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Lecithin-cholesterol acyltransferase deficiency
This genetic disorder, caused by changes in the LCAT gene, affects the enzyme responsible for converting free cholesterol into cholesterol esters. This can lead to a build-up of unesterified cholesterol in various tissues, impacting kidney function, vision, and red blood cells.
Overview
Lecithin-cholesterol acyltransferase (LCAT) deficiency is a group of rare inherited conditions caused by variants in the LCAT gene. This gene provides instructions for making an enzyme called LCAT, which plays a critical role in cholesterol metabolism. The LCAT enzyme is primarily produced in the liver and circulates in the blood, where it helps convert free cholesterol into a more stable form called cholesterol ester. This process is essential for maintaining healthy cholesterol levels and for the proper structure and function of high-density lipoprotein (HDL), often referred to as 'good' cholesterol [PMID:33678099].
When the LCAT enzyme is deficient or non-functional, free cholesterol can accumulate in various tissues and organs throughout the body. This accumulation can lead to a range of symptoms, affecting different systems. There are two main forms of LCAT deficiency: Familial LCAT Deficiency (FLD) and Fish-eye Disease (FED). FLD is the more severe form, affecting multiple organs, while FED primarily impacts vision [PMID:33678099]. Both forms are very rare.
Symptoms & clinical features
The symptoms of LCAT deficiency vary depending on whether an individual has Familial LCAT Deficiency (FLD) or Fish-eye Disease (FED). Individuals with FLD typically experience a broader range of symptoms. One common symptom across both forms is clouding of the cornea, the transparent outer layer of the eye. This corneal clouding can sometimes resemble a grey or cloudy ring and may affect vision over time.
In FLD, kidney problems are often a significant concern, potentially leading to proteinuria (protein in the urine) and, in some cases, kidney failure [PMID:33678099]. Anaemia, specifically haemolytic anaemia, can also occur, where red blood cells are destroyed prematurely. This may cause fatigue and weakness. Some individuals with FLD might also develop an enlarged spleen (splenomegaly) and liver involvement. In contrast, Fish-eye Disease primarily affects the eyes, with severe corneal clouding and very low HDL cholesterol levels, but generally does not involve the severe kidney disease or anaemia seen in FLD [PMID:28790343].
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Affected organs
Lecithin-cholesterol acyltransferase deficiency can affect several organ systems due to the impaired metabolism of cholesterol. The eyes are commonly affected in both forms, with corneal clouding being a hallmark sign. This clouding is caused by the deposition of unesterified cholesterol and phospholipids in the cornea [PMID:28790343].
In Familial LCAT Deficiency, the kidneys are often significantly impacted, with cholesterol deposits leading to kidney damage and a potential decline in kidney function over time. The blood is also affected, as the abnormal cholesterol processing can lead to haemolytic anaemia, where red blood cells are prematurely destroyed. The spleen and liver may also be affected, sometimes becoming enlarged.
Risks & severity
The severity of LCAT deficiency varies, with Familial LCAT Deficiency (FLD) typically being more severe than Fish-eye Disease (FED). FLD carries a risk of progressive kidney disease, which can sometimes lead to end-stage renal failure, necessitating dialysis or kidney transplantation. Haemolytic anaemia can also contribute to general ill-health. The corneal opacities can impair vision, though the degree of impairment differs among individuals.
Fish-eye Disease, while still impacting vision due to corneal clouding, generally has a milder prognosis as it does not typically involve the severe kidney or blood complications seen in FLD. The age of onset for symptoms can also vary, but corneal clouding is often observed in adolescence or early adulthood, with other symptoms potentially developing later. Exact prevalence figures are not well established, but LCAT deficiency is considered a very rare condition.
Genetic causes
Lecithin-cholesterol acyltransferase deficiency is caused by pathogenic variants in the LCAT gene. This gene provides the genetic blueprint for producing the lecithin-cholesterol acyltransferase enzyme. The LCAT enzyme is crucial for normal lipid metabolism, specifically for converting free cholesterol into cholesterol esters within high-density lipoprotein (HDL) particles [PMID:33678099]. This conversion is vital for moving cholesterol from peripheral tissues back to the liver, a process known as reverse cholesterol transport.
When variants in the LCAT gene lead to a deficient or non-functional enzyme, the ability to esterify cholesterol is impaired. This results in an accumulation of unesterified cholesterol and other lipids in various tissues, contributing to the symptoms observed in LCAT deficiency. Different variants in the LCAT gene can lead to either the severe Familial LCAT Deficiency or the milder Fish-eye Disease, depending on how significantly they affect the enzyme's activity [PMID:28790343].
- LCAT lecithin-cholesterol acyltransferase
Inheritance pattern
Lecithin-cholesterol acyltransferase deficiency is inherited in an autosomal recessive pattern. This means that an individual must inherit two altered copies of the LCAT gene - one from each parent - to develop the condition. People who have only one altered copy of the LCAT gene are called carriers. Carriers typically do not show symptoms of the condition because their single functional copy of the gene can still produce enough LCAT enzyme.
When both parents are carriers of a pathogenic LCAT variant, there is a 25% chance with each pregnancy that their child will inherit two altered copies and develop LCAT deficiency. There is a 50% chance the child will be a carrier like their parents, and a 25% chance the child will inherit two unaffected copies and not be a carrier.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
Diagnosis of Lecithin-cholesterol acyltransferase deficiency often begins with a clinical suspicion based on presenting symptoms, such as corneal clouding, kidney problems, or unexplained anaemia. Blood tests revealing very low levels of HDL cholesterol and altered lipid profiles, including high unesterified cholesterol, can further support the suspicion. Enzyme activity assays measuring LCAT function in the blood can help confirm a deficiency [PMID:28790343].
A definitive diagnosis is made through genetic testing, which involves analysing the LCAT gene for pathogenic variants. In the UK, genetic testing for LCAT deficiency may be accessed through the NHS Genomic Medicine Service (GMS). Referral to clinical genetics services for assessment and testing would typically be initiated by a specialist, such as a nephrologist, ophthalmologist, or lipid specialist. The relevant R-code for diagnostic testing would depend on the specific clinical indication and the testing strategy chosen by the regional Genomic Laboratory Hub.
Management & lifestyle
Management of Lecithin-cholesterol acyltransferase deficiency focuses on alleviating symptoms and preventing complications, as there is currently no cure. For corneal clouding, special contact lenses or, in severe cases, corneal transplantation may be considered to improve vision. Regular ophthalmic evaluations are important to monitor the progression of corneal opacities.
For kidney involvement in Familial LCAT Deficiency, management strategies include monitoring kidney function, controlling blood pressure, and managing proteinuria with medications. If kidney failure progresses, dialysis or kidney transplantation might be necessary. Anaemia may be managed symptomatically, and regular monitoring of blood counts is advised. Individuals are typically managed by a multidisciplinary team, which may include nephrologists, ophthalmologists, haematologists, and lipid specialists. Genetic counselling is also an important aspect of care, offering information about the condition, inheritance patterns, and support for families.
UK care pathway
In the UK, individuals suspected of having Lecithin-cholesterol acyltransferase deficiency would typically be referred by their GP or a specialist to a clinical genetics service. These services are part of the NHS Genomic Medicine Service (GMS) and can provide expert assessment, genetic counselling, and access to appropriate genetic testing. Genetic testing for LCAT deficiency would fall under an NHS R-code, facilitating a precise molecular diagnosis. A genetic counsellor can help families understand the inheritance pattern, implications for relatives, and available support.
Frequently asked questions
What is the difference between Familial LCAT Deficiency and Fish-eye Disease?
Familial LCAT Deficiency (FLD) is the more severe form, affecting multiple organs like the kidneys and causing anaemia, in addition to corneal clouding. Fish-eye Disease (FED) primarily affects the eyes, leading to significant corneal clouding, but generally does not involve the severe kidney or blood complications seen in FLD.
Can carriers of LCAT deficiency develop symptoms?
No, carriers of LCAT deficiency typically do not develop symptoms. They have one working copy of the LCAT gene, which usually produces enough LCAT enzyme to prevent the condition from manifesting. Carriers can, however, pass the altered gene copy to their children.
Is there a cure for LCAT deficiency?
Currently, there is no cure for LCAT deficiency. Treatment focuses on managing the symptoms and preventing complications. This can include monitoring kidney function, managing anaemia, and addressing vision problems caused by corneal clouding.
How is LCAT deficiency diagnosed?
Diagnosis often starts with clinical signs like corneal clouding and abnormal blood lipid levels. It is confirmed by measuring the activity of the LCAT enzyme and, definitively, through genetic testing of the LCAT gene to identify specific pathogenic variants.
If I have LCAT deficiency, what does this mean for my family?
Since LCAT deficiency is an autosomal recessive condition, both parents of an affected individual are typically carriers. Family members, especially siblings, may also be carriers. Genetic counselling can provide detailed information about the inheritance pattern and risks for other family members.
References
- Carty JR, Anastasopoulou C. Lecithin-Cholesterol Acyltransferase Deficiency. 2024. PMID: 38753926
- Klintworth GK. Corneal dystrophies. Orphanet journal of rare diseases. 2009. PMID: 19236704
- Vitali C, Rader DJ, Cuchel M. Novel therapeutic opportunities for familial lecithin:cholesterol acyltransferase deficiency: promises and challenges. Current opinion in lipidology. 2023. PMID: 36473023
- Ashorobi D, Liao H. Lipoprotein X-Induced Hyperlipidemia. 2024. PMID: 34283509
- Calabresi L, Simonelli S, Gomaraschi M. Genetic lecithin:cholesterol acyltransferase deficiency and cardiovascular disease. Atherosclerosis. 2012. PMID: 22189200
- Oldoni F, Baldassarre D, Castelnuovo S. Complete and Partial Lecithin:Cholesterol Acyltransferase Deficiency Is Differentially Associated With Atherosclerosis. Circulation. 2018. PMID: 29748187
- Saeedi R, Li M, Frohlich J. A review on lecithin:cholesterol acyltransferase deficiency. Clinical biochemistry. 2015. PMID: 25172171
- Vitali C, Bajaj A, Nguyen C. A systematic review of the natural history and biomarkers of primary lecithin:cholesterol acyltransferase deficiency. Journal of lipid research. 2022. PMID: 35065092