Disorder

Genetic defect & inheritance

Prevalence

Labs

Clinical Presentation

Treatment

Familial
Hypercholesterolemia (FH)

-Autosomal codominant with high penetrance

-Defect in LDL receptor (apoB/E receptor) on cell
membranes
reduced LDL clearance

Heterozygotes: 1:500

LDL
TC (7-13 mmol/L)

-Tendon xanthomas (Achilles, patellar,

-Diet
-Lipid-lowering drugs
-LDL apheresis
(severe)
-Liver transplant
(homozygotes)

Familial defective
ApoB100
Autosomal dominant
hypercholesterolemia
a.k.a.
PCSK9 (proprotein convertase
subtilisin/ kexin 9) gain of
function mutations

Familial combined
hyperlipidemia (FCHL)
Polygenic
hypercholesterolemia
Familial
hypertriglyceridemia
Familial chylomicronemia

Tangier disease
(Linked with familial
hypoalphalipoproteinemia)
Familial LCAT deficiency

Familial CETP deficiency

Apolipoprotein E gene
polymorphism

Familial
dysbetalipoproteinemia
(type III disease)

extensor tendons of hand)

-Corneal arcus
-Premature CAD (age 30-50)
-Tendon xanthomas
-Planar and tuberous xanthomas
-Premature CAD (age <18)

Homozygotes: 1:1 million

Particularly French Canadians,
Armenians, Lebanese, South
Africans of Dutch/French descent
-Heterozygotes: 1:800
-Its thought that ~5% of clinical
FH due to apoB mutation
-Unknown

LDL
TC (>13 mmol/L)

LDL
TC (7-13 mmol/L)
(not as severe as FH)
LDL
TC

-Similar to FH, just not as severe

-Diet
-Lipid-lowering drugs

-Similar to FH

-Diet
-Lipid-lowering drugs

-Autosomal dominant
-Unknown, ?mutation in USF-1 (upstream transcription
factor-1) which regulates genes in lipid metabolism
-Variable inheritance patterns
-Unknown cause (multiple defects)
-Autosomal dominant
-Unknown cause (multiple defects)

-Most common disorder!

-Gene frequency: 1:50

-Premature CAD
-Affects 20% of middle-aged MI
patients
-Premature CAD

-Diet
-Weight loss
-Lipid-lowering drugs

-Common

TC (6.5-13 mmol/L)
TG (2.8-8.5 mmol/L)
ApoB
TC (6.5-9 mmol/L)

-Common (1:100)

TG (2.3-5.7 mmol/L)

-Autosomal recessive
- or absent LPL activity
chylomicron clearance
-Due to mutation in 1 of the following:
a. LPL gene
b. apoC-II gene (LPL cofactor)
c. GPI-HBP1 gene (anchors LPL)
-Autosomal recessive
-Mutation in ABCA1 gene
-Tangier fibroblasts defective in removing cellular
cholesterol and phospholipids

-1:1 million (rare)

-Present worldwide

-Fasting
chylomicronemia
plasma TG (>8.5
mmol/L)

-Usually asymptomatic
-Hyperuricemia
-Early atherosclerosis
-Recurrent pancreatitis
-Hepatosplenomegaly
-Eruptive xanthomas
-Lipemia retinalis: white retinal BV
-Metabolic syndrome

-Extremely rare (40 people in

world)

or absent HDL
LDL
TG (moderate)

-Autosomal recessive
-Lack of LCAT activity
decreased maturation of
HDL
-Autosomal codominant
-Mutations in both alleles of CETP
-Delayed catabolism of HDL-CE and apoAI

-Extremely rare

or absent HDL
plasma phospholipids
unesterified cholesterol
HDL-C (large, rich
in cholesteryl esters)
apoA-I

-Autosomal dominant
-Mutation of apoB (defective LDL receptor-binding
region)
reduced LDL clearance
-Autosomal dominant
-Missense gain of function mutation of PCSK9

increased degradation of LDL receptors
reduced
LDL clearance
*Note: loss of function of PCSK9 will LDL
CV risk

ApoE2 mutation
reduced affinity for cell surface

receptors
accumulation of remnants, LDL
formation
ApoE3 mutation

TC
TG
LDL-C
TC

ApoE4 mutation

TC

-Autosomal recessive or dominant

-90% of apoE2 homozygotes + other genetic and/or
environmental stimulus
VLDL and chylomicron
remnant clearance

-Frequency 1:5000
-Recessive more common than
dominant

TC (6.5-13 mmol/L)
TG (2.8-5.6 mmol/L)
chylomicron remnants
& IDL

-Enlarged, yellow-orange tonsils

-Hepatosplenomegaly
-Peripheral neuropathy
-Premature CAD (some)
-Corneal opacities
-Corneal opacities
-Hemolytic anemia
-Renal failure
-No evidence of atherosclerosis
protection
-Possible risk of premature
atherosclerotic vascular disease
-1/50 of apoE2 homozygotes develop
dysbetalipoproteinemia combined with
additional genetic/environmental factors
-80% risk of dying in MI survivors
-40% risk of CHD compared to E3/E3
-Palmar xanthomas
-Tubero-eruptive xanthomas
-Yellow palmar creases
-Premature CAD

-Diet (total fat

restriction,
supplementation with
soluble vitamins and
medium-chain TGs)
-Low-fat diet

-Fat restriction
-Renal transplant

-Diet
-Lipid-lowering drugs