ESPE Abstracts (2018) 89 P-P2-173

Familial Hypercholesterolemia Due to Homozygous LDLRAP1 Mutation: Variability of Phenotype and Response to Medical Therapy

Evangelia Panoua, Johannes Schumacherb & Joachim Woelflea


aPediatric Endocrinology Division, Children’s Hospital, University of Bonn, Bonn, Germany; bInstitute of Human Genetics, University of Bonn, Bonn, Germany


Background: Familial hypercholesterolemia (FH) leads to markedly elevated circulating levels of low-density lipoprotein cholesterol (LDL-C) and is associated with a significantly increased cardiovascular mortality already in childhood and adolescence. FH is caused by dominant mutations in the genes encoding LDL-receptor (LDLR), ApoB-100 and protein convertase subtilin/kexin9 (PCSK9), whereas rarely recessive forms due to mutations in LDL receptor adaptor protein 1 (LDLRAP1) have been reported. Treatment strategies include lipid apheresis, plasmapheresis, pharmacological therapy with statins, PCSK9 inhibitors and bile acid sequestrants, and in few cases liver transplantation.

Objective: To describe the clinical course and response to pharmacotherapy in two patients with homozygous FH due to a homozygous LDLRAP1 gene mutation.

Methods/results: We report on two siblings of consanguinous Syrian parents with a late diagnosis of FH. The older sibling, a 10.5-year-old girl presented in our outpatient clinic for treatment of ‘molluscum contagiosum’ after a five-year-long history of exanthema on the extensor surfaces of her extremities. Based on the morphological appearance we suspected eruptive xanthomas. Subsequent biochemical analysis revealed drastically elevated levels of total cholesterol (18.4 mmol/l) and LDL-C (14.3 mmol/l). In addition, ultrasound of the carotid arteries demonstrated abnormal carotid intima-media thickness with small atherosclerotic plaque lesions. A 9-year-old brother did not yet present xanthomas. However, his laboratory tests also demonstrated significantly elevated levels of total cholesterol (9.8 mmol/l) and LDL-C (7.2 mmol/l). All remaining family members did neither exhibit hyperlipidaemia nor any history of cardiovascular diseases. Based on the biochemical findings and clinical picture, we suspected FH and started atorvastatin and ezetimibe treatment in both subjects, with a final daily dosage of atorvastatin 40 and 20 mg, respectively, and ezetimibe 10 mg in both. Combination therapy led to a decrease of total cholesterol to 5.5 mmol/l (girl) and 4.8 mmol/l (boy), respectively, and LDL-C of 3.2 and 3.3 mmol/l, respectively after 3 months. So far combination pharmacotherapy was efficient and safe for 12 months, with no relevant adverse events. Genetic analysis of the LDLRAP1 gene revealed a previously described homozygous mutation in the LDLRAP1 gene (c.406C>T; p.Gln136*) in both siblings, probably leading to an extremely shortened, non-functional protein.

Conclusion: Pharmacological combination therapy with statin/ezetimibe can effectively decrease cholesterol concentrations into the target range in homozygous FH. Still, to avoid accelerated atheromatous disease, an earlier diagnosis of FH through a general screening program would be warranted.

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