A novel ABCA1 mutation in Tangier disease associated with severe premature and rapidly progressive neurodegenerative disorder.

Tangier disease (TD) is a rare inherited disorder of lipoprotein metabolism, characterized by low levels of high-density lipoprotein-cholesterol (HDL-c) and accumulation of cholesterol esters in various tissues. It is caused by mutations in the ATP binding cassette transporter A1 (ABCA1). Clinical presentation is highly variable. Polyneuropathy is an encountered clinical presentation, whereas neurocognitive disorders are less frequently described. We present a case of a 68-year-old male with premature coronary heart disease, orange tonsils, thrombocytopenia, atypical neurodegenerative disease, and severe rapidly evolving neurocognitive disorder, until death. HDL-c levels were 6 mg/dL, apolipoprotein (Apo)AI was 2.8 mg/dL, and ApoE genotype was E2/E2. Genetic analysis revealed a homozygous c.1510-1 G>C variant in intron 12. This variant was considered of uncertain significance, because of the absence of reported clinical features. We suggest that this variant could be considered moderate/strong pathogenetic. We highlight the need to describe more clinical presentations related to genetic variants, given the limited data on genotype-phenotype correlations in TD.