Apolipoprotein A-I deficiency (ORPHA:425)
A rare lipoprotein metabolism disorder characterized biochemically by complete absence of apolipoprotein AI and extremely low plasma high density lipoprotein (HDL) cholesterol, and clinically by corneal opacities and xanthomas complicated with premature coronary heart disease (CHD).
Epidemiology
Prevalence of Apo A-I deficiency is unknown. The disease has been described in about 30 families.
Clinical description
Although extremely low plasma HDL cholesterol may be detected in any patient fortuitously from birth, the age of symptom onset and the clinical presentation varies greatly. While some patients remain asymptomatic until advanced adulthood, others may present from adolescence with a combination of the following symptoms: blurred vision due to corneal opacities or cataract, tubero-eruptive, tendinous, palmar and/or planar xanthomas, xanthelasmas, and premature CHD (e.g. myocardial infarction) and carotid atherosclerosis. Less often, Apo A-I deficiency may manifest with neurosensory signs (e.g. cerebellar ataxia, neurosensory hearing loss, proliferative retinopathy) or other multi-organ manifestations of secondary amyloidosis (e.g. hepatomegaly, nephropathy, cardiomyopathy), all potentially progressing into end-stage organ failure (liver, renal or cardiac failure).
Etiology
The disease is due to various deletions and mutations of the APOA1 gene (11q23-q24), encoding the apo A-I protein, a major constituent of HDL, that lead to decreased apo A-I production, impaired function or increased apo A-I catabolism. The clinical picture depends on the type of mutation. Mutations severely impairing Apo A-I expression (i.e. nonsense or frameshift point mutations, genomic rearrangements), result in premature CHD. Missense mutations associated with detectable plasma apoA-I and very low HDL cholesterol, result in milder cardiovascular symptoms and, occasionally, in systemic or neurological amyloidosis, or are associated with healthy patients with no signs of atherosclerosis.
Diagnostic methods
Diagnosis is based on biochemical analysis of plasma Apo A-I and HDL cholesterol levels showing extremely low HDL cholesterol levels and very low to undetectable Apo A-I (inferior to 5 mg/dL). Low HDL cholesterol levels are associated with normal VLDL and LDL cholesterol levels, and normal or decreased triglyceride levels. Histological examination of skin lesions reveals numerous foam cells. Diagnosis is confirmed by genetic testing.
Differential diagnosis
The differential diagnosis includes Tangier disease, LCAT deficiency (see these terms) and secondary causes of extremely low HDL cholesterol levels that include medications (androgenic steroids, paradoxical response to fibrates) and malignancies.
Antenatal diagnosis
Antenatal diagnosis is usually not performed, but is possible in families with severe systemic or neurological amyloidosis.
Genetic counseling
Transmission is autosomal dominant. Genetic counseling should be offered to the affected families informing them of the 50% risk the offspring has of inheriting the disease-causing mutation and therefore being affected with the disorder.
Management and treatment
To date, there is no curative therapy. In case of carotid atherosclerosis or cardiovascular complications, a low-fat diet balanced in anti-oxidants (e.g. Mediterranean type) may be combined with statins (HMGCoA reductase inhibitors) that lower LDL cholesterol levels below 70 mg/dL. Oral anti-oxidants, or infused synthetic HDL-mimetics or reconstituted HDL, are being investigated as potential anti-atherosclerotic therapies. Regular cardiovascular monitoring should be offered to Apo AI deficient patients with extremely low HDL cholesterol (<20 mg/dL) because of the increased risk (Odds Ratio x2-3) of coronary artery disease. In cases exhibiting signs of amyloidosis, long-term follow-up of target organ function should be proposed.
Prognosis
Prognosis depends on the occurrence of premature CHD and end-stage organ failure in cases with signs of amyloidosis.

                            Last update: 
                            December 2013


                            - Expert reviewer(s): 
                            Dr Pascale BENLIAN