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Familial HDL deficiency
Reviewed by Medicinsk Expert•Last updated: 2026-10-22•Condition

Familial HDL deficiency

Familial HDL deficiency is a rare genetic disorder characterized by low levels of high‑density lipoprotein (HDL) that increases the risk of early cardiovascular disease.

Overview

Familial HDL deficiency is a condition characterized by low levels of high‑density lipoprotei% (HDL) in the blood. HDL is a molecule that transports cholesterol and certain fats called phospholipids through the bloodstream from the body's tissues to the liver. Once in the liver, cholesterol and phospholipids are redistributed to other tissues or removed from the body. HDL is often referred to as “good cholesterol” because high levels of this substance reduce the chances of developing heart and blood vessel (cardiovascular) disease. People with familial HDL deficiency may develop cardiovascular disease at a relatively young age, often before age 50.

Severely reduced levels of HDL in the blood is a characteristic feature of a related disorder called Tangier disease. People with Tangier disease have additional signs and symptoms, such as disturbances in nerve function; enlarged, orange‑colored tonsils; and clouding of the clear covering of the eye (corneal clouding). However, people with familial HDL deficiency do not have these additional features.

Frequency

Familial HDL deficiency is a rare disorder, although the prevalence is unknown.

Causes

Mutations in the ABCA1 gene or the APOA1 gene cause familial HDL deficiency. The proteins produced from these genes work together to remove cholesterol and phospholipids from cells.

The ABCA1 gene provides instructions for making a protein that removes cholesterol and phospholipids from cells by moving them across the cell membrane. The movement of these substances across the membrane is enhanced by another protein called apolipoprotein A‑I (apoA‑I), which is produced by the APOA1 gene. Once outside the cell, the cholesterol and phospholipids combine with apoA‑I to form HDL. ApoA‑I also triggers a reaction that converts cholesterol to a form that can be fully integrated into HDL and transported through the bloodstream.

ABCA1 gene mutations and some APOA1 gene mutations prevent the release of cholesterol and phospholipids from cells. Other mutations in the APOA1 gene reduce the protein's ability to stimulate the conversion of cholesterol. These ABCA1 and APOA1 gene mutations decrease the amount of cholesterol or phospholipids available to form HDL, resulting in low levels of HDL in the blood. A shortage (deficiency) of HDL is believed to increase the risk of cardiovascular disease.

Learn more about the genes associated with Familial HDL deficiency

  • ABCA1
  • APOA1

Inheritance

Familial HDL deficiency is inherited in an , which means an alteration in one copy of either the ABCA1 or the APOA1 gene in each cell is sufficient to cause the disorder. People with alterations in both copies of the ABCA1 gene develop the related disorder Tangier disease.

Other Names for This Condition

  • Familial hypoalphalipoproteinemia
  • FHA
  • HDL deficiency, type 2
  • HDLD
  • Low serum HDL cholesterol
  • Primary hypoalphalipoproteinemia

Additional Information & Resources

Patient Support and Advocacy Resources

  • National Organization for Rare Disorders (NORD)

Clinical Trials

  • ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

  • HYPOALPHALIPOPROTEINEMIA, PRIMARY, 1

Scientific Articles on PubMed

  • PubMed

References

  • Batal R, Tremblay M, Krimbou L, Mamer O, Davignon J, Genest J Jr, Cohn JS. Familial HDL deficiency characterized by hypercatabolism of mature apoA‑I but not proapoA‑I. Arterioscler Thromb Vasc Biol. 1998 Apr;18(4):655‑64. doi: 10.1161/01.atv.18.4.655. Citation on PubMed
  • Marcil M, Brooks‑Wilson A, Clee SM, Roomp K, Zhang LH, Yu L, Collins JA, van Dam M, Molhuizen HO, Loubster O, Ouellette BF, Sensen CW, Fichter K, Mott S, Denis M, Boucher B, Pimstone S, Genest J Jr, Kastelein JJ, Hayden MR. Mutations in the ABC1 gene in familial HDL deficiency with defective cholesterol efflux. Lancet. 1999 Oct 16;354(9187):1341‑6. doi: 10.1016/s0140-6736(99)07026-9. Citation on PubMed
  • Mott S, Yu L, Marcil M, Boucher B, Rondeau C, Genest J Jr. Decreased cellular cholesterol efflux is a common cause of familial hypoalphalipoproteinemia: role of the ABCA1 gene mutations. Atherosclerosis. 2000 Oct;152(2):457‑68. doi: 10.1016/s0021-9150(99)00498-0. Citation on PubMed
  • Oram JF. HDL apolipoproteins and ABCA1: partners in the removal of excess cellular cholesterol. Arterioscler Thromb Vasc Biol. 2003 May 1;23(5):720‑7. doi: 10.1161/01.ATV.0000054662.44688.9A. Epub 2003 Jan 9. Citation on PubMed

Frequently Asked Questions

The disorder is typically autosomal recessive, meaning both parents must carry a pathogenic variant. First‑degree relatives have a 25% chance of being affected and a 50% chance of being carriers. Genetic counseling is recommended, and siblings can be offered targeted genetic testing. If a mutation is identified, parents can consider prenatal or preimplantation genetic diagnosis in future pregnancies.===
clinician will first order a fasting lipid panel that includes HDL, LDL, total cholesterol, and triglycerides. If HDL is markedly low (often <20 mg/dL) despite lifestyle changes, the next step is targeted genetic testing. Sequencing of the ABCA1 and APOA1 genes is performed, usually via next‑generation sequencing panels or whole‑exome sequencing, to identify pathogenic variants. In some cases, a copy‑number variation assay may be added if a deletion or duplication is suspected. The combination of a severely reduced HDL level and a pathogenic mutation in one of these genes confirms the diagnosis.
Patients should focus on a Mediterranean‑style diet rich in monounsaturated fats (olive oil, nuts), omega‑3 fatty acids (fatty fish), and high‑fiber foods (whole grains, legumes). Regular aerobic exercise (150 minutes per week of moderate activity) and resistance training can modestly increase HDL. Smoking cessation is crucial, as smoking lowers HDL by up to 10%. While these measures can raise HDL by 5–10 mg/dL, they rarely normalize HDL in genetically determined deficiency; therefore, they are adjuncts to medical therapy and cardiovascular risk management.
Because of the heightened risk of premature atherosclerosis, a baseline cardiovascular assessment is recommended at diagnosis, including carotid intima‑media thickness (CIMT) or coronary artery calcium scoring if age‑appropriate. Annual lipid panels and blood pressure checks are standard. If risk factors (diabetes, hypertension, smoking) are present, consider earlier imaging. For those with documented coronary disease, guideline‑based secondary prevention (statins, antiplatelet agents) is indicated, even though HDL‑raising drugs are limited.
Source: MedlinePlus, National Library of Medicine

MedlinePlus brings together authoritative health information from the National Library of Medicine (NLM), the National Institutes of Health (NIH), and other government agencies and health-related organizations.

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