personalized medicine in familial hypercholesterolaemia
TRANSCRIPT
Objectives
Review Lipoproteins
Familial Hypercholesterolemia, a Genetic Disorder
Pathophysiology of FH
Types of FH
FH Clinical Presentation
Diagnosis & Management
Treatment
Definition
• Familial hypercholesterolemia (FH) is an autosomal dominant disorder that causes severe elevations in total cholesterol and low-density lipoprotein cholesterol (LDLc).
Single Nucleotide Polymorph
isms
rs7566605,(Insulin-induced
gene 2 (INSIG2),
Chromosome2)
rs854560, (Paraoxonases
1(PON1 gene),
Chromosome2)
rs505151
(PCSK9 gene,
Chromosome1)
rs12720762, APOB gene,
Chromosome 19
Chromosome 19
FH is an autosomal dominant disorder
Mutations in the LDL receptor gene on Chromosome 19
3 Forms of FH
Familial Hypercholesterolemi
a
Autosomal Dominant
Hypercholesterolemia
Autosomal dominant
hypercholesterolemia,
type B
Autosomal recessive
hypercholesterolemia
FLDB = Familial ligand defective apoB-100 , CHD = Coronary Heart Disease
Homozygous FH Heterozygous FH
Symptomatic in Childhood Symptomatic mainly in Adulthood
Normal Triglycerides Normal Triglycerides
LDLc >600 mg/dL LDLc Usually >250 mg/dL<20 yrs: LDLc>200 mg/dL is FH/ (FLDB)Adults >20 yrs: >290-300 mg/dL
Total Cholesterol >600 mg/dL Total Cholesterol>250 mg/dL
Two major genetic defects in
LDL metabolism
One major genetic defect in LDL
metabolism
Tendon and cutaneous
xanthomas often before age 10
years
Arcus cornealis and Achilles tendon
xanthomas often present
CHD onset in childhood CHD onset 30-60 years
Poorly responsive to drugs;
apheresis often indicated
Most respond to drugs, but individual
response variable
The Urgency!
“For untreated FH homozygotes, the prognosis is down-right tragic. Heart
attacks have been documented in 2-year-old infants and more frequently at ages 8,
10, and 12 due to extremely aggressive coronary atherosclerosis. Untreated, most FH homozygotes will have heart attacks in their late teens, and few will survive past
their 20s.”
- Bob Carlson, MHA, Biotechnol Healthc Senior Contributing Editor
Routine Lipid Screening
Prenatal testing for pregnancies at high risk
Serial single-gene testing
Multi-gene panel testing
LaboratoryGenetic testing can identify genetic mutations associated with FH
Treatment
HMG-CoAReductaseInhibitors (Statins)
Vitamins
Bile acid Sequestrant
s (resins)
Lipid-Lowering Agents, Other
PCSK9 Inhibitors
Liver Transplantat
ion
Portacavalanastomosis
Estrogen replacement Therapy in
postmenopausal women
LDL Apheresis
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