Smith-Lemli-Opitz syndrome (SLOS) is a disorder of cholesterol synthesis caused by mutations in the DHCR7 gene which encodes for 7-dehydrocholesterol-delta7-reductase, an enzyme necessary for the production of cholesterol in the body. Affected individuals exhibit multiple malformations and intellectual disability. The features of SLOS are thought to be primarily related to cholesterol deficiency and accumulation of cholesterol precursors. However, the clinical phenotype is not well characterized, the biochemical pathogenesis is incompletely understood, and there is no proven therapy for this devastating condition. The long-term goal of this study is to learn as much as possible about SLOS by following a cohort of patients with SLOS over time, and to build a comprehensive SLOS patient registry and identify biomarkers that can be used for diagnostic testing, screening and outcome measures in future therapeutic trials. Although most patients are treated with enteral cholesterol, there is no evidence that cholesterol supplementation is beneficial.
The first aim of the study is thus to determine if cholesterol supplementation predicts changes in developmental and behavioral outcomes over time.
The second aim of the study is to take advantage of this cohort of well-characterized patients to follow them over time and better define the clinical and biochemical phenotypes of the disease (biomarkers) using a natural history study design. To accomplish these aims, we plan to measure cholesterol and other sterol levels, perform clinical observations, measure changes in whole body cholesterol pool size as a result of enteral cholesterol supplementation, and conduct imaging studies (brain MRI) to learn more about disease mechanisms and progression, variations in the clinical features among individuals with SLOS, and evaluate the effect of cholesterol supplementation in this condition.
of the proposed research cannot be understated. Almost all patients diagnosed with SLOS are treated with cholesterol. Yet, the efficacy of this treatment has not been proven. Further, the natural history of the disease is not fully characterized. It is thus a major intervention and natural history study awaited by families with children affected by the conditoin, their health care providers, and by researchers.
| 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 |
| 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 |
| 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 |
Showing the most recent 10 out of 27 publications
