Lifelong course of Zellweger spectrum disorders: A cohort study

Abstract

Objective: Zellweger spectrum disorders (ZSD) are a group of genetic metabolic disorders caused by a defect in peroxisome biogenesis due to mutations in one of the PEX genes. Although originally seen as a rapidly lethal pediatric disease, an increasing number of patients with a relatively mild or aspecific phenotype were recognized over the past few years as a result of improved clinical and biochemical characterization. Consequently, a substantial percentage of ZSD patients reach adulthood nowadays. Since only limited data on the natural course of the disease in these relatively mild patients are available, this retrospective cohort study aims to gain insight in the natural course of these patients. Methods: Clinical and laboratory data were collected retrospectively from a large cohort of patients with a genetically confirmed ZSD. All patients were regularly followed up and examined as a part of standard patient care. Results: A total of 22 patients in this ZSD cohort reached adulthood. All patients, except one patient with PEX10 mutations, had vision and hearing impairment. Neurological symptoms comprised pyramidal tract dysfunction, cerebellar syndrome and peripheral neuropathy, in most cases eventually leading to a gait disorder. Two patients suffered from epileptic seizures. In multiple adult patients, a relatively rapid progression of mainly neurological symptoms is described after a long period of stabilization, accompanied by diffuse white matter abnormalities and general cerebral atrophy on MRI- imaging. Conclusion: Most patients with a ZSD at the mild end of the spectrum suffer from slowly progressive neurological symptoms, vision and hearing impairment. Rapid progression of neurological symptoms after a long period of stabilization can occur, whilst biochemical abnormalities have normalized over the years. The exact pathophysiology of this rapid deterioration remains to be elucidated.