Evolution of phenotypes in adult male patients with X-linked adrenoleukodystrophy

Our objective was to study the phenotype evolution of X-linked adrenoleukodystrophy (X-ALD) and the relation between axonal degeneration and cerebral demyelination. Although different X-ALD phenotypes are recognized, little is known about their evolution. Neuropathological and electrophysiological studies have shown that X-ALD is a disease with mixed features of axonal degeneration, leading to myeloneuropathy, and a severe inflammatory reaction in the cerebral white matter, resulting in demyelination. Retrospectively, 129 men with X-ALD were studied who were 1) at least 20 years presently or at the time of death, and 2) regularly monitored. Phenotype assignments were made at diagnosis and at present, or at death, using medical history and findings of neurological examination. Handicap was studied with the modified Rankin scale, and cerebral abnormalities with the X-ALD MRI severity (Loes) score. The mean follow-up internal was 10.1 ± 5.0 years. Among 32 patients neurologically asymptomatic at diagnosis, 16 (50%) development, 13 (19%) additionally developed cerebral demyelination. In a subset of 60 AMN patients, a moderate handicap evolved over a period of 16.2 ± 8.9 years. Among 13 AMN patients with additional definite or probable cerebral involvement at diagnosis, eight died and one remained in a vegetative state. Most of the 16 patients with the cerebral phenotypes deteriorated. There is a high risk for adult neurologically asymptomatic patients to develop neurological deficits and for AMN patients to develop cerebral demyelination. Axonal degeneration and cerebral demyelination emerge in X-ALD independently of each other. This may have implications for the phenotype classification, the search for modifying factors, and the development and evaluation of new therapies.