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

Abstract

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.

• Authors: Rossi P Naoumova, Isabella Tosi, Dilip Patel, Clare Neuwirth, Stuart D Horswell, A David Marais, Charles van Heyningen, Anne K Soutar
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 25 Issue 12 Pg. 2654-60 (Dec 2005) ISSN: 1524-4636 [Electronic] United States
• PMID: 16224054 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cholesterol, LDL
• Receptors, LDL
• PCSK9 protein, human
• Proprotein Convertase 9
• Proprotein Convertases
• Serine Endopeptidases

Topics

• Adolescent
• Adult
• Atherosclerosis (genetics, therapy)
• Child
• Cholesterol, LDL (chemistry, metabolism)
• Family Health
• Female
• Fibroblasts (metabolism)
• Follow-Up Studies
• Humans
• Hypercholesterolemia (genetics, therapy)
• Male
• Middle Aged
• Particle Size
• Point Mutation
• Proprotein Convertase 9
• Proprotein Convertases
• Receptors, LDL (genetics, metabolism)
• Retrospective Studies
• Serine Endopeptidases (genetics)
• Severity of Illness Index
• Skin (cytology)
• United Kingdom
• White People