title: Desmosterolosis presenting with multiple congenital anomalies and profound developmental delay.
abstract: Desmosterol (cholesta-5,24-dien-3beta-ol) is a minor sterol that forms as an intermediate in the cholesterol biosynthetic pathway when the 24-unsaturated sterol bond is reduced as the last step rather than earlier in the conversion of lanosterol to cholesterol. In 1998, FitzPatrick et al. reported a premature infant who died shortly after birth and had marked tissue elevations of desmosterol and a strikingly abnormal phenotype. We describe here the first living patient with desmosterolosis and show biochemical evidence in plasma and cultured lymphoblasts for an autosomal recessive deficiency of 24-dehydrocholesterol reductase (DHCR24). The infant has severe microcephaly, agenesis of the corpus callosum, downslanting palpebral fissures, micrognathia, submucous cleft palate, clubfoot, and a persistent patent ductus arteriosus. Plasma sterol quantification in the patient at age 2 years demonstrated a normal cholesterol level, but a 100-fold increased level of desmosterol (60 mcg/ml; nl 0.5 +/- 0.3 mcg/ml (SD)) suggesting deficient activity of 24-dehydrocholesterol (desmosterol) reductase (DHCR24). Both parents had mildly increased levels of desmosterol in plasma (mother: 1.4 mcg/ml; father: 1.8 mcg/ml), consistent with heterozygosity for DHCR24 deficiency. Analysis of sterol metabolism in cultured transformed lymphoblasts showed a 100-fold increased level of desmosterol and a moderately decreased level of cholesterol in the patient's cells and a 10-fold elevation of desmosterol in the mother's cells. At the age of 3.5 years, the patient stands but does not walk, uses a 5-word vocabulary, and lacks any major medical problems. This unique patient broadens the spectrum of inborn errors of cholesterol biosynthesis and suggests additional candidate clinical phenotypes associated with abnormal cholesterol metabolism.
authors.affiliation: Hayward Genetics Center and Department of Pediatrics, Tulane University Medical School, New Orleans, Louisiana 70112, USA. handers@tulane.edu
authors.forename: Hans C
authors.initials: HC
authors.lastname: Andersson
authors.forename: Lisa
authors.initials: L
authors.lastname: Kratz
authors.forename: Richard
authors.initials: R
authors.lastname: Kelley
mesh_terms: D000015:Abnormalities, Multiple / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D002675:Child, Preschool; D002784:Cholesterol / Q000097:blood; D003897:Desmosterol / Q000032:analysis / Q000097:blood / Q000378:metabolism*; D002658:Developmental Disabilities / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D005192:Family Health; D006801:Humans; D008052:Lipid Metabolism, Inborn Errors / Q000201:enzymology / Q000503:physiopathology*; D008214:Lymphocytes / Q000737:chemistry; D008297:Male; D009419:Nerve Tissue Proteins; D010088:Oxidoreductases / Q000172:deficiency; D044925:Oxidoreductases Acting on CH-CH Group Donors; D010641:Phenotype
chemical_list: D009419:Nerve Tissue Proteins; D003897:Desmosterol; D002784:Cholesterol; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; C437069:3beta-hydroxysterol delta24-reductase; C499055:DHCR24 protein, human