Familial LCAT deficiency (ORPHA:79293)
Familial LCAT (lecithin-cholesterol acyltransferase) deficiency (FLD) is a form of lecithin-cholesterol acyltransferase deficiency (LCAT; see this term) characterized clinically by corneal opacities, hemolytic anemia, and renal failure, and biochemically by severely decreased HDL cholesterol and complete deficiency of the LCAT enzyme.
Epidemiology
Prevalence and incidence of FLD are unknown. The disease is very rare: about 70 cases have been reported to date.
Clinical description
Age of onset and severity of clinical manifestations are variable. Corneal opacities usually develop in early childhood and are characterized by grayish dots throughout the corneal stroma. Over time, corneal opacities may lead to severe visual impairment requiring corneal transplantation. The degree of hemolytic anemia is variable. Renal insufficiency is often observed from the second or third decade of life and may present with proteinuria. Renal disease may progress to end-stage renal failure requiring hemodialysis and/or kidney transplantation. Signs of atherosclerosis, hepatomegaly, splenomegaly, and lymphadenopathy have been reported in rare cases.
Etiology
FLD is caused by mutations in the LCAT gene (16q22.1) encoding the LCAT enzyme which catalyzes the formation of cholesterol esters in lipoproteins, leading to progressive lipid deposition in body tissues. More than 70 different mutations have been identified and appear to result in absence of LCAT production or synthesis of an enzyme with no alpha- or beta-LCAT activity (i.e., the activity of LCAT in esterifying cholesterol within HDL or other lipoproteins, respectively). There is no clear genotype-phenotype correlation since family members with the same mutation have been found to have different clinical and biochemical pictures. Environmental factors or other minor genes may therefore also be involved in the disorder.
Diagnostic methods
Family history of characteristic disease features may be useful in diagnosis of the disorder. Diagnostic suspicion is also based on clinical signs and on laboratory tests showing a severe reduction of plasma HDL cholesterol. Kidney biopsy showing distinctive lipid deposits in the glomeruli on histology may also assist in diagnosis. Definitive diagnosis requires molecular genetic testing of the LCAT gene and functional analysis of the gene product.
Differential diagnosis
Differential diagnosis includes fish eye disease (FED) and Tangier Disease (see these terms).
Antenatal diagnosis
Prenatal diagnosis is possible.
Genetic counseling
FLD follows an autosomal recessive pattern of inheritance. Genetic counseling is recommended in affected families.
Management and treatment
Kidney function and visual acuity should be monitored in affected patients. Treatment for anemia and renal insufficiency is symptomatic. Hemodialysis or even kidney transplantation may be needed. Severe visual impairment may require corneal transplantation.
Prognosis
Prognosis is variable. End-stage renal disease is the most serious outcome.

                            Last update: 
                            March 2012


                            - Expert reviewer(s): 
                            Pr Laura CALABRESI  - Pr Guido FRANCESCHINI