Acute necrotizing encephalopathy (ANE) is a rapidly progressive encephalopathy that can occur in otherwise healthy children after common viral infections such as influenza and parainfluenza. Most ANE is sporadic and nonrecurrent (isolated ANE). However, we identified a 7 Mb interval containing a susceptibility locus (ANE1) in a family segregating recurrent ANE as an incompletely penetrant, autosomal-dominant trait. We now report that all affected individuals and obligate carriers in this family are heterozygous for a missense mutation (c.1880C-->T, p.Thr585Met) in the gene encoding the nuclear pore protein Ran Binding Protein 2 (RANBP2). To determine whether this mutation is the susceptibility allele, we screened controls and other patients with ANE who are unrelated to the index family. Patients from 9 of 15 additional kindreds with familial or recurrent ANE had the identical mutation. It arose de novo in two families and independently in several other families. Two other patients with familial ANE had different RANBP2 missense mutations that altered conserved residues. None of the three RANBP2 missense mutations were found in 19 patients with isolated ANE or in unaffected controls. We conclude that missense mutations in RANBP2 are susceptibility alleles for familial and recurrent cases of ANE.

A new CT pattern was observed in 2 patients with adrenoleukodystrophy (ALD). This pattern, which the authors call Type II, is characterized by the absence of posterior periventricular areas of decreased attenuation around the trigone on non-contrast scans: after contrast infusion, however, there is striking enhancement of various white-matter structures (tracts or fiber systems) such as the internal capsules, corpus callosum, corona radiata, forceps major, and cerebral peduncles. This is different from numerous previous descriptions of the CT pattern in ALD. Type II ALD does not appear to have been seen in any other leukoencephalopathy and is probably specific for a phenotypic variant or an evolving stage of ALD.

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.

(Developmental and Metabolic Neurology Branch, National Institute of Neurological and Communicative Disorders and Stroke, National Institutes of Health, Bethesda, Maryland).

Our findings on computer assisted tomography of the brain in four cases of adrenoleukodystrophy are sufficiently consistent to warrant delineation. Early changes, which may predate obvious clinical findings, are represented by areas of decreased attenuation coefficient in the posterior (parieto-occipital) white matter around the trigonum of each lateral ventricle. Subsequently the temporal, parietal, and frontal lobes are involved, and the extensive areas of decreased attenuation coefficient in the white matter become almost indistinguishable from the conspicuously enlarged ventricles. Only a thin ependymal wall separates the ventricular cavities from the leukomalacia lesions. Contrast medium enhancement at the periphery of the affected regions is an important, although inconsistent, feature.