Lovastatin for X-Linked Adrenoleukodystrophy

Abstract

X-linked adrenoleukodystrophy is an inherited recessive disorder characterized by a defect in peroxisomal $β$-oxidation of very-long-chain fatty acids (those with more than 22 carbon atoms) and secondary neuroinflammatory damage.1,2 Even though the accumulation of very-long-chain fatty acids in plasma and tissues occurs early, the neurologic manifestations are not observed until the age of 4 to 8 years for childhood adrenoleukodystrophy or 20 to 30 years for adrenomyeloneuropathy. The neurologic damage in X-linked adrenoleukodystrophy may be mediated by the activation of astrocytes and the induction of proinflammatory cytokines. At present, dietary restrictions and therapy with Lorenzo's oil are used to lower plasma levels of very-long-chain fatty acids, but these measures do not address the neuroinflammatory aspects of the disorder.1,2 Recently, in animal studies, we have shown that lovastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, and sodium phenylacetate, an inhibitor of mevalonate pyrophosphate decarboxylase, inhibit the induction of inducible nitric oxide synthase and proinflammatory cytokines (tumor necrosis factor $α$, interleukin-1$β$, and interleukin-6) involved in the pathogenesis of neurologic damage in X-linked adrenoleukodystrophy.3 We have also shown that lovastatin, sodium phenylacetate,4 and compounds that increase intracellular cyclic AMP and protein kinase A activity 5 normalize the levels of very-long-chain fatty acids in cultured skin fibroblasts from patients with childhood adrenoleukodystrophy and adrenomyeloneuropathy. We have treated seven patients from three families with lovastatin for two to six months. The study was approved by the institutional review board at our medical school, and the patients provided informed consent. The diagnosis was established in each case by clinical findings and documentation of elevated plasma levels of total very-long-chain fatty acids by two different laboratories. Each patient was treated with 20 mg of lovastatin per day for two weeks; the dose was increased to 40 mg per day if no adverse effects were noted. Plasma total very-long-chain fatty acids were measured periodically throughout the study. Adverse events and compliance were assessed on the basis of the patients' reports and by periodic measurement of plasma total cholesterol, creatine kinase, aspartate aminotransferase, and alanine aminotransferase. One patient (Patient 4) was withdrawn from the study because of persistent diarrhea and a marked elevation of serum creatine kinase levels. Another (Patient 5) discontinued treatment. Our results (Table 1TABLE 1 Effect of Lovastatin Therapy on Plasma Levels of Very-Long-Chain Fatty Acids in Patients with X-Linked Adrenoleukodystrophy.) show that plasma levels of total very-long-chain fatty acids declined from their pretreatment values within one month after the initiation of lovastatin therapy in each patient and remained low and within the normal range for up to six months in the five patients who continued the treatment. Their lower post-treatment cholesterol values (Table 1) provide evidence of compliance with therapy. The short duration and small size of the study did not allow us to assess whether there was a clinical benefit. These results suggest that lovastatin treatment may represent a simple, safe, and effective way to reduce the accumulated plasma very-long-chain fatty acids in adult patients with X-linked adrenoleukodystrophy. On the basis of this finding, together with the results of our in vitro and animal studies showing that lovastatin blocks the induction of inflammatory mediators of neurologic damage in X-linked adrenoleukodystrophy,4 we believe further evaluation of this therapeutic approach is warranted.