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.


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.
Naoumova
Rossi P
RP
MRC Clinical Sciences Centre, Hammersmith Hospital, London W12 0NN, UK. rossi.naoumova@csc.mrc.ac.uk
Tosi
Isabella
I
Patel
Dilip
D
Neuwirth
Clare
C
Horswell
Stuart D
SD
Marais
A David
AD
van Heyningen
Charles
C
Soutar
Anne K
AK
D000293:Adolescent; D000328:Adult; D050197:Atherosclerosis / Q000235:genetics / Q000628:therapy; D002648:Child; D008078:Cholesterol, LDL / Q000737:chemistry / Q000378:metabolism; D005192:Family Health; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005500:Follow-Up Studies; D006801:Humans; D006937:Hypercholesterolemia / Q000235:genetics* / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D010316:Particle Size; D017354:Point Mutation; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D012189:Retrospective Studies; D012697:Serine Endopeptidases / Q000235:genetics*; D012720:Severity of Illness Index; D012867:Skin / Q000166:cytology; D006113:United Kingdom; D044465:White People
D008078:Cholesterol, LDL; D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases