A 6-month-old female with no family history of neurologic disease was born with dysmorphic features and hypotonia the cause of which could not be determined despite extensive laboratory evaluation for a primary metabolic disorder. Neuroimaging studies disclosed progressive cerebral atrophy and ventricular dilatation. Post-mortem examination of the brain revealed micrencephaly and severe neuronal cytoplasmic vacuolation notably in the thalamus and inferior olivary nuclei. The neurons of the cortex, cerebellum, and brain stem were also vacuolated, but to a lesser extent. The white matter was predominantly intact. While superficially reminsicent to the cases of spongy glio-neuronal dystrophy of Jellinger and Seitelberger [(1970) Acta Neuropathol (Berl) 16:125-40], the severity of the neuronal vacuolation without neuronal loss and absence of seizures in this patient suggests that this condition represents a distinct pathologic entity.