The leukodystrophies that become apparent only in later life pose yet another problem: the clinical and radiologic differentiation from cerebral forms of multiple sclerosis. In identifying the metabolic diseases of myelin, one is helped by the relative symmetry and steady progression of the clinical signs; the early onset of cognitive impairment (which is uncharacteristic of multiple sclerosis); and the symmetrical and massive degeneration of the cerebral white matter (in distinction to the asymmetrical and often multiple lesions of demyelinative disease). At various times in life, particularly in young individuals, CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) enters into the differential diagnosis (see Chap. 33); late in life, distinguishing a metabolic disorder of myelin from the subcortical multiple infarctions of Binswanger disease and from the ubiquitous rarefaction of the periventricular regions of the cerebrum may be a problem. Differentiation from cerebral gliomatosis, brain lymphoma, toxic forms of leukodystrophy, and progressive multifocal leukoencephalopathy, all affecting deep cerebral or white matter structures, offers less difficulty.
This disorder traditionally combines a cerebral leukodystrophy and Addison disease, originally included under the rubric of Schilder disease, but now set apart as an independent metabolic encephalopathy with specific genetic etiology. It is transmitted as an X-linked recessive trait with an incidence of 1 in 20,000 male births. The fundamental defect is impairment in peroxisomal oxidation of very-long-chain fatty acids (VLCFAs), leading to their accumulation in the brain and adrenal glands (see the publications of H.W. Moser and of Igarashi and associates). The deficient membrane protein, encoded by a gene that maps to chromosome X28, is a peroxisomal membrane transporter (ABCD1). The gene is located close to the gene for color vision. In the typical X-linked adrenoleukodystrophy (ALD), there is an inability to metabolize VLCFAs, but it came as a surprise that the disease was not caused by an enzyme deficiency. The modern classification of the disease categorizes it as a disorder of peroxisomes, subcellular organelles containing numerous enzymes, each of which is unaffected. This peroxisomal assignation connects adrenoleukodystrophy with Zellweger and Refsum disease.