Lecithin cholesterol acyltransferase deficiency

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Lecithin cholesterol acyltransferase deficiency
Other namesLCAT deficiency
Specialty Medical genetics   OOjs UI icon edit-ltr-progressive.svg

Lecithin cholesterol acyltransferase deficiency is a disorder of lipoprotein metabolism. [1] The disease has two forms: [2] Familial LCAT deficiency, in which there is complete LCAT deficiency, and Fish-eye disease, in which there is a partial deficiency. [3]

Contents

Lecithin cholesterol acyltransferase catalyzes the formation of cholesterol esters in lipoproteins.

Signs and symptoms

Symptoms of the familial form include visual impairment caused by diffuse corneal opacities, target cell hemolytic anemia, and kidney failure. Less common symptoms include atherosclerosis, hepatomegaly (enlarged liver), splenomegaly (enlarged spleen), and enlarged lymph nodes. [4]

Fish-eye disease is less severe and most commonly presents with impaired vision due to corneal opacification. It rarely presents with other findings, although, atherosclerosis, hepatomegaly, splenomegaly, and lymphadenopathy can occur. [4] Carlson and Philipson found that the disease was named so because the cornea of the eye was so opaque or cloudy with dots of cholesterol that it resembled a boiled fish. [5]

If an individual only carries one copy of the mutated gene, they typically do not show symptoms. [6]

Pathophysiology

A deficiency of LCAT causes accumulation of unesterified cholesterol in certain body tissues. Cholesterol effluxes from cells as free cholesterol and is transported in HDL as esterified cholesterol. LCAT is the enzyme that esterifies the free cholesterol on HDL to cholesterol ester and allows the maturation of HDL. LCAT deficiency does not allow for HDL maturation resulting in its rapid catabolism of circulating apolipoprotein A1 and apolipoprotein A2. The remaining form of HDL resembles nascent HDL.[ citation needed ]

The LCAT glycoprotein produces lysophosphatidylcholine and cholesterol ester and binds to lipoproteins after being secreted by the liver. [5] Usually the enzyme produced is responsible for cholesterol ester formation and high density lipoprotein (HDL) metabolism, but in fish-eye disease the enzyme cannot esterify, or make the acid into an alkyl, cholesterol in HDL particles. [7] However, there is only a partial deficiency because the enzyme remains active on the cholesterol particles in very low density lipoproteins (VLDL) and low density lipoproteins (LDL). [7] The opaqueness of the eye is caused by the deposit of lipids onto the cornea. [7]

Diagnosis

Definitive diagnosis requires LCAT gene analysis for mutation and functional activity. However, numerous lab tests may help with making a diagnosis such as complete blood count (CBC), urinalysis, blood chemistries, lipid panels, and plasma LCAT activity. [8]

Fish-eye disease is characterized by abnormalities like visual impairment, plaques of fatty material, and dense opacification. [5] [7]

Types

Both the familial type and Fish-eye disease are autosomal recessive disorders caused by mutations of the LCAT gene located on chromosome 16q22.1, which is the long (q) arm of chromosome 16 a position 22.1. [7] Both diseases are very rare with ~70 reported cases of familial LCAT deficiency [9] and ~30 cases of fish-eye disease. [10]

Familial LCAT Deficiency Lab Findings

Fish-eye Disease Lab Findings

Genetic Findings in Fish-eye Disease

Mutations in the LCAT gene, which is localized in the q21–22 region of chromosome 16, cause fish-eye disease. [3] The mutation in the LCAT gene is homozygous for a Thr123→Ile mutation or Pro10→Leu mutation. [11] New mutations have been identified as homozygosity for an A2205→G nucleotide substitution in exon 4 of the LCAT gene which is predicted to be the cause of an Asp131→Asn substitution. [7]

Treatment

Currently, there is no specific treatment to correct the LCAT deficiency so therapy is focused on symptom relief. [12] Corneal transplant may be considered for patients presenting with severely impaired vision caused by cholesterol corneal opacities. Dialysis may be required for patients presenting with kidney failure, and kidney transplant may be considered.[ citation needed ]

Prognosis

Kidney failure is the major cause of morbidity and mortality in complete LCAT deficiency, while in partial deficiency (fish eye disease) major cause of morbidity is visual impairment due to corneal opacity. These patients have low HDL cholesterol but surprisingly premature atherosclerosis is not seen. However, there are some reported cases.[ citation needed ]

Related Research Articles

<span class="mw-page-title-main">Cholesterol</span> Sterol biosynthesized by all animal cells

Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol, a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell membranes. When chemically isolated, it is a yellowish crystalline solid.

High-density lipoprotein (HDL) is one of the five major groups of lipoproteins. Lipoproteins are complex particles composed of multiple proteins which transport all fat molecules (lipids) around the body within the water outside cells. They are typically composed of 80–100 proteins per particle and transporting up to hundreds of fat molecules per particle.

<span class="mw-page-title-main">Low-density lipoprotein</span> One of the five major groups of lipoprotein

Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL). LDL delivers fat molecules to cells. LDL is involved in atherosclerosis, a process in which it is oxidized within the walls of arteries.

<span class="mw-page-title-main">Lipoprotein</span> Biochemical assembly whose purpose is to transport hydrophobic lipid molecules

A lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid molecules in water, as in blood plasma or other extracellular fluids. They consist of a triglyceride and cholesterol center, surrounded by a phospholipid outer shell, with the hydrophilic portions oriented outward toward the surrounding water and lipophilic portions oriented inward toward the lipid center. A special kind of protein, called apolipoprotein, is embedded in the outer shell, both stabilising the complex and giving it a functional identity that determines its role.

<span class="mw-page-title-main">Hypercholesterolemia</span> High levels of cholesterol in the blood

Hypercholesterolemia, also called high cholesterol, is the presence of high levels of cholesterol in the blood. It is a form of hyperlipidemia, hyperlipoproteinemia, and dyslipidemia.

<span class="mw-page-title-main">Combined hyperlipidemia</span> Medical condition

Combined hyperlipidemia is a commonly occurring form of hypercholesterolemia characterised by increased LDL and triglyceride concentrations, often accompanied by decreased HDL. On lipoprotein electrophoresis it shows as a hyperlipoproteinemia type IIB. It is the most commonly inherited lipid disorder, occurring in around one in 200 persons. In fact, almost one in five individuals who develop coronary heart disease before the age of 60 have this disorder.

Intermediate-density lipoproteins (IDLs) belong to the lipoprotein particle family and are formed from the degradation of very low-density lipoproteins as well as high-density lipoproteins. IDL is one of the five major groups of lipoproteins that enable fats and cholesterol to move within the water-based solution of the bloodstream. Each native IDL particle consists of protein that encircles various lipids, enabling, as a water-soluble particle, these lipids to travel in the aqueous blood environment as part of the fat transport system within the body. Their size is, in general, 25 to 35 nm in diameter, and they contain primarily a range of triglycerides and cholesterol esters. They are cleared from the plasma into the liver by receptor-mediated endocytosis, or further degraded by hepatic lipase to form LDL particles.

<span class="mw-page-title-main">Apolipoprotein</span> Proteins that bind lipids to transport them in body fluids

Apolipoproteins are proteins that bind lipids to form lipoproteins. They transport lipids in blood, cerebrospinal fluid and lymph.

Hyperlipidemia is abnormally elevated levels of any or all lipids or lipoproteins in the blood. The term hyperlipidemia refers to the laboratory finding itself and is also used as an umbrella term covering any of various acquired or genetic disorders that result in that finding. Hyperlipidemia represents a subset of dyslipidemia and a superset of hypercholesterolemia. Hyperlipidemia is usually chronic and requires ongoing medication to control blood lipid levels.

<span class="mw-page-title-main">Cholesteryl ester transfer protein</span> Mammalian protein found in Homo sapiens

Cholesteryl ester transfer protein (CETP), also called plasma lipid transfer protein, is a plasma protein that facilitates the transport of cholesteryl esters and triglycerides between the lipoproteins. It collects triglycerides from very-low-density (VLDL) or Chylomicrons and exchanges them for cholesteryl esters from high-density lipoproteins (HDL), and vice versa. Most of the time, however, CETP does a heteroexchange, trading a triglyceride for a cholesteryl ester or a cholesteryl ester for a triglyceride.

Lipoprotein-X (Lp-X) is an abnormal low density lipoprotein found in cholestasis.

<span class="mw-page-title-main">Foam cell</span> Fat-laden M2 macrophages seen in atherosclerosis

Foam cells, also called lipid-laden macrophages, are a type of cell that contain cholesterol. These can form a plaque that can lead to atherosclerosis and trigger heart attacks and stroke.

<span class="mw-page-title-main">Lecithin–cholesterol acyltransferase</span> Mammalian protein found in Homo sapiens

Lecithin–cholesterol acyltransferase is an enzyme, in many animals including humans, that converts free cholesterol into cholesteryl ester, which is then sequestered into the core of a lipoprotein particle, eventually making the newly synthesized HDL spherical and forcing the reaction to become unidirectional since the particles are removed from the surface. The enzyme is bound to high-density lipoproteins (HDLs) (alpha-LCAT) and LDLs (beta-LCAT) in the blood plasma. LCAT deficiency can cause impaired vision due to cholesterol corneal opacities, anemia, and kidney damage. It belongs to the family of phospholipid:diacylglycerol acyltransferases.

<span class="mw-page-title-main">Apolipoprotein AI</span>

Apolipoprotein AI(ApoA-I) is a protein that in humans is encoded by the APOA1 gene. As the major component of HDL particles, it has a specific role in lipid metabolism.

<span class="mw-page-title-main">Apolipoprotein C-III</span>

Apolipoprotein C-III also known as apo-CIII, and apolipoprotein C3, is a protein that in humans is encoded by the APOC3 gene. Apo-CIII is secreted by the liver as well as the small intestine, and is found on triglyceride-rich lipoproteins such as chylomicrons, very low density lipoprotein (VLDL), and remnant cholesterol.

Blood lipids are lipids in the blood, either free or bound to other molecules. They are mostly transported in a protein capsule, and the density of the lipids and type of protein determines the fate of the particle and its influence on metabolism. The concentration of blood lipids depends on intake and excretion from the intestine, and uptake and secretion from cells. Hyperlipidemia is the presence of elevated or abnormal levels of lipids and/or lipoproteins in the blood, and is a major risk factor for cardiovascular disease.

Sterol O-acyltransferase is an intracellular protein located in the endoplasmic reticulum that forms cholesteryl esters from cholesterol.

Reverse cholesterol transport is a multi-step process resulting in the net movement of cholesterol from peripheral tissues back to the liver first via entering the lymphatic system, then the bloodstream.

A lipid profile or lipid panel is a panel of blood tests used to find abnormalities in lipids, such as cholesterol and triglycerides. The results of this test can identify certain genetic diseases and can determine approximate risks for cardiovascular disease, certain forms of pancreatitis, and other diseases.

Remnant cholesterol, also known as remnant lipoprotein, is a very atherogenic lipoprotein composed primarily of very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL). Stated another way, remnant cholesterol is all plasma cholesterol that is not LDL cholesterol or HDL cholesterol, which are triglyceride-poor lipoproteins. However, remnant cholesterol is primarily chylomicron and VLDL, and each remnant particle contains about 40 times more cholesterol than LDL.

References

  1. ↑ Kuivenhoven JA, Pritchard H, Hill J, Frohlich J, Assmann G, Kastelein J (February 1997). "The molecular pathology of lecithin:cholesterol acyltransferase (LCAT) deficiency syndromes". J. Lipid Res. 38 (2): 191–205. doi: 10.1016/S0022-2275(20)37433-2 . PMID   9162740.
  2. ↑ Calabresi L, Pisciotta L, Costantin A, Frigerio I, Eberini I, Alessandrini P, Arca M, Bon GB, Boscutti G, Busnach G, Frasc G, Gesualdo L, Gigante M, Lupattelli G, Montali A, Pizzolitto S, Rabbone I, Rolleri M, Ruotolo G, Sampietro T, Sessa A, Vaudo G, Cantafora A, Veglia F, Calandra S, Bertolini S, Franceschini G (Sep 2005). "The molecular basis of lecithin:cholesterol acyltransferase deficiency syndromes: a comprehensive study of molecular and biochemical findings in 13 unrelated Italian families". Arteriosclerosis, Thrombosis, and Vascular Biology. 25 (9): 1972–1978. doi: 10.1161/01.ATV.0000175751.30616.13 . ISSN   1079-5642. PMID   15994445.
  3. 1 2 Koster, H; Savoldelli, M; Dumon, M. F.; Dubourg, L; Clerc, M; Pouliquen, Y (1992). "A fish-eye disease-like familial condition with massive corneal clouding and dyslipoproteinemia. Report of clinical, histologic, electron microscopic, and biochemical features". Cornea. 11 (5): 452–64. doi:10.1097/00003226-199209000-00016. PMID   1424675. S2CID   27089164.
  4. 1 2 "Lecithin-Cholesterol Acyltransferase Deficiency: Overview, Presentation, Differential Diagnosis". 2016-08-08.{{cite journal}}: Cite journal requires |journal= (help)
  5. 1 2 3 Kuivenhoven, J. A.; Pritchard, H; Hill, J; Frohlich, J; Assmann, G; Kastelein, J (1997). "The molecular pathology of lecithin:cholesterol acyltransferase (LCAT) deficiency syndromes". Journal of Lipid Research. 38 (2): 191–205. doi: 10.1016/S0022-2275(20)37433-2 . PMID   9162740.
  6. ↑ Kaneshiro, N.K. (2014). "Autosomal Recessive". National Institutes of Health, Medline Plus.
  7. 1 2 3 4 5 6 Kuivenhoven, J. A.; van Voorst tot Voorst EJ; Wiebusch, H; Marcovina, S. M.; Funke, H; Assmann, G; Pritchard, P. H.; Kastelein, J. J. (1995). "A unique genetic and biochemical presentation of fish-eye disease". Journal of Clinical Investigation. 96 (6): 2783–91. doi:10.1172/JCI118348. PMC   185988 . PMID   8675648.
  8. ↑ "Lecithin-Cholesterol Acyltransferase Deficiency: Overview, Presentation, Differential Diagnosis". 2016-08-08.{{cite journal}}: Cite journal requires |journal= (help)
  9. ↑ Reference, Genetics Home. "complete LCAT deficiency". Genetics Home Reference. Retrieved 2016-12-11.
  10. ↑ Reference, Genetics Home. "fish-eye disease". Genetics Home Reference. Retrieved 2016-12-11.
  11. ↑ Contacos, C; Sullivan, D. R.; Rye, K. A.; Funke, H; Assmann, G (1996). "A new molecular defect in the lecithin: Cholesterol acyltransferase (LCAT) gene associated with fish eye disease". Journal of Lipid Research. 37 (1): 35–44. doi: 10.1016/S0022-2275(20)37633-1 . PMID   8820100.
  12. ↑ "Fish-eye disease | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2018-04-17.
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