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Last updated: 2/3/2025
Years published: 2025
NORD gratefully acknowledges Vikesh K. Singh, MD, MSc, Professor of Medicine, Director of Endoscopy, Johns Hopkins Hospital; Director of Pancreatology, Division of Gastroenterology, Johns Hopkins University School of Medicine, for assistance in the preparation of this report.
Familial chylomicronemia syndrome (FCS) is a rare inherited disease characterized by very high levels of a type of fat called triglyceride in the blood. This condition is caused by changes (variants) in genes that impair the normal breakdown of triglycerides carried by chylomicrons, the particles responsible for transporting the fats that are consumed in meals through the bloodstream.1 Chylomicrons and triglycerides become overabundant in FCS because chylomicron-triglyceride attachments cannot be properly broken down. As a result, triglycerides cannot be properly used and stored.2
Most commonly, FCS results from variants in the Lipoprotein Lipase (LPL) gene, which encodes an enzyme essential for breaking down triglycerides. Variants in other genes can also cause FCS. Inheritance is autosomal recessive.
The hallmark of FCS is persistent and severe hypertriglyceridemia, which can exceed 1,000 mg/dL. This condition significantly increases the risk of acute pancreatitis, a potentially life-threatening condition where the pancreas becomes inflamed, and its function is disrupted. Acute pancreatitis can lead to systemic complications, the most serious being organ failure.3,4,5
Other symptoms and signs of FCS may include recurrent abdominal pain, nausea, vomiting and visible fat deposits in the skin (eruptive xanthomas), as well as fatigue and difficulty concentrating due to the systemic effects of fat metabolism abnormalities.
Because FCS is rare and its symptoms overlap with more common conditions such as familial combined hyperlipidemia or poorly controlled diabetes, diagnosis is often delayed. Genetic testing is typically required to confirm FCS and distinguish it from other causes of high triglyceride levels.3,4,5
The primary treatment for FCS is a highly restrictive low-fat diet to minimize triglyceride intake and reduce chylomicron production. Advancements in medical research have led to the development of new therapies. Olezarsen (Tryngolza) is approved by the U.S. Food and Drug Administration (FDA) as an addition to diet, to reduce triglycerides in adults with FCS. Other therapies are being studied that focus on enhancing triglyceride metabolism or replacing deficient enzymes.
People affected with FCS have extremely high fasting triglyceride levels (>750 mg/dL, or >8.5 mmol/L) which can be up to 10 times higher than normal.³,⁵
Because FCS is a genetic condition, high triglyceride levels are more likely to occur at a younger age in people with FCS than in people who have high levels from other causes.
FCS may present as early as infancy, although some people do not start having symptoms until adulthood.²,⁶
People with FCS are less likely to have conditions associated with other causes of high triglyceride levels including:
Cardiovascular disease due to high triglyceride levels is also less likely in people with FCS compared with people affected with high levels due to other causes.⁶
High triglyceride-chylomicron levels affect blood flow to and fat storage in organs.⁵
FCS is also associated with cognitive and psychological symptoms including:
FCS has been linked to changes (variants) in several genes.3 A variant in the lipoprotein lipase (LPL) gene is the most common occurring in 60% to 80% of people with FCS.7 Lipoprotein lipase is an enzyme that helps break down chylomicrons and triglycerides. In people with FCS, lipoprotein lipase is either not produced or does not function properly.3,5 This is why they have high chylomicrons and triglyceride levels.
Variants in other genes have also been linked to FCS including GPIHBP1, APOA5I, APOC2I and LMF1. Variants in these genes affect the function of other proteins that lipoprotein lipase depends on to break down fat.5
FCS is an autosomal recessive genetic disorder.5 Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
FCS is estimated to affect 1 out of every 1 million people, or 3,000 to 5,000 people worldwide.5,6 It does not occur more often in one sex or race but does have a higher incidence in the geographic regions of Quebec, Canada and the Cayman Islands.3,5,8 FCS is thought to be the cause of high triglyceride levels in 1% to 2% of patients referred to clinics that manage severely elevated levels of triglycerides.12
FCS can be diagnosed without genetic testing, based on medical history, clinical examination and laboratory tests. People with FCS have extremely high triglyceride levels at a younger age and usually don’t have other conditions that are associated with high triglyceride levels like obesity and diabetes.2,12 These individuals also usually have a history of repeated episodes of abdominal pain and acute pancreatitis, and they have family members with high triglyceride levels.2,3
Laboratory testing reveals triglyceride levels above 750 mg/dL when the person has been fasting, and levels are elevated after several repeat tests.3,5 Blood drawn from someone with FCS will appear milky when refrigerated as the fat separates from the blood.2,5 Triglyceride levels of people with FCS do not respond to medications like statins, fibrates, niacin and omega-3 fatty acids, which are typically prescribed to treat high triglyceride levels from other causes.2,7
Genetic testing can identify gene variants associated with FCS. Since FCS is suspected to be caused by variants in other genes that have not yet been identified, genetic testing does not always find disease-causing variants.5
Medications that lower triglycerides for non-genetic causes of high triglyceride levels are not effective for FCS.2 Instead, a low-fat diet is the main method of controlling triglyceride levels and preventing severe complications like acute pancreatitis. Specifically, daily fat consumption should be less than 10-15% of their daily calories, or no more than 15 to 20 grams of fat per day.21 People with FCS should also avoid alcohol and processed, sugary foods. An appropriate diet includes vegetables, whole grains, beans, lean proteins, the occasional fruit and fat-free milk products with no added sugars.21 Dietary restrictions can be difficult for people with FCS to maintain. 5
People with FCS should be encouraged to exercise to maintain their weight within a healthy range.8 To supplement any nutrients lacking from their restricted diet (including fatty acids), fat-soluble vitamins and fatty acid supplements like alpha-linolenic acid and linolenic acid are also recommended.21 Fatty acids are created from broken down triglyceride and these supplements do not increase triglyceride levels.22 Medications that raise triglyceride levels like beta-blockers, certain diuretics and hormones like estrogen and steroids, should be avoided.6
In 2024, olezarsen (Tryngolza) was approved by the U.S. Food and Drug Administration (FDA) as an addition to diet, to reduce triglycerides in adults with FCS.
People with FCS typically receive healthcare from endocrinologists or lipidologists (doctors who treat hormone or fat disorders) and dieticians to manage their condition.5
Genetic counseling is recommended for people with FCS and their family members.8
Medications known as apolipoprotein (apo) C-III inhibitors are being studied to treat high triglyceride levels in people with FCS.7 These drugs block apo C-III, a type of glycoprotein (protein combined with a carbohydrate) that increases triglyceride levels. Apo C-III increases triglyceride levels by reducing lipoprotein lipase activity (the enzyme that is diminished in most people with FCS), affecting how the liver stores and releases substances that raise triglycerides in the bloodstream, and blocking removal of triglycerides from the bloodstream.7,23 Apo C-III became a target for lowering triglyceride levels in people with FCS based on observation of lower triglyceride levels in people with gene variants that naturally inhibit apo C-III.7
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
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Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.
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