X-linked adrenoleukodystrophy (ALD) is a relatively common disorder that shows a great deal of phenotypic variability. Approximately half of the patients have the rapidly progressive childhood cerebral form that is associated with an inflammatory response in brain and leads to total disability or death during the first decade. Twenty five per cent or more of the patients have adrenomyeloneuropathy (AMN), a form that progresses slowly, involves the spinal cord mainly, shows little or no inflammatory response, manifests in adulthood, and is compatible with a near-normal life span. The two forms of the disease occur frequently within the same kindreds and nuclear families. Segregation analysis based on 3862 individuals in 89 kindreds points to the existence of an autosomal modifier locus with a likelihood ratio of 20:1. In addition, we present preliminary results of three types of therapy. Two hundred and four patients have received a dietary regimen that combines the administration of oils containing mono-unsaturated fatty acids (oleic and erucic) with the restricted intake of very long-chain fatty acids. This regimen normalizes the levels of satured very long-chain fatty acids in plasma within 4 weeks. It appears to improve peripheral nerve function in patients with AMN, and a large-scale trial is in progress to determine whether it can prevent the onset of neurological involvement in patients who have the biochemical abnormality of ALD but are neurologically intact. We report early results of bone marrow transplantation in 14 patients. There is encouraging but still preliminary evidence that transplantation can arrest the progression of the disease in patients with mild neurological involvement. There is urgent need to develop methods to combat the rapid progression of the cerebral forms of the disease, which so far has resisted therapeutic intervention, including immunosuppression or the administration of immunoglobulin.
Adrenoleukodystrophy is an X-linked metabolic disorder with very-long-chain fatty acid (VLCFA) accumulation and multifocal nervous system demyelination, often with early involvement of visual pathways. Dietary therapy with glycerol trioleate and glycerol trierucate (Lorenzo oil) diminishes VLCFA levels. In a study of patients with the adrenomyeloneuropathy phenotype of adrenoleukodystrophy, we used pattern-reversal visual evoked potentials to evaluate visual pathways before and after treatment. Of 108 patients tested, all 26 women and 68 of the 82 men had normal potentials at baseline. Seventy patients were retested at 1 year, at which time VLCFA levels were markedly diminished. Of them, the responses in the 10 men who showed abnormalities at baseline remained abnormal; the latencies in 4 men with initially normal responses became abnormal. No patients improved. There were no correlations between disease duration prior to treatment, baseline P100 latencies, VLCFA levels, or the change in P100 latencies and VLCFA levels after dietary treatment for 1 year. Pattern-reversal visual evoked potentials were abnormal in 17% of the men with adrenoleukodystrophy, and there was no evidence that reduction of VLCFA levels improved or retarded visual pathway demyelination.
We studied the visual system in 59 men with adrenomyeloneuropathy. Pattern-reversal visual evoked potentials, magnetic resonance imaging, and clinical examination revealed that visual pathways are affected in 63% of patients, involving the optic discs, optic nerves, lateral geniculate bodies, optic radiations, and parietooccipital cortex. This indicates both primary demyelination of the optic nerves and discs, and more diffuse involvement of postchiasmal structures.
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