Plasma very long chain fatty acids in 3,000 peroxisome disease patients and 29,000 controls

Abstract

The assay of plasma very long chain fatty acids (VLCFAs), developed in our laboratory in 1981, has become the most widely used procedure for the diagnosis of X‐linked adrenoleukodystrophy (X‐ALD) and other peroxisomal disorders. We present here our 17 years' experience with this assay. Three VLCFA parameters, the level of hexacosanoic acid (C26:0), the ratio of C26:0 to tetracosanoic acid (C24:0), and of C26:0 to docosanoic acid (C22:0), were measured in 1,097 males (hemizygotes) with X‐ALD, 1,282 women heterozygous for this disorder, including 379 obligate heterozygotes, 797 patients with other peroxisomal disorders, and 29,600 control subjects. All X‐ALD hemizygotes who had not previously received Lorenzo's oil or a diet with a high erucic acid content had increased VLCFA levels, but the application of a discriminant function based on all three measurements is required to avoid the serious consequences of a false‐negative result. VLCFA levels are increased at day of birth, thus providing the potential for neonatal mass screening, are identical in the childhood and adult forms, and do not change with age. Eighty‐five percent of obligate heterozygotes had abnormally high VLCFA levels, but a normal result does not exclude carrier status. VLCFA levels were increased in all patients homozygous for Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum's disease, and in patients with deficiencies of peroxisomal acyl‐coenzyme A oxidase, bifunctional enzyme, and 3‐oxoacyl‐coenzyme A thiolase. In these patients the degree of VLCFA excess correlated with clinical severity. Ann Neurol 1999;45:100–110

Therapy of X-linked adrenoleukodystrophy

“…50 years later Powers and Schaumburg [1] demonstrated characteristic inclusions in adrenal cortical cells ( Fig 1C) and in brain macrophages, which were then identified as saturated very long chain fatty acids (VLCFA) by Igarashi et al [2]. This led to the recognition that X-ALD is a metabolic disease and the identification of thousands of new patients with the various clinical phenotypes by the detection of increased VLCFA plasma levels [3][4][5]. X-linkage of this disease was first proposed on basis of a pedigree analysis by Fanconi et al 1963 [6].…”

Therapy of X-linked adrenoleukodystrophy

“…3 For reasons that are not yet understood this defect leads to the accumulation of saturated very long chain fatty acids (VLCFA) such as hexacosanoic acid (C26:0) in the adrenal gland and nervous system white matter 4 and other tissues and in plasma. 5 The VLCFA excess appears to be due to their impaired degradation, 5,6 a reaction that normally takes place in the peroxisome, 7 although recent studies indicate that the defects in fatty acid metabolism are complex and not yet fully understood. 8 Demonstration of excess of VLCFA in plasma is the most commonly used diagnostic assay.…”

“…8 Demonstration of excess of VLCFA in plasma is the most commonly used diagnostic assay. 5 The VLCFA excess may also contribute to pathogenesis. 9 The mode of inheritance is X-linked.…”

“…Demonstration of a characteristic pattern of increase in the levels of VLCFA in plasma is a reliable method for confirming the diagnosis in males; these levels are already increased at birth. 5 False negative results with the plasma VLCFA assay occur in 15 to 20% of women heterozygous for X-ALD, and mutation analysis is required for the definitive identification of carriers.…”

Microglial dysfunction as a key pathological change in adrenomyeloneuropathy

“…Mutations in ABCD1 result in the accumulation of unbranched saturated very‐long‐chain fatty acids (VLCFAs) in body fluid and tissues,5, 6, 7 and the highest concentrations of VLCFAs reside within lysophosphatidylcholine (LPC) 8. High‐dose LPC injections lead to brain demyelination in mice, but the impact of LPC upon axonal degeneration and AMN pathogenesis has not been studied 4.…”