PREDOMINANT INVOLVEMENT OF WHITE MATTER
X-linked adrenoleukodystrophy is a metabolic disorder that predominantly affects the central nervous system (CNS), adrenal glands, and testicles. The clinical manifestations of this disorder relate to excessive accumulation of very long chain fatty acids (particularly hexacosanoic acid) in tissues and plasma. The underlying defect is failure of normal peroxisomal oxidative degradation (Table 18-1). Abnormalities of adrenal function are present in most children with symptomatic cerebral X-linked adrenoleukodystrophy. Almost all symptomatic patients with this disorder are hemizygotic males. MR evidence of white matter abnormalities is present in 10% to 20% of female carriers. The estimated prevalence of X-linked adrenoleukodystrophy is 1:20,000 to 1:100,000 male births.1,2
Table 18–1.Peroxisomal Disorders Associated With Leukodystrophy |Favorite Table|Download (.pdf) Table 18–1. Peroxisomal Disorders Associated With Leukodystrophy
|X-linked adrenoleukodystrophy |
|Zellweger syndrome |
|Neonatal adrenoleukodystrophy |
|Refsum disease |
|Hyperpipecolic acidemia |
|Cerebrotendinous xanthomatosis |
Based on the clinical features, X-linked adrenoleukodystrophy is classified into several phenotypes: childhood cerebral X-linked, adolescent cerebral X-linked, adult cerebral X-linked, adrenomyeloneuropathy, Addison disease– only type, and asymptomatic type. Childhood cerebral X-linked adrenoleukodystrophy is the most severe form. Most of these children develop normally until the later part of the first decade of life, at which time neurological alterations such as memory impairment and emotional instability develop, followed by progressive deterioration of vision, hearing, and motor function. Manifestations of adrenal dysfunction and gonadal insufficiency can also occur. The prompt institution of therapy (diet control, medication, or bone marrow transplantation) following an early diagnosis modifies the clinical course of this disorder.
In the childhood form of cerebral X-linked adrenoleukodystrophy, the typical CNS lesions include extensive demyelination in the periventricular deep white matter (especially in the parieto-occipital areas), cavitation, and perivascular lymphocytic infiltrates. There is sparing of the U fibers and cortex. The cerebral white matter lesions are divided histopathologically into 3 distinct zones: an outermost zone (Schaumburg zone 1), with active destruction of the myelin sheath and a lack of perivascular inflammatory cells; a middle layer zone (Schaumburg zone 2), characterized by perivascular inflammatory cells and demyelination, with preservation of axons; and a central zone (Schaumburg zone 3), consisting of gliosis and scattered astrocytes in the absence of oligodendroglia, axons, myelin, and inflammatory cells.
Areas of brain involvement with X-linked adrenoleukodystrophy have abnormal high signal intensity on T2-weighted MR images and diminished attenuation on CT. Diffusion-weighted sequences may demonstrate elevated apparent diffusion coefficient (ADC) values (i.e., increased diffusion). The site of greatest involvement for approximately 80% of patients is the parieto-occipital white matter and the splenium. The splenium is enlarged in the acute phase, but eventually becomes atrophic. Other potential sites include the genu of the corpus callosum, visual pathway (optic radiation, lateral geniculate body), acoustic pathway (acoustic radiation, medial geniculate body, brachium of the inferior colliculus, lateral lemniscus), corticospinal tract in the brainstem, ...