Lecture…: Rare Lipid Disorders Flashcards
What Lipids do we Measure?
• Total Cholesterol <5.0 mmol/L
• HDL-cholesterol >1.0(M) >1.2(F) mmol/L
• Triglycerides (TG) <2.0 mmol/L
• LDL-cholesterol (calculated) <3.0 mmol/L
• LDL = Total C – HDLC – TG/2.2
• ApoB <1.0 g/L
• Fasting
What is Apolipoprotein (apo) B - 4
- Essential for the formation of ‘triglyceride-rich lipoproteins’
- LIVER secretes FULL-LENGTH apoB-100
- INTESTINE secretes apoB-48
- Both forms are ENCODED by the APOB GENE on CHROMOSOME 2
Lipoprotein Metabolism - diagram
On slide 5
Inherited Lipid Disorders - 5
- INCREASE LDL
- Familial hypercholesterolaemia - LDLR, APOB, PCSK9
- Autosomal recessive hypercholesterolaemia - LDLRAP1
- Sitosterolaemia - ABCG5, ABCG8
*INCREASE CVD RISK - INCREASE IDL
- Familial dysbetalipoproteinaemia - APOE
*INCREASE CVD RISK - INCREASE IN TG
- Familial chylomicronaemia syndrome
- LPL, APOA5, APOC2, LMF1, GPIHBP1, PPARG
*INCREASE PANCREATIC RISK - DECREASE IN LDL
- Abetalipoproteinaemia - MTTP
- Familial hypobetalipoproteinaemia - APOB
- Anderson disease - SAR1B
- Familial combined hypolipidaemia - ANGPTL3 - DECREASE HDL
- Tangier disease - ABCA1
- ApoA-I deficiency - APOA1
- LCAT deficiency - LCAT
*INCREASE CVD RISK
Case 1 - ↑ IDL
44-year-old man
• Atorvastatin 40 mg, Ezetimibe
10 mg
• No cardiovascular symptoms
TC 9.6 mmol/L
HDL-C 1.0 mmol/L
TG 10.5 mmol/L
Meas. LDL-C 1.9 mmol/L
ApoB 0.90 g/L
Familial dysbetalipoproteinaemia
• APOE genotype ε2/2
<20% of ε2 homozygotes will
develop dysbetalipoproteinaemia
(metabolic stress)
Case 2 – No HDL-C
62-year-old man with severe
anaemia secondary to splenic
haematoma
TC 1.7 mmol/L
HDL-C 0.02 mmol/L
TG 3.1 mmol/L
LDL-C 0.3 mmol/L
• Homozygous ABCA1 p.Arg1270*
Genetic causes of
- hypoalphalipoproteinaemia:
- Tangier disease (ABCA1)
- ApoA-I deficiency (APOA1)
- LCAT deficiency (LCAT)
Case 3 - ↑ Triglycerides
2-year-old Indian girl with
intermittent abdominal pain
and vomiting
Compound heterozygous for LPL
c.88+2insT and p.Pro214Ser
TC 5.9 mmol/L
HDL-C 0.4 mmol/L
TG 115 mmol/L
Lipase 2830 U/L (<60)
Familial chylomicronaemia
syndrome:
LPL deficiency (LPL)
ApoC-II deficiency (APOC2)
APOA5, LMF1, GPIHBP1
Frequency vs plasma TG concentration (mmol/l)
Graph on slide 10
Monogenic chylomicronaemia
Vs Polygenic chylomicronaemia
7 - IMPORTANT TABLE ON SLIDE 11
- Also known as:
Familial chylomicronaemia
Type 1 hyperlipoproteinaemia
Mixed dyslipidaemia
Type 5 hyperlipoproteinaemia
- Main lipoprotein disturbance
↑ Chylomicrons
↑ Chylomicrons, VLDL and their
remnants
- Onset
Paediatric or adolescent
Adulthood
- Prevalence
~1 in 100,000 to ~1 in 1,000,000
1 in 600
- Clinical features
Failure to thrive
Abdominal pain
Nausea
Vomiting
Eruptive xanthomas
Lipaemia retinalis
Pancreatitis
Hepatosplenomegaly
Abdominal pain
Nausea
Vomiting
Eruptive xanthomas (rare)
Lipaemia retinalis (rare)
Pancreatitis (~1% risk / year)
- Genetic features
Recessive (dominant)
Mutations in LPL, APOA5, APOC2,
LMF1, GPIHBP1, (PPARG)
May be familial clustering, but
no discrete pattern
Heterozygous variants in LPL
pathway genes and/or common
variants with small effects on TG
- Contribution of secondary
factors
- Minimal
- Major (obesity, alcohol, T2DM)
Lipoprotein Lipase (LPL) Deficiency
- WHAT IS IT?
- CLINCIAL MANIFESTATIONS?
- TREATMENT?
1 * ‘Rare autosomal recessive disorder’
characterised by ‘high triglycerides and
absence of LPL activity’
2 * Clinical manifestations
- (usually from early
childhood) include
- abdominal pain, episodes
of pancreatitis, hepatosplenomegaly, and
eruptive cutaneous xanthomatosis
- Treatment: strict adherence to a low-fat diet (<15% of total calories)
What is Alipogene tiparvovec, “Glybera”
what is it?
what does it do?
= 5
- Adeno-associated virus based gene therapy (intramuscular)
- Increases LPL activity, reduces plasma triglycerides and lowers risk of
pancreatitis in patients with LPL deficiency
- Increases LPL activity, reduces plasma triglycerides and lowers risk of
- LPL variant Ser447* (missing C-terminal serine and glycine)
– Carried by ~20% of population
– Associated with more favourable lipid profile – ↓TG, ↑HDL,
↓ CHD risk
- LPL variant Ser447* (missing C-terminal serine and glycine)
- Very expensive!
- Approved in Europe, but abandoned by company in 2017
– “The million-dollar drug: How a Canadian medical breakthrough that was 30
years in the making became the world’s most expensive drug — and then
quickly disappeared
Hypobetalipoproteinaemia
-Low LDL-C and apoB - <5th centile
- Absent LDL-C and apoB
- Low LDL-C and apoB - <5th centile
– vegans, malnutrition, malabsorption, cachexia,
hyperthyroidism, severe liver disease
– Familial hypobetalipoproteinaemia
* Generally asymptomatic, 1/3000, autosomal co-dominant due to
APOB mutations - Absent LDL-C and apoB
– Homozygous familial hypobetalipoproteinaemia (APOB),
Abetalipoproteinaemia (MTTP, recessive)
– Clinical spectrum varies but can include failure to thrive, severe gastrointestinal and neurological dysfunction
APOB Mutations Cause Low Cholesterol
~100 mutations described
- Most result in the production of truncated apoB
diagram on slide 15
Case 4 – Homozygous hypobetalipoproteinaemia
4 month old girl with failure to thrive
Treatment with vitamin E (&A
Western blot of plasma showed abnormal apoB
* 4339delT mutation identified in APOB
(Heterozygous) Familial
Hypobetalipoproteinaemia
- Individuals with FHBL are protected against atherosclerosis
FHBL – Liver
- Steatosis
- Potential progression to fibrosis, cirrhosis
