title: The desmosterolosis phenotype: spasticity, microcephaly and micrognathia with agenesis of corpus callosum and loss of white matter.
abstract: Desmosterolosis is a rare autosomal recessive disorder of elevated levels of the cholesterol precursor desmosterol in plasma, tissue and cultured cells. With only two sporadic cases described to date with two very different phenotypes, the clinical entity arising from mutations in 24-dehydrocholesterol reductase (DHCR24) has yet to be defined. We now describe consanguineous Bedouin kindred with four surviving affected individuals, all presenting with severe failure to thrive, psychomotor retardation, microcephaly, micrognathia and spasticity with variable degree of hand contractures. Convulsions near birth, nystagmus and strabismus were found in most. Brain MRI demonstrated significant reduction in white matter and near agenesis of corpus callosum in all. Genome-wide linkage analysis and fine mapping defined a 6.75 cM disease-associated locus in chromosome 1 (maximum multipoint LOD score of six), and sequencing of candidate genes within this locus identified in the affected individuals a homozygous missense mutation in DHCR24 leading to dramatically augmented plasma desmosterol levels. We thus establish a clear consistent phenotype of desmosterolosis (MIM 602398).
authors.affiliation: The Morris Kahn Laboratory of Human Genetics at the National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Jenny
authors.initials: J
authors.lastname: Zolotushko
authors.forename: Hagit
authors.initials: H
authors.lastname: Flusser
authors.forename: Barak
authors.initials: B
authors.lastname: Markus
authors.forename: Ilan
authors.initials: I
authors.lastname: Shelef
authors.forename: Yshaia
authors.initials: Y
authors.lastname: Langer
authors.forename: Maura
authors.initials: M
authors.lastname: Heverin
authors.forename: Ingemar
authors.initials: I
authors.lastname: Björkhem
authors.forename: Sara
authors.initials: S
authors.lastname: Sivan
authors.forename: Ohad S
authors.initials: OS
authors.lastname: Birk
mesh_terms: D061085:Agenesis of Corpus Callosum / Q000503:physiopathology*; D000595:Amino Acid Sequence; D018912:Arabs / Q000235:genetics; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D003241:Consanguinity; D003897:Desmosterol / Q000097:blood; D005260:Female; D006801:Humans; D007557:Israel; D008126:Lod Score; D008297:Male; D008831:Microcephaly / Q000235:genetics; D008844:Micrognathism / Q000235:genetics; D008969:Molecular Sequence Data; D009413:Nerve Fibers, Myelinated / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics*; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D016415:Sequence Alignment
chemical_list: D009419:Nerve Tissue Proteins; D003897:Desmosterol; D044925:Oxidoreductases Acting on CH-CH Group Donors; C499055:DHCR24 protein, human