesterolemia (FH). Typical phenotypes of sitosterolemia, including elevated low-density lipoprotein (LDL) cholesterol, tendon xanthomas, and premature coronary artery disease, overlap those of homozygous FH; however, there are substantial differences between these two diseases in terms of treatments and prognoses. Moreover, it is of note that sitosterolemia appears to be quite underdiagnosed, although accurate diagnosis and appropriate interventions will likely to lead to better prognoses compared with homozygous FH. Unlike cases of homozygous FH, dietary counseling is quite effective in reducing the LDL cholesterol as well as sitosterol of patients with sitosterolemia. In this chapter, we summarize the current understandings of this disease and provide useful tips for the diagnosis as well as better treatment of patients with sitosterolemia., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Sitosterolemia is a rare autosomal recessive disease characterized by phytosterol accumulation in the blood and tissues. However, the detailed clinical and genetic spectra are lacking., Objective: To describe and compare the clinical, biochemical, genetic, therapeutic, and follow-up characteristics of 55 pediatric and five adult sitosterolemia patients., Methods: Clinical, genetic and therapeutic data from 60 patients at Xinhua Hospital from January 2016 to June 2021 were retrospectively collected., Results: Pediatric patients' manifestations included xanthomas(93%), hematological disorders(30%), arthralgia(24%), splenomegaly(11%), atherosclerosis(10%). Adult patients had symptoms such as atherosclerosis(5/5), xanthomas(4/5), hematological disorders(3/5), arthralgia(3/5), splenomegaly(3/5). Elevated total cholesterol(TC) and low-density lipoprotein cholesterol(LDL-C) were observed in 96% patients (pediatric 98%, adult 3/4), and phytosterol levels in 100% patients. The age of onset was also negatively correlated with blood TC (P < 0.0001, r = -0.5548) and LDL-C (P = 0.0001, r = -0.4859) levels. Targeted treatments resulted in symptomatic remission(pediatric 96%, adult 4/5), and significantly decreased lipid and phytosterol levels(all P<0.05). In the dietary-therapy cohort(n=34), blood lipid levels decreased(all P<0.05). In the 13 pediatric patients from the dietary-therapy cohort who switched from dietary to combination therapy with ezetimibe, dietary therapy decreased TC and LDL-C levels by 54% and 52%, and ezetimibe further decreased them by 18% and 20%, respectively. Further, we identified 15 novel ABCG5/ABCG8 variants., Conclusions: This study expands the clinical and genetic spectra of sitosterolemia. The low-phytosterol diet is the cornerstone of sitosterolemia treatment. Ezetimibe can further decrease blood lipid levels and increase daily dietary phytosterol tolerance., Competing Interests: Declaration of Competing Interest There are no conflicts of interest to declare., (Copyright © 2021. Published by Elsevier Inc.)

Background: Sitosterolemia is a rare lipid disorder caused by mutations in adenosine triphosphate-binding cassette genes (ABCG) 5 and 8., Objective: To evaluate the phenotypic/genotypic features of sitosterolemia in a group of Turkish patients., Methods: Seven probands with unexplained hematologic abnormalities and their 13 relatives were enrolled. Sterol levels were measured by gas chromatography and genetic studies were performed using Sanger sequencing. Individuals were diagnosed with sitosterolemia if they were found to have frankly elevated sitosterol level >15 μg/mL and/or pathogenic variants of the ABCG5/ABCG8., Results: The seven probands and their six relatives  were diagnosed with frank sitosterolemia, and all these patients had hematologic abnormalities. The remaining seven relatives were asymptomatic heterozygous carriers. Three novel variants in the ABCG5 gene (c.161G>A, c.1375C>T, IVS10-1G>T), one novel variant in the ABCG8 gene (c.1762G>C) and one known variant in the ABCG5 gene (c.1336 C>T) were identified. No variant was identified in one case. The mean sitosterol level was significantly higher and mean platelet count was significantly lower in patients with homozygous variants compared to heterozygous variants (p<0.05, for all). Diets low in plant sterols were recommended for 13 symptomatic cases. Four homozygotes received ezetimibe, and their splenomegaly, anemia, and thrombocytopenia completely resolved except one., Conclusion: The five pathogenic variants identified in this study indicate the genetic heterogeneity of sitosterolemia in Turkish population. Patients with unexplained hematologic abnormalities (specifically macrothrombocytopenia) should have their sterol level measured as initial testing. Ezetimibe can be a good choice for sitosterolemia., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2021. Published by Elsevier Inc.)

Heart failure (HF) and cardiac arrhythmias share overlapping pathological mechanisms that act cooperatively to accelerate disease pathogenesis. Cardiac fibrosis is associated with both pathological conditions. Our previous work identified a link between phytosterol accumulation and cardiac injury in a mouse model of phytosterolemia, a rare disorder characterized by elevated circulating phytosterols and increased cardiovascular disease risk. Here, we uncover a previously unknown pathological link between phytosterols and cardiac arrhythmias in the same animal model. Phytosterolemia resulted in inflammatory pathway induction, premature ventricular contractions (PVC) and ventricular tachycardia (VT). Blockade of phytosterol absorption either by therapeutic inhibition or by genetic inactivation of NPC1L1 prevented the induction of inflammation and arrhythmogenesis. Inhibition of phytosterol absorption reduced inflammation and cardiac fibrosis, improved cardiac function, reduced the incidence of arrhythmias and increased survival in a mouse model of phytosterolemia. Collectively, this work identified a pathological mechanism whereby elevated phytosterols result in inflammation and cardiac fibrosis leading to impaired cardiac function, arrhythmias and sudden death. These comorbidities provide insight into the underlying pathophysiological mechanism for phytosterolemia-associated risk of sudden cardiac death., (© 2021. The Author(s).)

Sitosterolemia is an inherited metabolic disorder characterized by increased levels of plant sterols, such as sitosterol. This disease is caused by loss-of-function genetic mutations in ATP-binding cassette (ABC) subfamily G member 5 or member 8 (ABCG5 or ABCG8, respectively), both of which play important roles in selective excretion of plant sterols from the liver and intestine, leading to failure to prevent absorption of food plant sterols. This disorder has been considered to be extremely rare. However, accumulated clinical data as well as genetics suggest the possibility of a much higher prevalence. Its clinical manifestations resemble those observed in patients with familial hypercholesterolemia (FH), including tendon xanthomas, hyper LDL-cholesterolemia, and premature coronary atherosclerosis. We provide an overview of this recessive genetic disease, diagnostic as well as therapeutic tips, and the latest diagnostic criteria in Japan.

Xanthomas are visibly deformed cholesterol deposits that are commonly associated with lipid disorders, such as familial hypercholesterolemia (FH) or rare sitosterolemia. We present the first report of two cases of carotid sheath xanthomas in patients with lipid disorders. Case 1 involved a 26-year-old woman presenting with two heterogeneous mutations on the ABCG5 gene-as noted on genetic testing-who was finally diagnosed with sitosterolemia. Ultrasonography (US) revealed hypoechoic masses centered in the bilateral carotid sheath, which gradually reduced in size after diet control and the use of ezetimibe. Case 2 involved a 27-year-old man who was diagnosed with possible FH and had recurrent bilateral buttock xanthomas, as well as bilateral carotid sheath masses detected by US. Postoperative pathological examination of the resected right neck mass confirmed a xanthoma with proliferation of multinucleated giant cells and deposition of cholesterol clefts., Competing Interests: Declarations of Competing Interest None., (Copyright © 2021. Published by Elsevier Inc.)

Cerebrotendinous xanthomatosis (CTX), sitosterolemia, and Smith-Lemli Opitz syndrome (SLOS) are rare inborn errors of metabolism. The diagnoses of CTX and sitosterolemia are often delayed for many years because of lack of physician awareness, often resulting in significant and unnecessary progression of disease. CTX may present with chronic diarrhea, juvenile onset cataracts, strikingly large xanthomas, and neurologic disease in the setting of a normal serum cholesterol, but markedly elevated serum or plasma cholestanol levels. These patients have a defect in producing the bile acid chenodoxycholate, and oral chenodeoxycholate therapy is essential for these patients in order to prevent neurologic complications. Sitosterolemia can present with xanthomas, anemia, thrombocytopenia, splenomegaly, very premature heart disease, and serum cholesterol levels that may be normal or elevated, along with marked elevations of plasma β-sitosterol. These patients have a defect causing overabsorption of β-sitosterol, and the treatment of choice is oral ezetimibe. SLOS presents with growth delay, intellectual disability, multiple structural anomalies, and low serum cholesterol levels, and the defect is reduced cholesterol production. Treatment consists of dietary cholesterol supplementation and oral bile acid therapy which raises serum cholesterol levels and may improve symptoms. The metabolic and genetic defects in these disorders have been defined. There is no one in our field that has contributed more to the diagnosis and treatment of these disorders than Gerald Salen, MD, who died in late 2020 at 85 years of age. He will be greatly missed by his family, friends, and colleagues from around the world., Competing Interests: Declarations of Competing Interest None of the authors has any conflicts of interest at the present. Drs. Schaefer, Duell and Steiner have served as consultants for Retrophin, now known as Travere Therapeutics, San Diego, CA, in the past, but not in the last 12 months. Dr. Duell has institutional grants and support from Travere Therapeutics. This company manufactures and distributes chenodeoxycholic acid. Dr. Schaefer is an employee of Boston Heart Diagnostics, a clinical diagnostic laboratory that provides sterol testing. Dr. Steiner is an employee of PreventionGenetics, a laboratory that offers commercial genetic testing for these and other other disocorders; he received an honorarium for development and presentation of educational content for Medscape., (Copyright © 2021. Published by Elsevier Inc.)

Background and Aims: Phytosterol (PS) consumption is associated with lower total and LDL-cholesterol (LDL-c) concentrations, but its impact on cardiovascular risk is unclear. This study assessed the effect of usual intake of PS on markers of subclinical atherosclerosis in the Longitudinal Study of Adult Health (ELSA-Brasil)., Methods and Results: This cross-sectional study included 2560 participants of ELSA-Brasil, aged 48 (43-54) years, with available food frequency questionnaires (FFQ), coronary artery calcium (CAC) scores, carotid intima media thickness (cIMT), and carotid-femoral pulse wave velocity (cf-PWV), at baseline. Several logistic and linear regression models were used, and significance level was set at a P < 0.05. Mean values (SD) for PS consumption were 256 (198) mg/day, CAC 22.78 (110.54) Agatston Units, cf-PWV 9.07 (1.60) m/s and cIMT 0.57 (0.12) mm. PS consumption in Q4 was associated with lower total- and LDL-c levels, and with higher percentiles of cf-PWV (P < 0.001). Proportion of subjects in Q4 of PS consumption was 1.5 times higher among individuals in cf-PWV Q4, than in Q1 (P = 0.002, for comparisons among quartiles). There was a trend (P = 0.003) for higher cf-PWV with higher PS intake. In crude logistic and linear regressions, PS intake was associated with cf-PWV. In the adjusted models, these associations disappeared. No associations were found between PS and cIMT or CAC., Conclusions: In this large and apparently healthy cross-sectional sample from ELSA-Brasil, usual PS consumption was associated with lower total- and LDL-cholesterol, but not with markers of subclinical atherosclerosis., Competing Interests: Declaration of competing interest The author(s) declare(s) that there is no conflict of interest. The authors alone are responsible for the content and writing of the paper., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Purpose of Review: In this review, we summarize the genetics and mechanisms of sitosterolemia and sterol trafficking, and provide an update on the understanding of the prevalence of ABCG5 and ABCG8 variants and their role in human disease., Recent Findings: Defects in ABCG5/G8 result in the accumulation of xenosterols. It had been previously thought that near total LoF of one of the proteins was required to cause pathology. However, recently there was the first report of a patient with Sitosterolemia who was heterozygous for mutations in both genes. Moreover, large population studies have demonstrated the even simple heterozygous carriers are associated with altered lipid profiles and cardiovascular risk. Broader screening has added to the rapidly growing list of gene variants indicating that the prevalence of ABCG5/G8 variants is higher than previous thought, especially in patients with hypercholesterolemia., Summary: These findings support a strategy of measuring xenosterol levels in patients with hypercholesterolemia to screen for ABCG5/G8 variants, and then tailoring treatment with a sterol absorption inhibitor, like ezetimibe, where indicated. Xenosterol trafficking affects remnant clearance and maybe pathogenically linked to the increased risk of atherosclerosis., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Sitosterolemia is a lipid disorder characterized by the accumulation of dietary xenosterols in plasma and tissues caused by mutations in either ABCG5 or ABCG8 . ABCG5 ABCG8 encodes a pair of ABC half transporters that form a heterodimer (G5G8), which then traffics to the surface of hepatocytes and enterocytes and promotes the secretion of cholesterol and xenosterols into the bile and the intestinal lumen. We review the literature from the initial description of the disease, the discovery of its genetic basis, current therapy, and what has been learned from animal, cellular, and molecular investigations of the transporter in the twenty years since its discovery. The genomic era has revealed that there are far more carriers of loss of function mutations and likely pathogenic variants of ABCG5 ABCG8 than previously thought. The impact of these variants on G5G8 structure and activity are largely unknown. We propose a classification system for ABCG5 ABCG8 mutants based on previously published systems for diseases caused by defects in ABC transporters. This system establishes a framework for the comprehensive analysis of disease-associated variants and their impact on G5G8 structure-function.

We herein report a rare case presenting with severe hypercholesterolemia, massive Achilles tendon xanthomas, and multi-vessel coronary artery disease. Initially, the patient was misdiagnosed with familial hypercholesterolemia. However, a genetic analysis using our custom sequencing panel covering genes associated with Mendelian lipid disorders revealed him to have a genetic basis of sitosterolemia with compound heterozygous mutations in the adenosine triphosphate binding cassette subfamily G5 (ABCG5) gene. A comprehensive genetic analysis can be particularly useful for diagnosing cases with severe phenotypes, leading to appropriate and medical therapies. Our patient was refractory to statins, whereas ezetimibe and PCSK9 inhibitor with a low-plant-sterol diet successfully reduced his serum levels of low-density lipoprotein cholesterol.

Sitosterolemia is caused by homozygous or compound heterozygous gene mutations in either ATP-binding cassette subfamily G member 5 (ABCG5) or 8 (ABCG8). Since ABCG5 and ABCG8 play pivotal roles in the excretion of neutral sterols into feces and bile, patients with sitosterolemia present elevated levels of serum plant sterols and in some cases also hypercholesterolemia. A 48-year-old woman was referred to our hospital for hypercholesterolemia. She had been misdiagnosed with familial hypercholesterolemia at the age of 20 and her serum low-density lipoprotein cholesterol (LDL-C) levels had remained about 200-300 mg/dL at the former clinic. Although the treatment of hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors was ineffective, her serum LDL-C levels were normalized by ezetimibe, a cholesterol transporter inhibitor. We noticed that her serum sitosterol and campesterol levels were relatively high. Targeted analysis sequencing identified a novel heterozygous ABCG5 variant (c.203A>T; p.Ile68Asn) in the patient, whereas no mutations were found in low-density lipoprotein receptor (LDLR), proprotein convertase subtilisin/kexin type 9 (PCSK9), or Niemann-Pick C1-like intracellular cholesterol transporter 1 (NPC1L1). While sitosterolemia is a rare disease, a recent study has reported that the incidence of loss-of-function mutation in the ABCG5 or ABCG8 gene is higher than we thought at 1 in 220 individuals. The present case suggests that serum plant sterol levels should be examined and ezetimibe treatment should be considered in patients with hypercholesterolemia who are resistant to HMG-CoA reductase inhibitors.