We will investigate the abnormal metabolism of very long chain fatty acids (VLFA) in patients with the inherited disorders, adrenoleukodystrophy (ALD), who are deficient in VLFA oxidation. The long-term goals of this research are to elucidate the primary enzymatic defect in ALD, understand the basis for phenotypic variation and devise an effective therapy. Residual VLFA oxidative activity will be correlated with the clinical phenotype using cultured skin fibroblasts from ALD patients that differ in clinical severity (childhood ALD or adrenomyeloneuropathy). In particular, the effects of competing fatty acids on VLFA oxidative activity will be investigated to determine whether differences in metabolism of shorter-chain fatty acids are responsible for phenotypic variation in ALD.
A specific aim i s to establish whether deficiency of lignoceroyl CoA synthetase is the primary defect in this disease, and methods will be developed to assay this enzyme in cultured skin fibroblasts. With the goal to identify new therapeutic approaches to ALD, we will explore the potential for acetylenic fatty acids to selectively lower saturated VLFA levels in ALD fibroblasts. The effects of acetylenic fatty acids on de nov VLFA synthesis and fatty acids elongation will be studied in intact cells and homogenates. Using a variety of radiochemical and biochemical techniques, the mechanism whereby erucic acid lowers saturated VLFA levels in ALD fibroblasts will be elucidated. A clinical trial will be conducted to determined whether dietary erucic acid supplementation is effective in the therapy of ALD. The clinical response to erucic acid therapy will be monitored with objective neuro-physiological, endocrine and biochemcial tests. These studies will provide fundamental information concerning the etiology and therapy of ALD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK033914-07
Application #
3232322
Study Section
Biochemistry Study Section (BIO)
Project Start
1984-04-01
Project End
1992-03-31
Budget Start
1990-04-01
Budget End
1992-03-31
Support Year
7
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Type
Schools of Medicine
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
Boles, D J; Rizzo, W B (1992) Dietary fatty acids temporarily alter liver very long-chain fatty acid composition in mice. J Nutr 122:1662-71
Emami, S; Rizzo, W B; Hanley, K P et al. (1992) Peroxisomal abnormality in fibroblasts from involved skin of CHILD syndrome. Case study and review of peroxisomal disorders in relation to skin disease. Arch Dermatol 128:1213-22
Zenger-Hain, J; Craft, D A; Rizzo, W B (1992) Diagnosis of inborn errors of phytanic acid oxidation using tritiated phytanic acid. Prog Clin Biol Res 375:399-407
Roesel, R A; Carroll, J E; Rizzo, W B et al. (1991) Dyggve-Melchior-Clausen syndrome with increased pipecolic acid in plasma and urine. J Inherit Metab Dis 14:876-80
Boles, D J; Craft, D A; Padgett, D A et al. (1991) Clinical variation in X-linked adrenoleukodystrophy: fatty acid and lipid metabolism in cultured fibroblasts. Biochem Med Metab Biol 45:74-91
Jensen, M E; Sawyer, R W; Braun, I F et al. (1990) MR imaging appearance of childhood adrenoleukodystrophy with auditory, visual, and motor pathway involvement. Radiographics 10:53-66
Proud, V K; Rizzo, W B; Patterson, J W et al. (1990) Fatty acid alterations and carboxylase deficiencies in the skin of biotin-deficient rats. Am J Clin Nutr 51:853-8
Rizzo, W B; Leshner, R T; Odone, A et al. (1989) Dietary erucic acid therapy for X-linked adrenoleukodystrophy. Neurology 39:1415-22
Rizzo, W B; Dammann, A L; Craft, D A et al. (1989) Sjogren-Larsson syndrome: inherited defect in the fatty alcohol cycle. J Pediatr 115:228-34