Familial hypercholesterolaemia

Question 1

mechanisms of lipid transport to tissues of VLDL -> LDL

Answer 1

1. VLDL exits liver then converted to IDL -> LDL
2. LDL: B100 binds to LDL receptor on peripheral cells = uptake OR (70%) binds to liver = uptake
   * if LDL receptor defect = accumulation of LDL

Question 2

Familial Hypercholesterolaemia-what it is? (pathophysiology)

Answer 2

LDL primarily elevated due to LDL-receptor mutations or Apo B100 mutation = less uptake of LDL in liver & tissues = LDL accumulate in blood => tiss. lipid deposition in BV wall

Question 3

factors that cause of hyperlipidaemia

Answer 3

• Genetics: primary cause
• poly genenic: effect of multiple genes & environmental/behavioural influences (diet/excercise)
• secondary cause: other disorders e.g. hypothyroidism, alcohol, diabietes, renal failure

Question 4

Examples of founder effects, and approach/consequences for molecular diagnosis

Answer 4

certain mutations commonly found in Certain popu. e.g.
- Afrikaner: 3 founder mutations
- Christian Lebanese: 10x homozygous freq
- French Canadians: 5 founder mutations

Question 5

Risk factors for CVD/coronary <3 disease

Answer 5

• Age, Sex, family Hx
• smoking, hyperlipidaemia, BMI, diabetes (modifiable RF)

Question 5

Type of lipoproteins & they function

Answer 5

• LDL & HDL > transports cholesterol to & from peripheral tiss
• VLDL > transports TG to peripheral tiss -> LDL
• Chylomicrons > similar func as VLDL
• IDL > intermediate for VLDL to LDL
• Chylomicron remnants > carry TG & cholesterol

Question 6

What are apolipoprotein (apo) & function?

Answer 6

• proteins assoc w/ lipoprotein particles
  > mediate Binding of lipoprotein to protein receptors
  > required for synthesis of lipoproteins
  > co-factors for enz involved in metabolism & remodelling of lipoprotein

Question 7

e.g. of Binding of lipoprotein to protein receptors
a) Apo B-100
b) Apo E-ligand
c) Apo A1 ligand

Answer 7

a) Apo B-100: (on LDL) binds to LDL receptor
b) Apo E-ligand: (on VLDL, chilomicron remnants) binds to LDL receptor
c) Apo A1 ligand: (on HDL) binds to ABCA1 receptor

Question 8

Genetics of FH
a) inheritance pattern
b) molecular genetics
c) mutation spectrum

Answer 8

a) autosomal dominant disorder (can be co-dominant) *homoz: severely affected
b) mostly LDLReceptor defect, some due to mutations in apo B-100 or PCSK9
c) wide mutation spectrum bc >1000 LDLR mutations

Question 9

What tests fall under the cascade testing for FH

Answer 9

• measure lipid levels
• genetic testing: by NGS then Sanger seq then MLPA OR by using Kits e.g. ARMS, reverse hybridization