Illustrating the variability in presentation among kindreds, Marsden and colleagues (1982) and, subsequently, Kobayashi and coworkers described a familial spinocerebellar syndrome, and Ohno and associates reported a sporadic instance of adrenoleukodystrophy presenting as olivopontocerebellar atrophy. Moser found cerebral forms alone in 30 percent, adrenomyeloneuropathy alone in 20 percent, and combined childhood cerebral and myelopathic forms in the remaining half.
Female heterozygotes Neurologic manifestations develop in up to 50 percent of female carriers but in our experience with siblings of affected patients, the figure has been lower. The onset of a spastic paraparesis tends to occur later in life, usually in the third or fourth decade, often combined with gait ataxia and urinary incontinence and progression tends to be slow, but an explosive onset has been reported (see Chap. 42 and Engelen et al). As already mentioned, multiple sclerosis is the main consideration in differential diagnosis, particularly as 20 percent of heterozygotes have white matter changes on cerebral MRI. Overt adrenal insufficiency is rare in female carriers, but scalp hair may be scant as a subtle manifestation of adrenal hypofunction.
Pathologically in classic X-linked instances, massive degeneration of the myelin occurs, often asymmetrically in various parts of the cerebrum, brainstem, optic nerves, and sometimes spinal cord (see Fig. 36-10). Degradation products of myelin are visible in macrophages in recent lesions, namely, sudanophilic demyelination. There is extensive astrocytic gliosis. Axons are damaged, but to a lesser degree. The cortex of the adrenal glands is atrophic, and the cells and invading histiocytes contain an abnormal lipid material. The testes show marked interstitial fibrosis and atrophy of the seminiferous tubules. Electron microscopically, the macrophages of the brain and adrenals and the Leydig cells of the testes contain characteristic lamellar cytoplasmic inclusions.
Laboratory diagnosis The diagnosis can be made by gene sequencing but a specific laboratory marker of the disease is an excess of VLCFAs, in particular three measurements are of value: the absolute level of hexacosanoic acid (C26), the ratio of C26 to C22 (docosahexanoic acid; C26:C22), and of C24 (tetracosanoic acid) to docosahexanoic acid (C24:C22) in plasma, erythrocytes, leukocytes, or cultured fibroblasts as detailed by Moser and colleagues (1999). This reflects the basic biochemical fault in this disease, namely defective fatty acid oxidation within the peroxisomes. If skin fibroblasts and plasma testing are both performed, 93 percent of female carriers will show the abnormal VLCFA. MRI of the brain is abnormal in the majority of patients with cerebral symptoms and in a proportion of others.
Other laboratory findings are low serum sodium and chloride levels and elevated potassium levels reflecting the atrophy of the adrenal glands. The latter results in reduced excretion of corticosteroids, low serum cortisol levels, and lack of rise in 17-hydroxyketosteroids after adrenocorticotropic hormone (ACTH) stimulation. The CSF protein may be elevated. As a research tool, Öz and colleagues have shown that magnetic resonance spectroscopy that measures the concentrations of several metabolites can be used as a guide to the progression of the disease and to gauge the effects of new therapies as they are introduced.