HoFH

HoFH, or homozygous familial hypercholesterolemia, is a rare genetic disorder causing very high LDL cholesterol from birth and premature atherosclerotic cardiovascular disease. Most cases arise from biallelic pathogenic variants in LDLR, though mutations in APOB, PCSK9, or LDLRAP1 can also cause HoFH. The condition results from markedly impaired clearance of LDL particles.

HoFH represents the severe end of familial hypercholesterolemia. It occurs when an individual inherits two pathogenic variants, one from each parent, or compound heterozygosity. In most patients, LDL receptor activity is severely reduced or absent, but the exact defect depends on the gene and mutation.

Clinical features include very high LDL-C levels often exceeding 400 mg/dL in childhood, and visible signs such as tendon xanthomas and corneal arcus. Affected individuals develop atherosclerotic disease early, with coronary, cerebral, and peripheral vascular involvement; valvular disease may occur in adulthood.

Diagnosis is based on LDL-C levels, physical findings, and genetic testing confirming pathogenic variants. It is important to distinguish HoFH from heterozygous FH, as management differs. Cascade screening of first-degree relatives is recommended when a pathogenic variant is found.

Management requires aggressive lipid lowering from infancy. Therapies include high-intensity statins with ezetimibe, and additional agents such as lomitapide or mipomersen; PCSK9 inhibitors may help in some genotypes. Lipoprotein apheresis is a central therapy for many patients. In refractory cases, liver transplantation or emerging gene therapies may be considered. Early diagnosis improves prognosis, but HoFH remains a high-risk, lifelong condition.