Hypercarotenemia And Vitamin A Deficiency, Autosomal Dominant

A number sign (#) is used with this entry because of evidence that autosomal dominant hypercarotenemia and vitamin A deficiency (HCVAD) is caused by heterozygous mutation in the BCMO1 gene (BCO1; 605748) on chromosome 16q23. One such patient has been reported.

See also 277350 for possible autosomal recessive inheritance.

Clinical Features

Sharvill (1970) described very high levels of blood carotene in a woman, her mother, a sib and her son. Low levels of vitamin A were also found at times. He postulated a defect in the conversion of carotene to vitamin A.

Frenk (1966) described 3 patients with yellow-colored keratoderma associated with a lowered level of serum vitamin A and a raised level of carotenes.

Attard-Montalto et al. (1992) described a 5-year-old girl with intermittent orange discoloration of her palms, soles, and face. There were persistently low levels of both vitamin A and serum-specific retinol-binding protein (RBP4; 180250). Attard-Montalto et al. (1992) postulated that the low serum RBP concentration resulted in slow uptake and release of vitamin A by the liver. The conversion of carotene to vitamin A was consequently inhibited, resulting in hypercarotenemia. Vitamin A supplements were unable to raise the serum vitamin A concentration and did not relieve the carotenemia.

Mapping

Plasma Level of Carotenoids Quantitative Trait Locus 1

In a genomewide association study of 1,190 Italians, Ferrucci et al. (2009) found significant associations between plasma levels of the carotenoids beta-carotene and lutein and several SNPs mapping to chromosome 16q (rs6420424, rs8044334, rs11645428, and rs6564851). The findings were replicated in additional cohorts of 615 and 2,136 individuals, respectively. Metaanalysis of all 3 studies showed that the G allele of rs6564851 had the highest association with increased plasma beta-carotene (p = 1.6 x 10(-24)). This allele was also associated with lower plasma lutein (p = 7.3 x 10(-15)). This SNP is located 7.7-kb from the BCMO1 gene, which encodes an enzyme that catalyzes the first step in the conversion of dietary provitamin carotenoids to vitamin A in the small intestine. Ferrucci et al. (2009) estimated that rs6564851 could explain 1.9% of the variance in plasma beta-carotene levels. There was no association with plasma retinol levels.

Molecular Genetics

In a patient with hypercarotenemia and vitamin A deficiency reported by Sharvill (1970), Lindqvist et al. (2007) identified a heterozygous mutation in the BCOM1 gene (605748.0001). The BCMO1 gene encodes beta-carotene 15,15-prime-monooxygenase, which converts carotenoids into vitamin A. Thus, deficiency of this enzyme results in hypercarotenemia and secondary vitamin A deficiency.