The deficiency of lecithin-cholesterol acyltransferase is a very rare disease (until now have been reported about 125 cases in the world) due to mutations of the LCAT gene coding for the enzyme that catalyzes the cholesterol esterification. The composition, the shape, and the concentration of all lipoproteins are abnormal. The mature HDL, which are formed by the reaction of LCAT, are absent in the patient plasma. Furthermore, the membrane of erythrocytes of people suffering contain a large amount of unesterified cholesterol and phosphatidylcholine.
It is an autosomal recessive desease.
The deficency is caused by mutations in the LCAT gene of the protein, which is located on chromosome 16 (16q22 region). 70 mutations of the gene have been identified. Mutations which determine the LCAT deficiency are missense and nonsense mutations.
The LCAT enzyme has the function to esterify cholesterol in plasma. Genetic defects involve a partial or complete inability to exert the function with subsequent deposit of unesterified cholesterol in body tissues. In the plasma of patients genotypically homozygotes has not been found any activity of LCAT; heterozygotes show activity reduced by 50-60%.
The genotype-phenotype correlation is unclear, since different clinical and biochemical studies have been reported in individuals of the same family with the same mutation. It is clear that that minor genes and environmental factors are probably implicated in the disease.
Genetic and phenotypic heterogeneity in familial lecithin
The prevalence and incidence are still unknown (it is estimated less than one in a million). Males and females are affected equally; the age of onset and severity of clinical signs are variable. Until now, about 30 cases have been reported in homozygous familial LCAT deficiency from 11 countries in Europe, North America, and India and Japan. However. In Norway the heterozygote frequency is estimated to be equal to 4%.
The desease manifests itself clinically with:
- Corneal opacities, initially visible only with a slit lamp and later with the naked eye; they are developed in early childhood and are characterized by gray dots in the corneal stroma.
- Hemolytic anemia, caused by hematuria. It has variable severity.
- Renal failure, caused by proteinuria. It usually strikes when the patient is 30-40 years old.
Sometimes atherosclerosis, hepatomegaly, splenomegaly, lymphadenopathy can even occur.
* Severe reduction of HDL-cholesterol
* Full-deficiency of LCAT enzyme
The on clinical features of disease may be useful for the diagnosis.
- Reduction of serum levels of: - HDL-cholesterol (<5mg/dl)
- ApoA-1 (<30-40 mg / dl)
- Frequent mild hypertriglyceridemia
- Very low ratio of total and esterified cholesterol
The diagnosis can be supported by a renal biopsy which, through histological examination, shows characteristic lipid deposits in the renal glomeruli.
The is based on the study with cholesterol, which show a marked deficiency of alpha-LCAT, beta-LCAT and esterification.
The can be confirmed by molecular analysis of the gene and functional analysis of the gene product.
Most patients are diagnosed during adulthood. Only a few cases have been diagnosed during the symptom-free teenage years.
In patients affected by the disease, renal function and visual acuity should be monitored and symptoms of anemia and renal failure should be treated. May be required dialysis and kidney transplantation.
The corneal opacity may lead to severe visual impairment and the need for a corneal transplant. Kidney failure can worsen up to require a kidney transplant and / or dialysis. The end-stage renal disease is the most serious outcome.
Currently there is no specific therapy. The cornea and kidney transplants carry the risk of relapse on the organ transplanted.