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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.
Insights
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.
Abstract:
We report about a brother and sister having clinical symptoms similar to those of homozygous familial hypercholesterolemia (FH) but surprisingly who have normal low density lipoprotein (LDL) receptor activities (M. Harada-Shiba et al, J Jpn Atheroscler Soc 1991; 19:227-242). The LDL receptor activities in the cultured fibroblasts of the patients were compared with those of FH heterozygotes and homozygotes for the LDL receptor mutation. The LDL receptor activities in the cultured fibroblasts of the patients were in the normal range, but their plasma cholesterol concentrations were similar to patients with homozygous FH. After the plasma LDL was removed by plasmapheresis in both patients, plasma cholesterol levels started to increase. The "rebound" of plasma cholesterol was compared with those for heterozygous and homozygous FH. The plasma cholesterol levels of the patients, which were greater than 410 mg/dl 2 weeks after plasmapheresis, were much higher than those of FH heterozygotes (232-311 mg/dl) but similar to those of FH homozygotes (345-464 mg/dl). The urinary mevalonate excretion rate, which reflects the rate of whole-body cholesterol synthesis, was higher for the brother (patient 1, 32.6 nmol/kg.day-1) than for the normal subjects (17.7 +/- 4.1 nmol/kg.day-1) but was similar to those of FH homozygotes (31.2 +/- 4.3 nmol/kg.day-1) and heterozygotes (29.8 +/- 10.9 nmol/kg.day-1). To estimate the catabolic and production rates of cholesterol in the brother, the time course for the increment in the total cholesterol level after plasmapheresis was analyzed by the two-compartment model.(ABSTRACT TRUNCATED AT 250 WORDS)