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The current prevalence estimate of homozygous familial hypercholesterolemia (FH) is approximately 1/315,000 (range 1/100,000-1,000,000) individuals, with a higher prevalence in founder populations (e.g. in the Middle East, Quebec and South Africa).

Classical clinical presentation is in childhood when xanthomas are first noted on extremities, trunk and in extensor tendons. Patients may also have corneal arcus, xanthelasmas, arterial bruits, cardiac ejection murmurs and diminished peripheral arterial pulses. A lipid profile demonstrates profoundly elevated levels of total and LDL cholesterol.

The core molecular defect involves loss of function of the LDL receptor on hepatocytes due to bi-allelic pathogenic variants in the LDLR gene in 80-90% of cases. There are >3000 reported pathogenic variants in LDLR. Clinical severity varies in relation to the extent of functional impairment imparted by the particular variant. A similar phenotype can result from bi-allelic binding-defective variants in APOB which encodes apolipoprotein B, the ligand for the LDL receptor. About 1-2% of cases result from bi-allelic gain-of-function variants in PCSK9 which encodes proprotein convertase subtilisin kexin type 9. A true recessive phenotype results from bi-allelic loss-of-function variants in LDLRAP1 encoding the LDL receptor adaptor protein. Even rarer variants in other genes can sometimes produce a phenotype that resembles homozygous HF.

Diagnosis is made based on clinical features, the degree of LDL cholesterol elevation, family history, plus DNA sequencing for a definitive diagnosis.

Differential diagnosis includes severe heterozygous FH, sitosterolemia, lysosomal acid lipase deficiency.

Prenatal diagnosis of homozygous FH is possible.

Transmission is semi-dominant when the causal gene is LDLR, APOB or PCSK9, meaning that heterozygous parents express an abnormal clinical and biochemical phenotype that is intermediate between a normal individual and a patient with homozygous FH. Parents either already know their own heterozygous status in advance, or sometimes are diagnosed retrospectively when a child is born with homozygous FH. Genetic counseling should be offered to at-risk couples: 25% of their children will have a normal lipid profile, 50% will have heterozygous FH which will require monitoring and sometimes pharmacotherapy starting at ages 8-10 years, and 25% will have homozygous FH requiring immediate attention. In true autosomal recessive FH due to bi-allelic loss-of-function variants in LDLRAP1, both parents are asymptomatic carriers of a disease-causing mutation with a 25% risk of having an affected child at each pregnancy.

The mainstay of treatment is serial (i.e. weekly or bi-weekly) lipoprotein apheresis, since statins and other commonly used lipid-lowering medications are minimally effective. Inhibitors of proprotein convertase subtilisin kexin type 9 have a variable but typically modest effect on LDL cholesterol. A new biologic medication - evinacumab, which is an intravenously administered monoclonal antibody against angiopoietin like protein 3 - is an extremely effective treatment recently made available in many jurisdictions.

Life expectancy without treatment is reduced by three to five decades. With apheresis, patients now survive into their fifth and sixth decades of life, but still can develop clinical end points of severe premature atherosclerotic cardiovascular disease and aortic disease.