Autosomal recessive hypercholesterolaemia

There is a condition that has a clinical phenotype with much in common with homozygous FH. This is ARH. As in homozygous FH, the FCR of LDL is diminished. However, LDL receptor expression in cultured fibroblasts from patients with ARH is normal or only moderately decreased. The mutation that leads to the condition is not in LDLR. It tracks to the chromosomal 1p35 region and is in a gene that encodes a protein that is predicted to have a phosphotyrosine-binding domain. This domain is a feature of adaptor proteins that bind to the cytoplasmic tail of cell surface receptors, facilitating their internalization by endocytosis.200-203

All of the patients so far described have originated in Sardinia. Heterozygotes do not express hypercholesterolaemia, but the affected homozygotes and compound heterozygotes have serum cholesterol levels generally in the range 12-22 mmol/l (500-900 mg/dl) and serum LDL cholesterol concentrations of 9-20 mmol/l (370-800 mg/dl), with low HDL cholesterol and triglyceride levels in the normal range.203,204

Autosomal recessive hypercholesterolaemia patients develop large, subcutaneous planar and tuberose xanthomata and tendon xanthomata similar to those in FH homozygotes.202,203 These are generally present in childhood, and the condition is associated with CHD in early life. Their prognosis is, however, much better than in most patients with homozygous FH and their response to statin therapy much greater.203