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.
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.
|Eroglu, Yasemen; Nguyen-Driver, Mina; Steiner, Robert D et al. (2017) Normal IQ is possible in Smith-Lemli-Opitz syndrome. Am J Med Genet A 173:2097-2100|
|Othman, Rgia A; Myrie, Semone B; Mymin, David et al. (2017) Thyroid Hormone Status in Sitosterolemia Is Modified by Ezetimibe. J Pediatr 188:198-204.e1|
|Hidalgo, Eveline Teresa; Orillac, Cordelia; Hersh, Andrew et al. (2017) Intrathecal Baclofen Therapy for the Treatment of Spasticity in Sjögren-Larsson Syndrome. J Child Neurol 32:100-103|
|Adang, Laura A; Sherbini, Omar; Ball, Laura et al. (2017) Revised consensus statement on the preventive and symptomatic care of patients with leukodystrophies. Mol Genet Metab 122:18-32|
|Othman, Rgia A; Myrie, Semone B; Mymin, David et al. (2017) Effect of ezetimibe on low- and high-density lipoprotein subclasses in sitosterolemia. Atherosclerosis 260:27-33|
|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|
|Rizzo, William B (2016) Genetics and prospective therapeutic targets for Sjögren-Larsson Syndrome. Expert Opin Orphan Drugs 4:395-406|
|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|
|Jack, Loren S; Benson, Christy; Sadiq, Mohammad A et al. (2015) Segmentation of Retinal Layers in Sjögren-Larsson Syndrome. Ophthalmology 122:1730-2|
|Ajagbe, Bridget O; Othman, Rgia A; Myrie, Semone B (2015) Plant Sterols, Stanols, and Sitosterolemia. J AOAC Int 98:716-23|
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