Aortic Xanthomatosis With Coronary Ostial Occlusion in a Child Homozygous for a Nonsense Mutation in
            <i>ABCG8</i>

Mymin, David; Wang, Jian; Fröhlich, Jiří; Hegele, Robert A.

doi:10.1161/01.cir.0000050545.21826.ad

Cited by 49 publications

(38 citation statements)

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“…They are expressed primarily in the liver and in-testine (21)(22)(23). Since the discovery of these two genes, several mutations responsible for sitosterolemia have been described (21)(22)(23)(24)(25)(26)(27). We present two contrasting mutations in subjects with sitosterolemia.…”

Section: Sitosterolemia [Mendelian Inheritance In Man (Mim)mentioning

confidence: 99%

Phenotypic heterogeneity of sitosterolemia

Wang

Joy

Mymin

et al. 2004

Journal of Lipid Research

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Sitosterolemia is a rare autosomal recessive disorder of lipoprotein metabolism characterized by xanthomas and increased plasma concentrations of plant sterols, such as sitosterol. Causative mutations occur in either the ABCG5 or ABCG8 gene, each of which encodes a sterol half-transporter expressed in the intestine. We report five Canadian subjects with nonsense mutations in these half-transporters: four related Caucasian subjects were homozygous for the ABCG8 S107X mutation, and one unrelated Japanese-Canadian subject was homozygous for a complex insertion/deletion (I/D) mutation in ABCG5 exon 3. A female subject with each mutation was symptomatic with coronary atherosclerosis: a 5-year-old ABCG8 S107X homozygote and a 75-year-old ABCG5 exon 3 I/D homozygote; these represent the extreme ends of the spectrum of vascular involvement in sitosterolemia. The largest reductions in plasma concentrations of sitosterol and LDL-cholesterol were seen with ezetimibe or bile acid sequestrant treatment, and less dramatic reductions were seen with statin drug treatment. These findings extend the range of clinical phenotypes in sitosterolemia caused by nonsense mutations in either ABCG5 or

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Section: Sitosterolemia [Mendelian Inheritance In Man (Mim)mentioning

confidence: 99%

Phenotypic heterogeneity of sitosterolemia

Wang

Joy

Mymin

et al. 2004

Journal of Lipid Research

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“…Deficiency of these transporters impairs plant sterol excretion from the enterocytes and hepatocytes, resulting in the accumulation of plant sterols in the plasma and tissues. Sitosterolemia is clinically characterized by massive xanthomatosis and premature atherosclerosis, which often causes the early onset of cardiovascular diseases and fatal myocardial infarction [12][13][14][15][16][17] . Some patients with sitosterolemia also exhibit other clinical findings, including hemolysis, platelet abnormalities and hypersplenism [18][19][20] .…”

Section: Introductionmentioning

confidence: 99%

Current Therapy for Patients with Sitosterolemia –Effect of Ezetimibe on Plant Sterol Metabolism

Tsubakio-Yamamoto

Nishida

Nakagawa-Toyama

et al. 2010

JAT

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Sitosterolemia is a rare, autosomal recessive inherited sterol storage disease associated with high tissue and serum plant sterol concentrations, caused by mutations in the adenosine triphosphate-binding cassette (ABC) transporter ABCG5 or ABCG8 genes. Markedly increased serum concentration of plant sterols. such as sitosterol and campesterol, cause premature atherosclerosis and massive xanthomas. Hitherto known treatments for sitosterolemia, including a low-sterol diet, bile-salt binding resins, ileal bypass surgery and low density lipoprotein (LDL) apheresis have not yielded sufficient reduction of serum plant sterol levels and many patients show a sustained elevation of plant sterol levels, subsequently developing premature atherosclerotic cardiovascular diseases. Ezetimibe, an inhibitor of intestinal cholesterol absorption through its binding to Niemann-Pick C1-like 1 (NPC1L1), has been widely used for decreasing serum LDL-cholesterol levels in patients with hypercholesterolemia. Ezetimibe also reduces the gastrointestinal absorption of plant sterols, thereby also lowering the serum concentrations of plant sterols. This pharmacological property of ezetimibe shows its potential as a novel effective therapy for sitosterolemia. In the current review, we discuss the current therapy for patients with sitosterolemia and present two Japanese adolescent patients with this disease, one of whom underwent percutaneous coronary intervention for accelerated coronary atherosclerosis. Ezetimibe administration in addition to conventional drug therapy successfully reduced serum sitosterol levels by 51.3% and 48.9%, respectively, in the two patients, demonstrating ezetimibe as a novel and potent treatment agent for sitosterolemia that could work additively with conventional drug therapy. J Atheroscler Thromb, 2010; 17:891-900.

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“…One member of the family, ABCG5, has been implicated as an etiological agent in motor neuron disease. Mutations in ABCG5 and ABCG8 have been found in sitosterolemic patients, but those subjects do not develop motor neuron disease (11)(12)(13)(14)(15)(16). Similarly, mice in which ABCG5 and ABCG8 have been inactivated develop sitosterolemia but not motor neuron disease (17).…”

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Liver X receptor β (LXRβ): A link between β-sitosterol and amyotrophic lateral sclerosis–Parkinson's dementia

Kim¹,

Fan²,

Gabbi³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

122

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Administration of ␤-sitosterol (42 mg/kg per day) for 3 weeks to 8-month-old male LXR␤ ؊/؊ mice resulted in the death of motor neurons in the lumbar region of the spinal cord and loss of tyrosine hydroxylase-positive dopaminergic neurons in the substantia nigra. In mice at 5 months of age, ␤-sitosterol had no observed toxicity but at 16 months of age, it caused severe paralysis and symptoms typical of dopaminergic dysfunction in LXR␤ ؊/؊ mice. WT mice were not affected by these doses of ␤-sitosterol. In 5-month-old mice, levels of the intestinal transporters, ABCG5/8 and Niemann-Pick C1 Like 1, were not affected by loss of liver X receptor (LXR) ␤ and/or treatment with ␤-sitosterol nor were there changes in plasma levels of cholesterol or ␤-sitosterol. In 8-monthold LXR␤ ؊/؊ mice there was activation of microglia in the substantia nigra pars reticulata and aggregates of ubiquitin and TDP-43 in the cytoplasm of large motor neurons in the lumbar spinal cord. Brain cholesterol concentrations were higher in LXR␤ ؊/؊ than in their WT counterparts, and treatment with ␤-sitosterol reduced brain cholesterol in both WT and LXR␤ ؊/؊ mice. In LXR␤ ؊/؊ mice but not in WT mice levels of 24-hydrocholesterol were increased upon ␤-sitosterol treatment. These data indicate that multiple mechanisms are involved in the sensitivity of LXR␤ ؊/؊ mice to ␤-sitosterol. These include activation of microglia, accumulation of protein aggregates in the cytoplasm of large motor neurons, and depletion of brain cholesterol.central nervous system ͉ cholesterol ͉ microglia ͉ neurodegenerative disease ͉ nuclear receptor

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Aortic Xanthomatosis With Coronary Ostial Occlusion in a Child Homozygous for a Nonsense Mutation in ABCG8

Cited by 49 publications

References 0 publications

Phenotypic heterogeneity of sitosterolemia

Phenotypic heterogeneity of sitosterolemia

Current Therapy for Patients with Sitosterolemia –Effect of Ezetimibe on Plant Sterol Metabolism

Liver X receptor β (LXRβ): A link between β-sitosterol and amyotrophic lateral sclerosis–Parkinson's dementia

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