A neurodegenerative disease is reported in 5 related families, belonging to a Dutch genetic isolate. Seven children (5 females, 2 males) had microcephaly, spastic pareses, severe extrapyramidal dyskinesia and failure to acquire any voluntary skills. Four died during childhood. Marked pontocerebellar hypoplasia and progressive cerebral atrophy were found by computed tomography of the brain. Autopsy in one case revealed widespread, progressive loss of neurons affecting the olivopontoneocerebellar system more severely than any other part of the brain, accounting for the macroscopic pontocerebellar hypoplasia. A neocortical biopsy from another patient indicated that rough endoplasmic reticulum in neurons as the earliest ultrastructural target of the pathological process. This study confirms the disease as an inherited neuronal degeneration with very early, probably prenatal onset.