Project 2 Sjogren-Larsson syndrome (SLS) is a rare genetic disease caused by mutations in ALDH3A2 that encodes fatty aldehyde dehydrogenase (FALDH) and results in defective isoprenol oxidation and abnormal lipid metabolism. Patients typically exhibit ichthyosis, intellectual disability, spasticity, seizures and a distinctive maculopathy. Although the disease was described more than 50 years ago, longitudinal natural history studies of SLS are non-existent and the clinical spectrum of this rare disease is not yet established. The pathogenic mechanisms of the disease remain unclear and no specific pathogenesis-based therapy exists. Moreover, biomarkers that correlate with disease severity or progression have not been established. We will conduct a longitudinal natural history study of SLS to define long term changes in clinical phenotype and search for biomarkers that correlate with symptom severity and clinical disease. Subjects of all ages will be enrolled. Patients will receive detailed clinical exams documenting their neurologic, dermatologic and cognitive disabilities. Neurologic, ophthalmologic, dermatologic, and neuropsychiatric changes will be documented with MRI/MRS, EEG, optical coherence tomography, cutaneous photographs and neuropsychiatric testing. Blood, urine, skin and cutaneous scales will be investigated for potential biomarkers using lipidomics, proteomics and gene expression methods. Clinical and laboratory data will be correlated to identify useful biomarkers that predict disease severity and progression. A SLS Biorepository of blood (plasma, erythrocytes), urine, skin biopsies and keratinocyte cultures will be established for sharing with STAIR and outside investigators. When this study is completed, we expect to have a thorough knowledge of the natural history and clinical variation of SLS. The biomarkers that will be discovered from this research should serve as validated measures of disease for monitoring therapeutic trials.

Public Health Relevance

This clinical investigation of SLS fits into the overall goals of STAIR and the RDCRN. It has relevance for understanding the natural history of this rare disease and implications for evaluating future therapy. lt is also relevant in a broader sense for understanding neurodevelopmental disabilities, myelin function and cutaneous disease.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
2U54HD061939-06
Application #
8936524
Study Section
Special Emphasis Panel (ZTR1-CI-8 (01))
Program Officer
Krotoski, Danuta
Project Start
2014-09-04
Project End
2019-08-31
Budget Start
2014-09-04
Budget End
2015-08-31
Support Year
6
Fiscal Year
2014
Total Cost
$180,001
Indirect Cost
$40,673
Name
University of Nebraska Medical Center
Department
Type
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
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; 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
DeBarber, Andrea E; Luo, Jenny; Giugliani, Roberto et al. (2014) A useful multi-analyte blood test for cerebrotendinous xanthomatosis. Clin Biochem 47:860-3
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
Liu, Wei; Xu, Libin; Lamberson, Connor R et al. (2013) Assays of plasma dehydrocholesteryl esters and oxysterols from Smith-Lemli-Opitz syndrome patients. J Lipid Res 54:244-53
Kanungo, Shibani; Soares, Neelkamal; He, Miao et al. (2013) Sterol metabolism disorders and neurodevelopment-an update. Dev Disabil Res Rev 17:197-210
Simon, Anna; Drenth, Joost P H; Matern, Dietrich et al. (2013) Long chain fatty acid (Lcfa) abnormalities in hyper Igd syndrome (Hids) and Familial Mediterranean Fever (Fmf): new insight into heritable periodic fevers. Mol Genet Metab 108:166-71
Hager, Elizabeth J; Piganelli, Jon D; Tse, Hubert M et al. (2012) Aberrant expression of costimulatory molecules in splenocytes of the mevalonate kinase-deficient mouse model of human hyper-IgD syndrome (HIDS). J Inherit Metab Dis 35:159-68
DeBarber, Andrea E; Eroglu, Yasemen; Merkens, Louise S et al. (2011) Smith-Lemli-Opitz syndrome. Expert Rev Mol Med 13:e24
Monson, Dinelli M; DeBarber, Andrea E; Bock, Charles J et al. (2011) Cerebrotendinous xanthomatosis: a treatable disease with juvenile cataracts as a presenting sign. Arch Ophthalmol 129:1087-8

Showing the most recent 10 out of 13 publications