CMAJ • April 11, 2006; 174 (8). doi:10.1503/cmaj.051313.
© 2006 CMA Media Inc. or its licensors
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Review

Heterozygous familial hypercholesterolemia: an underrecognized cause of early cardiovascular disease

George Yuan, Jian Wang and Robert A. Hegele

From the Department of Medicine (Yuan, Hegele), Schulich School of Medicine and Dentistry, University of Western Ontario, and the Blackburn Cardiovascular Genetics Laboratory (Wang, Hegele), Robarts Research Institute, London, Ont.

Correspondence to: Dr. Robert A. Hegele, Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, 406—100 Perth Dr., London ON N6A 5K8; fax 519 663-3037; hegele{at}robarts.ca

Abstract

Heterozygous familial hypercholesterolemia (HeFH) is a monogenic disorder that affects about 1 in 500 people, with a higher prevalence in certain subpopulations such as people of Quebecois, Christian Lebanese and Dutch South Afrikaner extraction. HeFH is characterized by cholesterol deposits affecting the corneas, eyelids and extensor tendons; elevated plasma concentrations of low-density lipoprotein (LDL) cholesterol; and accelerated vascular disease, especially coronary artery disease (CAD). Although HeFH is genetically heterogeneous, it is most often caused by heterozygous mutations in the LDLR gene encoding the LDL receptor. We describe a man who was diagnosed with HeFH after he had a myocardial infarction at 33 years of age. By DNA sequence analysis, he was found to have a heterozygous splicing mutation in his LDLR gene. This discovery expanded the growing mutational spectrum in patients with HeFH in Ontario. Given that HeFH is a treatable cause of early vascular disease, it is important that this condition be recognized, diagnosed and treated in affected patients; but as yet, there is no consensus on the best approach. Diagnostic criteria based on family history and clinical presentation have been proposed for patients with suspected HeFH. Biochemical or molecular screening might be considered to detect new cases of HeFH in populations with a relatively high HeFH prevalence and a relatively small number of possible causative mutations. So far, however, the most cost-effective and efficient systematic strategy to detect previously undiagnosed cases of HeFH is still cascade testing: clinical and biochemical screening of close relatives of the proband patient diagnosed with HeFH. Pharmacologic treatment of HeFH is cost-effective.




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