A genetic mutation within one of four well-studied genes—LDLR, LDLRAP1, APOB, or PCSK9—causes the disorder. The most frequent cause of FH is due to mutations found on the LDLR gene. These mutations affect production of certain proteins required for LDL particles to function properly. It’s possible that other, yet unknown genetic mutations influence the development of FH. 

There are two different kinds of FH, based on whether a variant gene copy is inherited from just one parent or both. The latter is very rare.

• Heterozygous familial hypercholesterolemia (HeFH) – a person inherits a gene variant from one parent with the condition. Most people with FH have this type of the disease. Children with HeFH usually have LDL cholesterol levels greater than 130 mg/dL and adults greater than 190 mg/dL. LDL levels should ideally be less than 110 mg/dL in kids and less than 100 mg/dL in adults.
• Homozygous familial hypercholesterolemia (HoFH) – a person inherits genetic variants from both parents, who both have the disorder. People with this rare type of FH usually have LDL cholesterol levels greater than 300 mg/dL for adults and above 400-500 mg/dL for children are at increased risk for heart attacks and coronary artery disease at a very young age. In general, HoFH must be treated earlier and more aggressively than HeFH.   

Regular cholesterol screening is the best way to detect the most prominent signs or symptoms of this condition, which is high LDL cholesterol levels. Other common signs of this condition include the following:

• Family history of high total and LDL cholesterol levels and/or early heart attack
• High LDL cholesterol levels that do not respond well to medications
• Chest pain (angina)
• Cholesterol deposits in the eyelids that usually don’t cause any problems (called xanthelasmas)
• Cholesterol buildup in the skin or tendons that can be painful, depending where on the body they appear (called xanthomas)
• Cholesterol around the cornea of the eye, which doesn’t interfere with vision (called arcus lipoidicus) 

FH can be diagnosed through clinical and/or genetic tests. Cholesterol screening is recommended to begin between ages 9 and 11 and once more between ages 17 and 21 and should be continued through adulthood. If the following criteria is met, then a diagnosis of FH could be considered: 

• LDL cholesterol levels equal to or greater than 190 mg/dL for adults 20 years or older
• LDL cholesterol levels equal to or greater than 160 mg/dL based for those younger than 20 years
• A patient’s family history of vascular-related diseases
• Physical examination for visible symptoms
• Current diagnoses of vascular-related diseases

Multi-gene panel testing (a genetic test that searches for mutations in several genes at once) that searches for variants in the LDLR, LDLRAP1, APOB, and PCSK9 genes can also be used to diagnose FH. However, a negative genetic test does not completely rule out FH if clinical signs clearly point toward the condition. 

It’s possible that other genes and variants that have not yet been discovered could contribute to the disorder. Here at Yale we can perform whole exome sequencing that provides information on all mutations that affect a protein in the body. This allows identification of previously unknown genetic mutations.

For adults with FH, a treatment plan usually includes one of several types of cholesterol-lowering medication and lifestyle changes that include a healthy diet and exercise. Children diagnosed with FH can be safely prescribed statins from age 10 and up.

 The most common kinds of treatments for adults (and children 10 and over) include the following:

• Statins. This class of drugs reduces LDL cholesterol levels. Statins (in combination with diet and exercise) are usually prescribed as the first treatment option. Examples include atorvastatin (Lipitor) and rosuvastatin (Crestor).  
• Bile acid sequestrants. This is an older type of drug that, on its own or in combination with statins, can also lower LDL cholesterol levels. Examples include cholestyramine (Prevalite) and colesevelam (Welchol).  
• PCSK9 inhibitors. First approved in 2015 specifically for FH, this newer class of drugs may be prescribed together with other cholesterol-lowering drugs. Examples include alirocumab (Praluent) and evolocumab (Repatha).
• LDL apheresis. If oral medications are not effectively lowering LDL cholesterol levels, then a medical procedure called apheresis might be recommended, and it can be helpful for young children, too. In this procedure, the patient’s blood is filtered through a machine—similar to what happens during kidney dialysis—to remove LDL cholesterol.    
• Liver transplantation. This is an alternative therapy to apheresis. If a liver transplant is available, it is preferred to apheresis as no regular therapy is needed. Unfortunately, the number of liver transplants available in this country is limited. 

We provide comprehensive care to patients with hyperlipidemia (elevated cholesterol and another lipid called triglycerides). “For some patients, we can perform a test known as whole exome sequencing. The test is performed on state-of-the-art instruments,” Dr. Mani says.

The analysis is performed geneticists and cardiovascular research experts. If a mutation in the known disease genes (LDLR, LDLRAP1, APOB, and PCSK9) is not identified, our experts will search for mutations in other genes that could explain the trait. Although the treatment and management of the patient’s FH likely won’t change, knowing the disease mutation will allow better screening of family members and relatives, Dr. Mani says.