BioHoFH - Biomarker for Homozygous Familial Hypercholesterolemia AN INTERNATIONAL, MULTICENTER, EPIDEMIOLOGICAL PROTOCOL

Homozygous familial hypercholesterolemia (HoFH) is a rare hereditary disorder of lipoprotein metabolism characterized by exceptionally high levels of low-density lipoprotein cholesterol (LDL-C). Clinical manifestations may vary but often include markedly premature coronary artery disease, supravalvular aortic stenosis due to aortic root atheroma, and cutaneous manifestations such as tendon xanthomata. Although there are no universally ac-cepted clinical diagnostic criteria for HoFH, an untreated serum LDL-C of >13 mmol/L (500 mg/dL), or an on-treatment LDL-C of more 8 mmol/L (300 mg/dL) together with the appearance of cutaneous xanthomata before the age of 10 years, have often been used to diagnose HoFH clinically. As molecular diagnostic techniques have advanced, genotyping of patients with severe hypercholesterolemia has become an integral part of clinical practice in many settings. This has led to the realization that the spectrum of clinical severity in HoFH is much wider than initially thought and that the clinical criteria often fail to identify patients with milder phenotypes.

Although the HoFH phenotype may result from mutations in multiple genes, low-density lipoprotein receptor (LDL-R) dysfunction is the final common pathophysiological pathway leading to LDL-C elevation in patients with HoFH and LDL-R mutations are by far the most common genetic causes of HoFH. Patients with HoFH secondary to LDL-R mutations inherit a mutated allele from each parent, resulting in severe functional impairment of the LDL-R pathway. Residual LDL-R activity may vary considerably between mutations. Patients with HoFH can be classified as receptor negative or receptor defective (<2% or 2%-25% of residual activity, respectively) based on LDL uptake studies in cultured fibroblasts, although receptor function is nowadays often inferred after the identification of specific mutations.

Historically, the prevalence of HoFH has been reported as 1 case per million. However, emerging studies suggest that the prevalence of HeFH, and consequently HoFH, may be higher than previously thought. Recent literature suggests an estimated prevalence of HeFH of ∼1 case in 2002 and of deleterious LDLR mutations in 0.45% of a control population and 1.9% of individuals with early-onset myocardial infarction or coronary artery dis-ease.Extrapolating from these data, the prevalence of HoFH is estimated to be ∼6 cases per million. Analysis of a Dutch database of molecularly defined HoFH suggested a prevalence of ∼1 case per 160,000-300,000. Prevalence data are, however, continuing to evolve, and these calculations could be underestimates or overestimates of the prevalence in the general patient population. Information on the prevalence of FH in non-European populations is generally limited, and conclusions about the possible worldwide prevalence remain speculative. However, as a result of founder effects, the prevalence of HeFH and HoFH is higher in certain populations such as the Afrikaners in South Africa, Christian Lebanese, and French Canadians.

The range of untreated and treated LDL-C levels in HoFH is wide. In two recent clinical tri-als of novel therapies for HoFH, the LDL-C levels at study entry in conventionally treated patients ranged from a mean of 8.7 ± 2.9 mmol/L (336 ± 112 mg/dL) to 11.4 ± 3.6 mmol/L (441 ± 139 mg/dL). Not all patients with HoFH have extreme LDL-C elevations. In a study from the Netherlands, only 50% of patients with molecularly defined HoFH met the clinical criterion of untreated LDL-C >13 mmol/L (500 mg/dL), with some patients presenting with untreated LDL-C levels as low as 4.4 mmol/L (170 mg/dL).

Reported LDL-C levels for clinical and genetic diagnoses of FH. Improved molecular diagnosis has led to the understanding that a conventional diagnosis of HoFH encompasses a wide range of underlying mutations with different effects on LDL-C levels, and highlights the need for caution in interpreting historical LDL-C values. Furthermore, some patients with clinical FH (10%-40%) lack an identified disease-causing mutation.