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Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype–phenotype relationship, and clinical outcome

Barbara SjoukeDepartment of Vascular Medicine, Academic Medical Center, PO Box 22660, 1100 DD Amsterdam, The NetherlandsD. Meeike KustersDepartment of Vascular Medicine, Academic Medical Center, PO Box 22660, 1100 DD Amsterdam, The NetherlandsIris KindtJoost BesselingDepartment of Vascular Medicine, Academic Medical Center, PO Box 22660, 1100 DD Amsterdam, The NetherlandsJoep C. DefescheDepartment of Experimental Vascular Medicine, Academic Medical Center, PO Box 22660, 1100 DD Amsterdam, The NetherlandsEric J.G. SijbrandsJeanine E. Roeters van LennepAnton F. H. StalenhoefDepartment of Internal Medicine, Division of Vascular Medicine, Radboud University Nijmegen Medical Center, PO Box 9101, 6500 HB Nijmegen, The NetherlandsAlbert WiegmanDepartment of Paediatrics, Academic Medical Center, PO Box 22660, 1100 DD Amsterdam, The NetherlandsJacqueline de GraafDepartment of Internal Medicine, Division of Vascular Medicine, Radboud University Nijmegen Medical Center, PO Box 9101, 6500 HB Nijmegen, The NetherlandsSigrid W. FouchierDepartment of Experimental Vascular Medicine, Academic Medical Center, PO Box 22660, 1100 DD Amsterdam, The NetherlandsJohn J.P. KasteleinDepartment of Vascular Medicine, Academic Medical Center, PO Box 22660, 1100 DD Amsterdam, The Netherlands Department of Vascular Medicine, Academic Medical Center, Meibergdreef 9, Room F4-159.2, 1105 AZ Amsterdam, The Netherlands [email protected]G. Kees HovinghDepartment of Vascular Medicine, Academic Medical Center, PO Box 22660, 1100 DD Amsterdam, The Netherlands Department of Vascular Medicine, Academic Medical Center, Meibergdreef 9, Room F4-159.2, 1105 AZ Amsterdam, The Netherlands [email protected]

2014en

ABI

Annotatsiya

AIMS: Homozygous autosomal dominant hypercholesterolaemia (hoADH), an orphan disease caused by mutations in low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin-kexin type 9 (PCSK9), is characterized by elevated plasma low-density lipoprotein-cholesterol (LDL-C) levels and high risk for premature cardiovascular disease (CVD). The exact prevalence of molecularly defined hoADH is unknown. Therefore, we investigated the prevalence and phenotypical characteristics of this disease in an open society, i.e. the Netherlands. METHODS AND RESULTS: The database of the nationwide ADH molecular diagnostic center was queried to identify all molecularly defined hoADH patients. Carriers of non-pathogenic mutations were excluded. Medical records were analysed for data regarding lipid levels and CVD events. Of 104,682 individuals screened for molecular defects, 49 were classified as hoADH (0.05%); 20 were true homozygotes, 25 were compound heterozygotes for LDLR mutations, and 4 were homozygous for APOB mutations. No bi-allelic PCSK9 mutation carriers were identified. Consequently, the prevalence of hoADH was estimated to be ∼1 : 300,000. Mean LDL-C levels prior to lipid-lowering treatment were 12.9 ± 5.1 mmol/L (range 4.4-21.5 mmol/L). Surprisingly, only 50% of the patients met the clinical criteria for hoADH (LDL-C >13.0 mmol/L); 29% of patients suffered from a CVD event. CONCLUSION: The prevalence of molecularly defined hoADH is much higher and the clinical phenotype is more variable than previously assumed. In light of the fact that novel therapies are, or will be registered for the treatment of hoADH patients, an uniform definition of hoADH either as a phenotypic or molecular entity is warranted in order to identify patients who are considered to be eligible for these novel agents.

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DOI: 10.1093/eurheartj/ehu058

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