Dolichols are long-chain isoprenoid products of the mevalonate pathway that act in the initial steps of glycosylation of proteins and certain lipids. Recently, inherited disorders of dolichol synthesis or utilization have been discovered. Patients present with variable multiorgan symptoms and exhibit defective lipid and protein glycosylation. Few patients have been identified and little or nothing is known about the longitudinal natural history these diseases. Although many patients have underglycosylated proteins, a biomarker that correlates with disease severity or can be used for monitoring disease progression has not been identified. Further, effective therapy for the isoprenoid diseases does not yet exist. Based on the known dolichol synthesis pathway, it is likely that new diseases of dolichol metabolism are waiting to be identified. We propose to define the natural history of inborn errors of dolichol metabolism by systematically characterizing their clinical features and documenting how they change over time. Comprehensive clinical evaluations will be performed every year to determine the frequency and variability of symptoms. We will search for the most useful biomarkers that correlate with disease severity and progression. For those patients lacking a DNA diagnosis, we will perform mutation analysis to characterize the molecular defects in the known dolichol genes and search for additional new dolichol-related disease genes using whole exome sequencing. In this fashion, we will achieve new insight into the clinical features and natural history of these rare diseases.

Public Health Relevance

Owing to the rare nature of dolichol metabolim diseases and their recent discovery, the proposed studies to characterize their clinical features and define their natural history are highly relvant for these diseases.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZTR1-CI-8 (01))
Program Officer
Krotoski, Danuta
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Nebraska Medical Center
United States
Zip Code
Freeman, Kurt A; Olufs, Erin; Tudor, Megan et al. (2016) A Pilot Study of the Association of Markers of Cholesterol Synthesis with Disturbed Sleep in Smith-Lemli-Opitz Syndrome. J Dev Behav Pediatr 37:424-30
Rizzo, William B (2016) Genetics and prospective therapeutic targets for Sjögren-Larsson Syndrome. Expert Opin Orphan Drugs 4:395-406
Merkel, Peter A; Manion, Michele; Gopal-Srivastava, Rashmi et al. (2016) The partnership of patient advocacy groups and clinical investigators in the rare diseases clinical research network. Orphanet J Rare Dis 11:66
Othman, Rgia A; Myrie, Semone B; Mymin, David et al. (2015) Ezetimibe reduces plant sterol accumulation and favorably increases platelet count in sitosterolemia. J Pediatr 166:125-31
Ajagbe, Bridget O; Othman, Rgia A; Myrie, Semone B (2015) Plant Sterols, Stanols, and Sitosterolemia. J AOAC Int 98:716-23
Jack, Loren S; Benson, Christy; Sadiq, Mohammad A et al. (2015) Segmentation of Retinal Layers in Sjögren-Larsson Syndrome. Ophthalmology 122:1730-2
Merkens, Mark J; Sinden, Nancy L; Brown, Christine D et al. (2014) Feeding impairments associated with plasma sterols in Smith-Lemli-Opitz syndrome. J Pediatr 165:836-41.e1
DeBarber, Andrea E; Luo, Jenny; Giugliani, Roberto et al. (2014) A useful multi-analyte blood test for cerebrotendinous xanthomatosis. Clin Biochem 47:860-3
DeBarber, Andrea E; Luo, Jenny; Star-Weinstock, Michal et al. (2014) A blood test for cerebrotendinous xanthomatosis with potential for disease detection in newborns. J Lipid Res 55:146-54
He, Miao; Smith, Laurie D; Chang, Richard et al. (2014) The role of sterol-C4-methyl oxidase in epidermal biology. Biochim Biophys Acta 1841:331-5

Showing the most recent 10 out of 22 publications