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Siblings with normal LDL receptor activity and severe hypercholesterolemia
M Harada-Shiba1, S Tajima, S Yokoyama
1National Cardiovascular Center, Department of Etiology, Osaka, Japan.
Arteriosclerosis and Thrombosis : a Journal of Vascular Biology
|September 1, 1992
Summary
This study investigates siblings with familial hypercholesterolemia (FH) symptoms but normal LDL receptor activity. Their cholesterol levels rebound significantly after plasmapheresis, similar to homozygous FH patients, indicating a potential alternative pathway for high cholesterol.
Area of Science:
- Biochemistry
- Genetics
- Cardiovascular Medicine
Background:
- Familial hypercholesterolemia (FH) is typically caused by LDL receptor mutations.
- This study examines siblings presenting with FH symptoms despite normal LDL receptor activity.
Purpose of the Study:
- To investigate the underlying cause of severe hypercholesterolemia in patients with seemingly normal LDL receptor function.
- To compare cholesterol metabolism and response to plasmapheresis in these patients versus known FH genotypes.
Main Methods:
- Assessed LDL receptor activity in cultured fibroblasts.
- Measured plasma cholesterol levels before and after plasmapheresis.
- Analyzed urinary mevalonate excretion as a marker of cholesterol synthesis.
- Utilized a two-compartment model to analyze cholesterol kinetics.
Main Results:
- Patients exhibited normal LDL receptor activity but severely elevated plasma cholesterol, akin to homozygous FH.
- Plasma cholesterol levels rebounded rapidly and significantly after plasmapheresis, exceeding heterozygous FH levels.
- Urinary mevalonate excretion was elevated, suggesting increased whole-body cholesterol synthesis.
Conclusions:
- The findings suggest a potential novel mechanism contributing to severe hypercholesterolemia independent of canonical LDL receptor defects.
- Further research is warranted to elucidate the specific molecular pathways involved in this FH variant.