Adrenoleukodystrophy: Biochemical procedures in diagnosis, prevention and treatment

Abstract

The childhood form of adrenoleukodystrophy is an X-linked recessive disorder which is characterized biochemically by elevated concentrations of saturated very long chain fatty acids in tissues and plasma and impaired very long chain fatty acid oxidation in fibroblasts and leukocytes from adrenoleukodystrophy patients. The most consistently observed increase is that in hexacosanoic acid (C_26:0); thus, measurement of plasma C_26:0 concentration by gas-liquid chromatography provides a rapid, sensitive method of diagnosis. Prenatal diagnosis of adrenoleukodystrophy can be made by measurement of C_26:0 concentrations in amniocytes and chorionic villus cells. Heterozygote (carrier) detection has also been accomplished by biochemical measurement of C_26:0 in plasma and skin fibroblasts. In a study of over 200 obligate heterozygotes, >90% showed abnormal concentrations of C_26:0. Hybridization studies using the cloned DNA fragment St14 detects polymorphisms in the distal end of the long arm of the X chromosome (Xq27–28) and six informative kindreds have shown co-segregation of adrenoleukodystrophy and the St14 marker through 65 meioses. Thus, such studies can supplement very long chain fatty acid concentrations in heterozygote detection. Therapeutic interventions for adrenoleukodystrophy, such as dietary restriction of very long chain fatty acids, administration of clofibrate or carnitine, immunosuppression and adrenal hormone replacement, have not been successful. Recently, a modification of the very long chain fatty acid-restricted diet has been employed in which this diet is supplemented with synthetic glycerol trioleate. The rationale for this diet is that decreased very long chain fatty acid synthesis by fibroblasts from patients with adrenoleukodystrophy was observed when oleic acid was added to the culture medium. In a study of 14 patients on this diet from 2 to 11 months, there was a mean reduction in plasma C_26:0 levels of 46%, with one patient achieving a normal plasma level. The effect of lowering plasma very long chain fatty acid concentrations on the neurologic status of patients with adrenoleukodystrophy and on the development of symptoms in asymptomatic individuals with elevated very long chain fatty acid concentrations remains to be established.