Extreme Lipid Phenotypes in Autosomal Dominant Hypercholesterolemia: The ELePHANT Study

Autosomal Dominant Hypercholesterolemia (ADH) is characterized by sharply
elevated plasma LDL-C levels and is caused by mutations in LDLR, APOB and/or
PCSK9.
Homozygosity for mutations in these genes is commonly considered to result in
an extreme clinical phenotype (LDL-C levels above 13mmo/L). In a recent study,
however, we observed that LDL-C levels were considerably lower in 50% of the
patients with molecular defined homozygous ADH.
In contrast; in 0.05% of all heterozygous ADH patients (with an expected LDL-C
level in the range 5-8 mmol/L) we observed LDL-C levels that were considerably
higher and based on clinical criteria, one would these patients classify as
hoADH. This exemplifies the disconnect between the molecular diagnosis and the
clinical phenotype. Aim of our study is to identify (epi) genetic and
biological factors underlying these extremes in phenotypical variation.
Moreover, vascular imaging studies will be performed to study the consequences
of the dyslipidemia in these two patient cohorts. This will contribute to a new
definition of homozygous ADH.

1) To investigate the underlying mechanisms of the variable ADH phenotypes in
two extreme ADH populations.
- Genetically homozygous patients with a phenotype resembling the phenotype
encountered in heterozygous ADH patients.
- Genetically heterozygous patients who were presented with a phenotype similar
to the clinical phenotype seen in clinical homozygous ADH patients

2) To study the vascular consequences of these extreme ADH phenotypes by using
cIMT measurements.

Observational cross-sectional study

This study does not involve interventions with significant risk for
participating individuals. The only risk exists of possible development of a
haematoma on the injection site, after blood sampling and possible development
of a scar on the side of the skinbiopsy. Measurement of carotid Intima Media
Thickness is a non-invasive procedure using ultrasonography.