1. SECTIONS:
2. preface & acknowledgements
3. genetics at a glance
4. contacts, support & testing
5. testing & pregnancy
6. newborn screening
7. cancer in the family
8. cardiovascular conditions
9. chromosomal conditions
10. clotting & bleeding conditions
11. cystic fibrosis
12. diabetes
13. fragile X syndrome and other causes of developmental delay
14. haemoglobinopathies
15. hereditary haemochromatosis
16. neurofibromatosis
17. neurological conditions
18. psychiatric conditions
19. genetics in practice
20. emerging genetic technologies
21. glossary

Familial hypercholesterolaemia (FH)

 

Clinical features

1. Diagnostic criteria for familial hypercholesterolaemia are based on the modified UK criteria:
2. a: DNA mutation
3. b: Tendon xanthomas in patient or 1°/2° relative
4. c: Family history MI <50 years in 2° or <60 years in 1° relative
5. d: Family history of cholesterol >7.5 in 1° or 2° relative
6. e: Cholesterol >7.5 (adult) or >6.7 (age <16 years)
7. f : LDL-C >4.9 (adult) or >4.0 (age <16 years)

 

Diagnosis	Combinations of criteria as described above
Definite FH	(e or f) + a
Probable FH	(e or f) + b
Possible FH	(e or f) + (c or d)

 

1. Affected individuals suffer metabolic and clinical features including:
2. Lifelong marked hypercholesterolaemia (low density lipoprotein cholesterol (LDL-C) > 5 mmol/L)
3. Cholesterol deposition that occurs in tissues: tendinous xanthomata (particularly involving the Achilles), corneal arcus, palpebral xanthomas and xanthelasma
4. Atherosclerosis beginning in early childhood. Children with FH are known to have endothelial dysfunction and increased carotid intima media thickness (CIMT), both surrogate markers of cardiovascular disease
5. Rapidly progressive carotid atherosclerosis in FH during childhood, at a rate proportional to plasma LDL cholesterol levels

 

Genetics

1. FH is due to an inherited susceptibility to high levels of LDL-C. Other environmental factors such as a
   lifestyle and diet associated with coronary heart disease (CHD) must be present for the condition to develop.
2. Elevated LDL generally follows a pattern of autosomal dominant inheritance with approximately 50% risk for offspring and siblings of affected family members.
3. FH involves mutations in the genes for the LDL receptor (LDLR), the LDL ligand and a protease known as NARC-1.
4. To date, about 1000 mutations have been identified in the LDLR gene but most are family-specific which makes the search for an unknown mutation challenging and expensive.
5. Homozygotes typically have higher levels of LDL and a more severe phenotype than heterozygotes.
6. A mutation in the apolipoprotein B gene (APOB) may result in a clinical and biochemical picture that is indistinguishable from classic FH, although cholesterol levels are generally not as elevated and tendon xanthomas are less common.
7. An autosomal recessive form of FH has also been described. The clinical picture of this condition is similar to that of individuals who are homozygous for the mutations in genes associated with the autosomal dominant form of the condition, although it is generally less severe and more variable, with greater responsiveness to therapy.

 

Prevalence

1. Familial hypercholesterolaemia is thought to account for about 5 to10% of CHD that occurs before the
   age of 55 years. It is estimated that, of the roughly 40,000 cases of FH in Australia, about 20% are diagnosed and less than 10% are being adequately treated. However, less than 5% have been formally identified.
2. In the general population, frequency of FH heterozygosity for a mutation in the genes involved in the autosomal dominant form of FH is about 1 in 500, while the homozygous state is exceedingly rare (about 1 in 1,000,000 people).
3. There is greater frequency of the heterozygous state in people whose ancestry is:
4. Christian Lebanese, 1 in 170
5. Afrikaaner (Dutch descent), 1 in 70 to 1 in 100
6. French Canadian, 1 in 200 to 1 in 270

 

Investigations

1. Genetic testing to determine if a high cholesterol level is associated with FH should be aimed at those
   with ancestry from the population groups above.

 

Management

1. If detected early, FH can be treated by lifestyle modification and statins.
2. Without treatment:
3. 50% of heterozygous males will develop CHD before the age of 50 years and 100% by the age of 70 years
4. Approximately 12% of the heterozygous females will have CHD by age 50 years. However this
   increases to 74% by age 70 years
5. In homozygotes with mutations in the genes involved in the autosomal dominant form of FH, drugs are less effective and it is typically lethal at an early age without special intervention, such as LDL aphaeresis and liver transplantation.
6. Refer to a specialist lipid clinic or Genetics Services.

 

Implications for family members

1. Children of an affected parent should be screened when a cholesterol-lowering diet can be safely implemented and advice given about avoidance of smoking.
2. Statin therapy is only used in children from severely affected families.
3. Genetic testing at an appropriate age can assist with identification of risk status as:
4. A normal lipid profile does not necessarily rule out carrier status for an FH-causing gene mutation
5. A false negative and false positive rate based on LDL levels alone in affected families is approximately 15%

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