desmosterolosis

Definition: Desmosterolosis is a rare autosomal recessive disorder characterized by multiple congenital anomalies and elevated levels of the cholesterol precursor desmosterol in plasma, tissue, and cultured cells.

Desmosterolosis is caused by mutation in the DHCR24 gene (MIM.606418).

The enzyme 3-beta-hydroxysterol delta-24-reductase (DHCR24), a member of the flavin adenine dinucleotide (FAD)-dependent oxidoreductases, catalyzes the reduction of the delta-24 double bond of sterol intermediates during cholesterol biosynthesis.

Physiopathology

Two major pathways of cholesterol synthesis operate in parallel. The first uses 7-DHC as the immediate precursor of cholesterol. In the second, the enzyme 3β-hydroxysterol Δ24-reductase reduces the Δ24 double bond in desmosterol to yield cholesterol.

Desmosterolosis (MIM.602398) is an autosomal recessive malformation syndrome resulting from a deficiency of this enzyme.

It was the second human malformation syndrome shown to arise from an inborn error of cholesterol synthesis, after the Smith-Lemli-Opitz syndrome.

Since only two cases have been identified, the desmosterolosis phenotype has yet to be fully delineated.

The initial patient, identified by Clayton et al., was an infant who died soon after birth. This patient had macrocephaly, craniofacial malformations including cleft palate and a thick alveolar ridge, a congenital heart malformation, hypoplastic lungs, renal hypoplasia, ambiguous genitalia, short limbs, and osteosclerosis.

The second patient was a 4-year-old male with marked developmental delay, microcephaly, dysmorphic facial features, and limb malformations. Sterol analysis by liquid gas chromatography-mass spectrometry (LGC-MS) showed marked elevations of desmosterol in serum and tissues from both of these patients.

The human 3β-hydroxysterol Δ24-reductase gene (DHCR24), identified and cloned by Waterham et al. , encodes a 516–amino acid polypeptide with one predicted transmembrane domain. The first patient had one missense mutation, Y471S, on one allele, and two missense mutations, N294T and K306N, on the second allele. The second patient was homozygous for an E191K mutation. All four missense mutations independently decreased DHCR24 activity, and the combination of N294T with K306N was more severe than either mutation by itself.

See also

 pathways of cholesterol synthesis
 inborn error of cholesterol synthesis, after the Smith-Lemli-Opitz syndrome.

References

 Malformation syndromes due to inborn errors of cholesterol synthesis Forbes D. Porter http://www.jci.org/articles/view/16386