Familial hypercholesterolemia (FH) is a genetic disorder that affects the liver’s ability to process low-density lipoprotein (LDL) cholesterol. FH is inherited in an autosomal dominant pattern, meaning that one copy of the FH gene mutation from one parent can lead to the development of FH. This article will explore the FH gene mutation and its impact on the development of FH.
The FH Gene Mutation
The FH gene mutation occurs in the LDL receptor gene, which is located on chromosome 19. The LDL receptor is responsible for removing LDL cholesterol from the bloodstream, but in individuals with FH, the receptor is either missing or not functioning properly.
The LDL receptor gene is composed of 18 exons, which are sections of the gene that are used to produce the protein. The FH gene mutation can occur in any of these exons, but most commonly occurs in exon 4, exon 7, or exon 9.
There are over 2,000 known FH gene mutations, and each one can cause varying degrees of LDL receptor dysfunction. Some mutations only reduce the receptor’s function, while others completely eliminate its ability to remove LDL cholesterol from the bloodstream.
The Impact of FH Gene Mutation
The FH gene mutation is the primary cause of FH, a condition that affects approximately 1 in 250 individuals worldwide. FH can lead to the early onset of atherosclerotic cardiovascular disease (ASCVD) and increase the risk of heart attack and stroke.
Individuals with FH have elevated levels of LDL cholesterol from birth, but the severity of FH’s symptoms can vary depending on the type of FH gene mutation that is present.
Homozygous FH is the most severe form of FH and occurs when an individual inherits two copies of the FH gene mutation, one from each parent. Homozygous FH is rare, occurring in only 1 in 1 million individuals, and results in extremely high levels of LDL cholesterol, leading to atherosclerosis and ASCVD at a young age.
Heterozygous FH is the more common form of FH and occurs when an individual inherits one copy of the FH gene mutation. Heterozygous FH affects approximately 1 in 200-500 individuals worldwide and can lead to the development of ASCVD in early adulthood.
The Diagnosis of FH
The diagnosis of FH is typically made through a combination of physical exams, medical history, and blood tests. The most common diagnostic test for FH is a lipid panel, which measures the levels of total cholesterol, LDL cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides in the bloodstream.
Individuals with FH will have elevated levels of LDL cholesterol, with the severity of the elevation depending on the specific FH gene mutation present. A cholesterol level of over 190 mg/dL in adults or over 160 mg/dL in children can be a sign of FH.
Other diagnostic tests may include genetic testing to identify the specific FH gene mutation present and imaging tests, such as an ultrasound or computed tomography (CT) scan, to assess the buildup of plaque in the arteries.
The Treatment of FH
The treatment of FH typically involves a combination of lifestyle modifications and medications. Lifestyle modifications may include a heart-healthy diet, regular exercise, and avoiding tobacco products.
The primary medication used to treat FH is a class of drugs called statins, which work by reducing the liver’s production of cholesterol. Statins can be effective in lowering LDL cholesterol levels in individuals with FH but may not be sufficient in individuals with more severe forms of FH.
Other medications that may be used to treat FH include ezetimibe, which works by inhibiting the absorption of cholesterol in the intestine, and PCSK9 inhibitors, which work by blocking a protein that reduces the number of LDL receptors in the liver.
In some cases, individuals with FH may require more aggressive treatment, such as LDL apheresis, a process where blood is removed from the body, and the LDL cholesterol is filtered out before being returned to the body.
The FH gene mutation is the primary cause of FH, a genetic disorder that affects the liver’s ability to process LDL cholesterol. There are over 2,000 known FH gene mutations, each with varying degrees of LDL receptor dysfunction.
FH can lead to the early onset of ASCVD and increase the risk of heart attack and stroke. The diagnosis of FH is typically made through a combination of physical exams, medical history, and blood tests, and the treatment of FH typically involves a combination of lifestyle modifications and medications.
While FH cannot be cured, early diagnosis and treatment can lead to better outcomes, including a reduced risk of ASCVD and increased lifespan. If you or a loved one has a family history of high cholesterol or early-onset ASCVD, it is critical to speak with a healthcare provider about the possibility of FH and undergo appropriate screening and diagnostic testing.