We describe the natural history of patients with a Zellweger spectrum disorder (ZSD) surviving into adulthood.

Retrospective cohort study in patients with a genetically confirmed ZSD.

All patients (n = 19; aged 16–35 years) had a follow‐up period of 1–24.4 years (mean 16 years). Seven patients had a progressive disease course, while 12 remained clinically stable during follow‐up. Disease progression usually manifests in adolescence as a gait disorder, caused by central and/or peripheral nervous system involvement. Nine were capable of living a partly independent life with supported employment. Systematic MRI review revealed T2 hyperintense white matter abnormalities in the hilus of the dentate nucleus and/or peridentate region in nine out of 16 patients. Biochemical analyses in blood showed abnormal peroxisomal biomarkers in all patients in infancy and childhood, whereas in adolescence/adulthood we observed normalization of some metabolites.

The patients described here represent a distinct subgroup within the ZSDs who survive into adulthood. Most remain stable over many years. Disease progression may occur and is mainly due to cerebral and cerebellar white matter abnormalities, and peripheral neuropathy.