title: Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, PO Box 22660, 1100 DD Amsterdam, The Netherlands.
authors.forename: Barbara
authors.initials: B
authors.lastname: Sjouke
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, PO Box 22660, 1100 DD Amsterdam, The Netherlands.
authors.forename: D Meeike
authors.initials: DM
authors.lastname: Kusters
authors.affiliation: Foundation for the Identification of Persons with Inherited Hypercholesterolemia, Paasheuvelweg 15, 1105 BE Amsterdam, The Netherlands.
authors.forename: Iris
authors.initials: I
authors.lastname: Kindt
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, PO Box 22660, 1100 DD Amsterdam, The Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: Besseling
authors.affiliation: Department of Experimental Vascular Medicine, Academic Medical Center, PO Box 22660, 1100 DD Amsterdam, The Netherlands.
authors.forename: Joep C
authors.initials: JC
authors.lastname: Defesche
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Erasmus University of Rotterdam, 's Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
authors.forename: Eric J G
authors.initials: EJ
authors.lastname: Sijbrands
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Erasmus University of Rotterdam, 's Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
authors.forename: Jeanine E
authors.initials: JE
authors.lastname: Roeters van Lennep
authors.affiliation: Department of Internal Medicine, Division of Vascular Medicine, Radboud University Nijmegen Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Anton F H
authors.initials: AF
authors.lastname: Stalenhoef
authors.affiliation: Department of Paediatrics, Academic Medical Center, PO Box 22660, 1100 DD Amsterdam, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Wiegman
authors.affiliation: Department of Internal Medicine, Division of Vascular Medicine, Radboud University Nijmegen Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: de Graaf
authors.affiliation: Department of Experimental Vascular Medicine, Academic Medical Center, PO Box 22660, 1100 DD Amsterdam, The Netherlands.
authors.forename: Sigrid W
authors.initials: SW
authors.lastname: Fouchier
authors.affiliation: Department 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 j.s.jansen@amc.uva.nl.
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.affiliation: Department 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 j.s.jansen@amc.uva.nl.
authors.forename: G Kees
authors.initials: GK
authors.lastname: Hovingh
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D053299:Apolipoprotein B-100 / Q000235:genetics; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000453:epidemiology* / Q000235:genetics; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009426:Netherlands / Q000453:epidemiology; D010641:Phenotype; D015995:Prevalence; D011379:Prognosis; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics; D055815:Young Adult
chemical_list: C569471:APOB protein, human; D053299:Apolipoprotein B-100; C573412:LDLR protein, human; D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
keywords: Autosomal dominant hypercholesterolemia; Familial hypercholesterolaemia; Homozygous; Phenotype; Prevalence