Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene - Long-term follow-up and treatment response

Objective - Analysis of long-term (30 years) clinical history and response to treatment of 13 patients with the D374Y mutation of PCSK9 (PCSK9 patients) from 4 unrelated white British families compared with 36 white British patients with heterozygous familial hypercholesterolemia attributable to 3 specific mutations in the low-density lipoprotein (LDL) receptor gene (LDLR) known to cause severe phenotype. Methods and Results - The PCSK9 patients, when compared with the LDLR patients, were younger at presentation (20.8 +/- 14.7 versus 30.2 +/- 15.7 years; P = 0.003), had higher pretreatment serum cholesterol levels (13.6 +/- 2.9 versus 9.6 +/- 1.6 mmol/ L; P = 0.004) that remained higher during treatment with simvastatin (10.1 +/- 3.0 versus 6.5 +/- 0.9 mmol/ L; P = 0.006), atorvastatin (9.6 +/- 2.9 versus 6.4 +/- 1.0 mmol/ L; P = 0.006), or current lipid-lowering therapy, including LDL apheresis and partial ileal bypass in 2 PCSK9 patients (7.0 +/- 1.6 versus 5.4 +/- 1.0 mmol/ L; P = 0.001), and were affected > 10 years earlier by premature coronary artery disease (35.2 +/- 4.8 versus 46.8 +/- 8.9 years; P = 0.002). LDL from PCSK9 patients competed significantly less well for binding to fibroblast LDL receptors than LDL from either controls or LDLR patients. Conclusions - These British PCSK9 patients with the D374Y mutation have an unpredictably severe clinical phenotype, which may be a unique feature for this cohort, and requires early and aggressive lipid-lowering management to prevent cardiovascular complications.