A case of sitosterolemia due to compound heterozygous mutations in <i>ABCG5</i>: clinical features and treatment outcomes obtained with colestimide and ezetimibe

Abstract

Abstract.Sitosterolemia is a rare, autosomal recessively inherited disorder of lipid metabolism caused by mutations in the “ATP-binding cassette, subfamily G” member 5 and 8 proteins (encoded by the ABCG5 and ABCG8 genes, respectively), which play critical roles in the intestinal and biliary excretion of plant sterols. We report the clinical features and treatment outcomes of an 18-month-old Japanese girl with sitosterolemia, who presented with multiple linear and intertriginous xanthomas around the joint areas. Serum lipid analyses revealed elevated levels of total cholesterol (T-Chol: 866 mg/dL), low density lipoprotein-cholesterol (LDL-C: 679 mg/dL), and plant sterols (sitosterol: 24.6 mg/dL, campesterol: 19.2 mg/dL, stigmasterol: 1.8 mg/dL). Compound heterozygous mutations (p.R419H and p.R389H) were identified in ABCG5. The patient was placed on a low cholesterol/low plant sterol diet and treated with colestimide (a bile acid sequestrant) and ezetimibe (an NPC1L1 inhibitor). Serum T-Chol and LDL-C levels decreased to normal within 2 mo, and plant sterol levels decreased by 30% within 4 mo. The xanthomas regressed gradually, and almost completely disappeared after 1.5 yr of treatment. No further reductions of plant sterol levels were observed. Long-term follow-up is important to verify appropriate therapeutic goals to prevent premature atherosclerosis and coronary artery disease.

Two novel variants of the ABCG5 gene cause xanthelasmas and macrothrombocytopenia: a brief review of hematologic abnormalities of sitosterolemia

“…Several of these are nonsense variants (eight) or frameshift variants (three), or affect the splicing site (eight) or code for truncated polypeptides (two). Others are missense variants (seven) that interfere with the formation of stable ABCG5–ABCG8 heterodimers and their trafficking out of the endoplasmic reticulum (Fig. ).…”

“…Clinical features of STLS usually include tendinous and cutaneous xanthomas, premature coronary atherosclerosis and derived complications, and arthritis or arthralgia . These characteristics are shared with familial hypercholesterolemia (FH), so STSL may be misdiagnosed as homozygous FH, especially in pediatric patients . Unlike patients with FH, patients with STSL usually respond well to a low‐cholesterol diet and/or bile acid sequestrants such as colestimide and colestyramine .…”

“…These characteristics are shared with familial hypercholesterolemia (FH), so STSL may be misdiagnosed as homozygous FH, especially in pediatric patients . Unlike patients with FH, patients with STSL usually respond well to a low‐cholesterol diet and/or bile acid sequestrants such as colestimide and colestyramine . Hematologic abnormalities, e.g.…”

Hereditary stomatocytosis: An underdiagnosed condition

“…Severe hypercholesterolemia has been described in these patients . It is caused by increased intestinal absorption and decreased biliary excretion of sterols resulting from biallelic mutations (homozygous of compound heterozygous state) in either ABCG5 or ABCG8 (Table a) . Patients with phytosterolemia show extreme phenotypic heterogeneity, ranging from almost asymptomatic patients to those with severe hypercholesterolemia, leading to accelerated atherosclerosis and premature cardiac death .…”

“…Ezetimibe is the first‐line drug therapy for these patients, but bile acid sequestrants can be also used, such as colestimide and colestyramine. Evaluation of adherence at such diet should be carefully evaluated in pediatric patients, due to the possibly delayed growth …”