Dietary erucic acid therapy for X-linked adrenoleukodystrophy.

We investigated the biochemical and clinical efficacy of dietary erucic acid (C22:1) therapy for X-linked adrenoleukodystrophy (ALD). In a double-blind crossover study of patients who were on chronic oleic acid (C18:1) therapy, addition of erucic acid to the diet led to a further reduction in plasma hexacosanoic acid (C26:0) concentration. We treated 12 newly diagnosed ALD patients with a diet enriched with erucic acid and oleic acid for 2 to 19 months. Mean plasma C26:0 concentration decreased to normal by 4 weeks, and the C26:0 composition of plasma sphingomyelin and phosphatidylcholine became normal by 4 months on therapy. Fatty acid analysis of postmortem tissues from 1 boy treated for 10 months suggested that dietary erucic acid entered the heart, liver, adrenal gland, and brain. Eight patients remained on treatment long enough (mean, 12 +/- 3 months) to evaluate their clinical response; 6 of these patients with moderate to advanced disease deteriorated neurologically or showed progression of white matter disease on brain magnetic resonance imaging whereas 2 mildly affected patients remained clinically stable after 10 and 19 months. No adverse effects of the diet occurred. We conclude that dietary erucic acid therapy is effective in lowering plasma C26:0 to normal in ALD patients, and may prevent further demyelination in some mildly affected boys.

Sjögren-Larsson syndrome: inherited defect in the fatty alcohol cycle.

We investigated fatty alcohol metabolism in eight patients with Sjögren-Larsson syndrome, and in nine obligate heterozygotes. Fatty alcohol: nicotinamide-adenine dinucleotide oxidoreductase (FAO) activity was deficient in cultured skin fibroblasts (mean 18% of normal, n = 8) and peripheral blood leukocytes (mean 22% of normal, n = 3) from patients with Sjögren-Larsson syndrome. The palmitoyl coenzyme A-inhibitable component of FAO activity was decreased to 10% and 15% of normal in fibroblasts and leukocytes, respectively, of patients with Sjögren-Larsson syndrome. Most affected patients accumulated long-chain fatty alcohol in plasma, with a greater relative accumulation of octadecanol (mean threefold greater than normal) than hexadecanol (mean twofold greater than normal). Erythrocyte lipid alkyl ether linkages derived from hexadecanol were slightly increased in three of four patients. Fibroblasts and leukocytes from heterozygotes with Sjögren-Larsson syndrome showed mean FAO activities that were intermediate between those seen in homozygotes and in normal control subjects. The heterozygotes had normal fatty alcohol concentrations in plasma. These studies demonstrate FAO deficiency in patients with Sjögren-Larsson syndrome, and suggest that accumulation of fatty alcohol or its metabolic products may be important in the pathogenesis of this disorder.

Sjögren-Larsson syndrome. Impaired fatty alcohol oxidation in cultured fibroblasts due to deficient fatty alcohol:nicotinamide adenine dinucleotide oxidoreductase activity.

Lipid metabolism was studied in cultured skin fibroblasts from patients with the inherited disorder, Sjögren-Larsson syndrome (SLS). Intact SLS fibroblasts incubated in the presence of [1-14C]palmitate accumulated more radioactive hexadecanol than did normal cells, whereas incorporation of radioactivity into other cellular lipids was unaltered. The hexadecanol content of SLS fibroblasts was abnormally elevated. Hexadecanol accumulation was not due to increased fatty alcohol synthesis nor its deficient utilization for glycerol ether synthesis. The half-life of intracellular hexadecanol loaded into SLS fibroblasts was increased (70 min) compared with normal (15 min), and intact SLS fibroblasts showed impaired oxidation of [14C]-hexadecanol to fatty acid. Fatty alcohol:NAD+ oxidoreductase, the enzyme catalyzing this reaction, was deficient in SLS fibroblasts. Mean total activity in SLS fibroblasts (n = 5) was 13% of that in normal fibroblasts, and palmitoyl CoA-inhibitable activity was 1% of normal. Fibroblasts from two obligate SLS heterozygotes had enzyme activities intermediate between that in normal fibroblasts and individuals with SLS. These results suggest that the primary defect in SLS is deficiency of fatty alcohol:NAD+ oxidoreductase. SLS represents the first inherited disorder in man associated with an isolated abnormality in fatty alcohol metabolism.

Fatty alcohol metabolism in cultured human fibroblasts. Evidence for a fatty alcohol cycle.

Intact cultured human fibroblasts reduced [1-14C]palmitate to radioactive hexadecanol in a concentration-dependent manner. In the presence of 30 microM radioactive palmitate, cellular levels of labeled hexadecanol increased over time and reached a steady state corresponding to at least 0.1% of cell-associated radioactive palmitate. These levels of [14C]hexadecanol were increased up to 10-fold when exogenous nonradioactive hexadecanol was present, suggesting that radioactive hexadecanol was actively metabolized. Cells incubated in fatty acid-free medium with [1-14C]hexadecanol rapidly oxidized it to palmitic acid; less than 2% of the hexadecanol taken up by the cells was incorporated into the ether linkage of phosphatidylethanolamine, and no incorporation into wax esters was detected. Double-label experiments involving incubation of intact fibroblast with [3H]palmitate and [14C]hexadecanol demonstrated simultaneous synthesis of hexadecanol from palmitate and oxidation of hexadecanol to palmitate. Addition of exogenous palmitate to the medium of intact cells inhibited the oxidation of hexadecanol to fatty acid in a concentration-dependent fashion. This was associated with an increase in the fibroblast content of hexadecanol and loss of hexadecanol into the medium. Activity of fatty alcohol:NAD+ oxidoreductase, which catalyzes the oxidation of hexadecanol to palmitic acid, was inhibited by palmitoyl-CoA and NADH, but not by palmitic acid. These results are consistent with the presence of a "fatty alcohol cycle" in which hexadecanol is synthesized from palmitate via acyl-CoA and simultaneously oxidized back to free fatty acid. Fatty acyl-CoA, which is the primary substrate for fatty alcohol synthesis, may also regulate the intracellular level of fatty alcohol by inhibiting its oxidation.

Adrenoleukodystrophy: dietary oleic acid lowers hexacosanoate levels.

Adrenoleukodystrophy (ALD) is an X-linked disorder characterized by demyelination, adrenal insufficiency, and accumulation of saturated very-long-chain fatty acids (VLFA), particularly hexacosanoate (C26:0). We treated 5 patients with adrenoleukodystrophy (3 males and 2 symptomatic female carriers) for 6 months with a diet enriched in oleic acid (C18:1) and moderately restricted in C26:0. Elevated plasma and erythrocyte levels of C26:0 decreased in a time-dependent manner during treatment. Total plasma C26:0 concentration was lowered by 50 +/- 9% (p less than 0.01); it became normal in the female carriers. The total erythrocyte level of C26:0 decreased (44 +/- 5%; p less than 0.001) into the normal range in all patients. Significant decreases were noted in the saturated VLFA composition of plasma and erythrocyte sphingomyelin and erythrocyte phosphatidylcholine during dietary treatment. In general, decreases in saturated VLFA levels were accompanied by increases in monounsaturated VLFA levels, while total VLFA values did not change. This novel approach to the treatment of adrenoleukodystrophy, in which there is an exchange of monounsaturated VLFA for the more toxic saturated VLFA, may prove clinically beneficial in this disorder.