Null variant homozygous familial hypercholesterolaemia: genetic analysis and 34 years follow-up

Abstract

A seven-year-old girl presented with lack of energy, a systolic heart murmur, total cholesterol of 18.7 mmol/L and skin xanthomas. During aortic valve surgery, atheroma was found in the ascending aorta. Initial treatments were diet, lipid-regulating medication and lipoprotein apharesis followed by aortic valve replacement and coronary artery bypass grafting.

At age 17 years she had a combined heart and liver transplant. Thirteen years later she developed a recurrence of ischaemic heart disease symptoms and autoimmune chronic liver disease and hence was given a second liver transplant. She died from a cardiac arrest at the age of 41 years caused by cardiac allograft immune vasculopathy.

Genome analysis showed two mutations in the LDL receptor gene, confirming a diagnosis of homozygous familial hypercholesterolaemia. Complete loss of LDL receptor function was demonstrated on fibroblast bioassay. New LDL receptor- independent therapies for homozygous familial hyper- cholesterolaemia have recently become available.