Late onset white matter disease in peroxisome biogenesis disorder

Objective: To report late onset cerebral white matter disease as a distinct ive phenotype in peroxisome biogenesis disorder (PBD). Background: There is phenotypic and genetic overlap among the PBD known as Zellweger syndrome ( ZS), infantile Refsum disease (IRD), and neonatal adrenoleukodystrophy (NAL D). Distinctive external features are variable among these three disorders, and neurologic deficit has its onset at birth or in infancy. In a structur ed follow-up cohort of 25 patients with PBD, not including ZS, three patien ts had an unusual pattern of cerebral white matter disease with onset past the age of 1, not conforming to any of the classic PBD phenotypes. Methods: Clinical phenotyping and follow-up, peroxisomal biochemical determinations in body fluids and fibroblasts, identification of affected PEX gene by gen etic complementation in fibroblasts, and MRI studies. Results: Two unrelate d patients with PBD without distinctive external features had normal neurod evelopmental milestones during their first year, followed by rapid deterior ation including severe hypotonic pareses, seizures, retinopathy, and deafne ss. A third patient initially diagnosed with IRD developed cerebral white m atter degeneration in the third year of life, complicating the original dia gnosis. MRI in all three patients showed cerebral demyelination with sparin g of subcortical fibers and pronounced central cerebellar demyelination. Co nclusions: Late-onset cerebral white matter disease may occur in PBD, eithe r following IRD or following normal early development and in the absence of distinctive external features. Peroxisome biogenesis disorder should be in cluded in the differential diagnosis of post-infantile onset of cerebral wh ite matter disease.