New phenotypic variant of adrenoleukodystrophy. Pathologic, ultrastructural, and biochemical study in two brothers

Adrenoleukodystrophy is not usually considered in the differential diagnosis of the infantile onset of failure to thrive with motor and intellectual retardation. Rather, symptoms have started in childhood and have progressed over some years; not all patients have had overt adrenocortical insufficiency. The two brothers reported here developed symptoms in the neonatal period. In each the nature of the primary cerebral disorder was not recognized, because other etiologic factors clouded the diagnostic studies. In the younger brother, Case 1, a high titer (1:256) for cytomegalovirus (CMV) led to the suspicion that CMV infection accounted for the neurologic and ophthalmologic findings. Progressive neurologic deterioration at the age of 6 years prompted brain biopsy to confirm the diagnosis of progressive CMV encephalitis. In the older brother, Case 2, hemogenic hydrocephalus due to traumatic birth injury was held responsible for the psychomotor retardation and cerebral palsy. At necropsy, the adrenal glands in both cases were severly atrophic. In Case 1, a markedly inflammatory leukodystrophic process affected chiefly the frontal centra semiovalia and internal capsules, with relative sparing of parieto-occipital white matter and subcortical U-fibers. Heavy lymphocyte and monocyte cuffs surrounded many blood vessels in the white matter, and oil-red-O and PAS-positive macrophages were scattered in the zones of myelin disintegration and loss. Focally, the leukodystrophic process was so intense that cavitation necrosis was present, especially in the internal capsules. Further, PAS-positive, striated macrophages were aggregated in large clusters in liver, spleen, and lymph nodes. At the ultrastructural level, linear and gently arced, parallel, coapted or widely separated leaflets measuring 3-4 nm in width were identified in macrophages of the brain biopsy and in autopsy liver and lymph node. Biochemical analysis of fresh, frozen autopsy brain demonstrated cholesterol esters with long-chain fatty acids by thin-layer and gas-liquid chromatography. In Case 2, the leukodystrophic process could be readily identified in the brainstem and cerebellum but was masked in the cerebral hemispheres by the extensive hydrocephalus. The adrenal glands were atrophic and at light microscopy revealed adenomatoid nodules, many ballooned coritcal cells and very rare cells with striated cytoplasm. Masses of PAS-positive macrophages were encountered in liver and lymph nodes. In both cases, only old Wallerian degeneration of the corticospinal tracts was found in the spinal cord.