Tangier disease

Tangier disease (named after Tangier Island, Virginia) is a multisystem disorder of cholesterol efflux characterised by hyperplastic yellow-orange palatine and pharyngeal tonsils, peripheral neuropathy, and hepatosplenomegaly. Hyperplastic tonsils are typically first noted in late childhood or adolescence; they are usually asymptomatic but may occasionally cause difficulty breathing or swallowing, recurrent ear or sinus infections, or obstructive sleep apnoea. Peripheral neuropathy commonly follows a benign, relapsing-remitting course with sensory abnormalities but can be progressive in some affected individuals. Premature atherosclerotic coronary artery disease may develop, usually in the sixth or seventh decade and rarely before age 40 years; some affected individuals also show heart valve involvement. Additional findings include corneal opacities, thrombocytopenia with stomatocytosis, and lipid-laden macrophage infiltration of the intestinal mucosa, lymph nodes, spleen, and liver. Clinical expression is variable, with some individuals showing only biochemical perturbation.

Due to insufficient data, no reliable statement on prevalence can currently be made. Fewer than 100 cases have been published worldwide, with the exception of small founder populations such as Tangier Island, Virginia.

Tangier disease is caused by biallelic germline loss-of-function pathogenic variants in ABCA1 (9q31.1), the sole causative gene. ABCA1 encodes a phospholipid-transporting ATPase (flippase) that facilitates the formation of HDL particles by transferring cholesterol and phospholipids onto apolipoprotein A-I within nascent HDL and promotes cholesterol efflux from vascular endothelial cells and macrophages. Loss of ABCA1 function reduces circulating HDL-cholesterol and causes accumulation of cholesteryl esters in reticuloendothelial cells throughout the body, accounting for the characteristic clinical manifestations.

Tangier disease is inherited in an autosomal recessive manner. The parents of an affected individual are obligate heterozygotes and typically show approximately half-normal HDL-cholesterol levels without clinical disease. With both parents heterozygous, each sib of an affected individual has a 25% risk of being affected, a 50% risk of being a heterozygote, and a 25% risk of inheriting neither pathogenic variant. Prenatal molecular testing is technically possible once the familial pathogenic variants have been identified.

The diagnosis is based on biochemical findings combined with molecular confirmation, as formal clinical diagnostic criteria have not been published. Characteristic laboratory findings include very low plasma HDL-cholesterol (typically <5 mg/dl, 0.125 mmol/l) and very low or absent apolipoprotein A-I (usually <30 mg/dl, often <5 mg/dl), supported by a small or absent alpha band on lipoprotein electrophoresis. The diagnosis is established in a proband with these biochemical findings together with biallelic pathogenic variants in ABCA1 identified on molecular genetic testing.

Main differential diagnoses include:

• Apolipoprotein A-I deficiency: plasma apo A-I is undetectable, compared with very low (but detectable) plasma apo A-I in Tangier disease; APOA1
• LCAT deficiency: marked corneal opacification with renal disease in individuals with complete LCAT deficiency; LCAT
• : marked corneal opacification as the predominant feature; allelic LCAT disorder; LCAT

• Establishing the molecular diagnosis confirms the clinical and biochemical suspicion and provides the basis for informed genetic counselling of the family.
• A confirmed molecular diagnosis enables specific and individualised surveillance and clinical management, including early identification of at-risk relatives who may benefit from prompt initiation of preventive measures against premature atherosclerotic disease, with decisions on scope and timing made by the treating physicians in consultation with the affected individual.
• Once the familial pathogenic variants are known, predictive testing of at-risk relatives is technically possible and supports reproductive counselling and family planning.

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