White matter vacuolization of the spinal cord is present in approximately 30 percent of patients with AIDS. The vacuolization is progressive, and a significant number of patients develop symptoms of myelopathy. In the later stages of the disease, AIDS-associated vacuolar myelopathy (VM) may lead to severe spastic paraparesis and incontinence. Its pathogenesis is unknown, probably related to metabolic abnormalities rather than caused by direct HIV infection. Abnormal metabolism of the B-12 dependent trans-methylation pathway may play an important role in the pathogenesis of VM. Hypomethylation of myelin basic protein is considered responsible for the spinal cord vacuolization in vitamin B-12 deficiency. Vacuolization of the spinal cord indistinguishable from the AIDS associated VM and the myelopathy of vitamin B12 deficiency is present in other toxic and metabolic diseases affecting trans-methylation, and can be induced experimentally by interfering with the production of methionine or its active metabolite S-adenosyl-methionine (SAM). HIV infection and cytokine activation may lead to decreased production and increased consumption of methionine and SAM. Based on the hypothesis that VM is related to abnormal methionine metabolism, and our pilot data suggesting beneficial effect of methionine treatment in VM, we are conducting a double-blind, placebo-controlled clinical trial with methionine 6g/day vs. placebo. The trial has an enrollment goal of 50 patients. In the three years since the beginning of the study, we have enrolled 40 patients. In this revised competitive renewal application we present progress data on the clinical trial and baseline clinical and biochemical observations. In particular, we report severe reduction of CSF levels of SAM in patients with VM compared to HIV- and HIV+ non myelopathic controls, offering additional evidence for a metabolic disorder in the pathogenesis of VM. We request to complete the clinical trial and the metabolic observations of the study.
