Diagnosis and Management of Sitosterolemia 2021

Tada, Hayato; Nomura, Akihiro; Ogura, Mariko; Ikewaki, Katsunori; Ishigaki, Yasushi; Inagaki, Kyoko; Tsukamoto, Kazuhisa; Dobashi, Kazushige; Nakamura, Kimitoshi; Hori, Mika; Matsuki, Kota; Yamashita, Shizuya; Yokoyama, Shinji; Kawashiri, Masa‐aki; Harada‐Shiba, Mariko

doi:10.5551/jat.rv17052

Cited by 65 publications

(65 citation statements)

References 56 publications

(64 reference statements)

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“…Limiting phytosterols and cholesterol should be the first strategy (Fig. 2 ) [ 35 , 36 ]. For patients with an incomplete response to ezetimibe, combination with cholestyramine may be a feasible additional treatment [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

Features of chinese patients with sitosterolemia

Zhou

Su²,

Cai³

et al. 2022

Lipids Health Dis

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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.

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Section: Discussionmentioning

confidence: 99%

Features of chinese patients with sitosterolemia

Zhou

Su²,

Cai³

et al. 2022

Lipids Health Dis

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“…Hayato Tada suggested that sitosterolemia can be diagnosed if the following conditions are all met at the same time ( 25 ): (1) clinical manifestations (xanthoma of skin or tendon); (2) laboratory tests (serum sitosterol ≥1 mg/dl); (3) familial hypercholesterolemia and cerebrotendinous xanthomatosis are excluded; (4) pathogenic mutations ABCG5 or ABCG8 . But the clinical manifestations of sitosterolemia are highly heterogeneous, although the genotype and phenotype lack an obvious correlation, and most laboratories lack conditions for phytosterol determination ( 26 ).…”

Section: Discussionmentioning

confidence: 99%

“…And based on the pathophysiology of sitosterolemia,ezetimibe and low phytosterols diet are currently effective methods for the treatment of sitosterolemia. Ezetimibe, a Niemann-Pick C1 Like 1 inhibitor, can effectively reduce plasma phytosterols and cholesterol in patients with sitosterolemia by affecting the absorption of various sterols in the intestine ( 25 , 28 – 30 ).…”

Section: Discussionmentioning

confidence: 99%

Clinical and Genetic Analysis of a Family With Sitosterolemia Caused by a Novel ATP-Binding Cassette Subfamily G Member 5 Compound Heterozygous Mutation

Shen

Chen

et al. 2022

Front. Cardiovasc. Med.

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Sitosterolemia (OMIM ##210250), also known as phytosterolemia, is a rare autosomal recessive disorder caused by mutations in the ATP-binding cassette subfamily G member 5 (ABCG5) or member 8 (ABCG8) genes. This leads to abnormal functions of the transporter sterolin-1 protein encoded by ABCG5 and sterolin-2 protein encoded by ABCG8, respectively, which can hinder the formation of stable ABCG5/G8 heterodimers, decreasing its ability to transport sterols. As a result, phytosterols in tissue or plasma are significantly increased, leading to early onset atherosclerosis-related diseases and xanthelasma of tendons and skin. In this study, whole exome sequencing was performed on a Chinese Han proband with sitosterolemia to capture the target gene and screen for suspected pathogenic mutations. Sanger sequencing of the family members was performed to verify the relationship between family genetics and phenotypes. The structural and functional changes in the transporter sterolin-1 protein after the responsible mutation were predicted using bioinformatics analysis. A novel compound heterozygous mutation in the ABCG5 gene (NM_022436) was identified in a proband with sitosterolemia, one of which was inherited from the father: c.296T >G (p.M99R), and one from the mother: c.−76 C >T. SIFT, Polyphen2, and Mutation Taster software predicted that p.M99R may be the responsible variant and a novel variant. RNAFold software predicts that c.−76 C >T may affect the transcriptional information or the binding of RNA binding proteins by regulating the structure of RNA, and ultimately affect gene transcription or RNA stability and translation. Swiss model software predicts that the amino acid sequence around p.M99R is highly conserved, and p.M99R leads to instability of the tertiary structure of the ABCG5/ABCG8 heterodimer. GPS 5.0 predicted that M99R affects the phosphorylation of nearby amino acid sequences, and DUET and VarSite software predicted that M99R affects the stability of sterolin-1 and cause disease. The p.M99R and c.−76 C >T mutations led to the formation of unstable heterodimers, which disturbed sterol absorption and excretion in vivo. The compound heterozygous variants c.296 T >G (p.m99r) and C.−76 C >T on exon 3 of ABCG5 in this family may be the molecular genetic basis of sitosterolemia.

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“…ABCG5 and ABCG8 are cause sitosterolemia, which is a recessive disorder. 84 The effect size of ABCG5 mutation may be smaller than that of LDLR mutation. Moreover, a single rare mutation in both genes can increase LDL cholesterol levels and the risk of CAD.…”

Section: Factors Contributing To the Phenotypic Variations Of Fhmentioning

confidence: 99%

Individualized Treatment for Patients With Familial Hypercholesterolemia

Tada

Takamura

Kawashiri

2022

J Lipid Atheroscler

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Familial hypercholesterolemia (FH) is one of the most common and, therefore, important inherited disorders in preventive cardiology. This disease is mainly caused by a single pathogenic mutation in the low-density lipoprotein receptor or its associated genes. Moreover, it is correlated with a high risk of cardiovascular disease. However, the phenotype severity even in this monogenic disease significantly varies. Thus, the current study aimed to describe FH and its importance and the factors (inherited and acquired) contributing to differences in phenotype severity. Different lipid-modification therapies according to these factors can lead to individualized treatments, which are also essential in the general populations.

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Diagnosis and Management of Sitosterolemia 2021

Cited by 65 publications

References 56 publications

Features of chinese patients with sitosterolemia

Features of chinese patients with sitosterolemia

Clinical and Genetic Analysis of a Family With Sitosterolemia Caused by a Novel ATP-Binding Cassette Subfamily G Member 5 Compound Heterozygous Mutation

Individualized Treatment for Patients With Familial Hypercholesterolemia

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