Peroxisomal Disorders

The peroxisomal disorders comprise a heterogeneous group of genetic diseases either caused by a defect in peroxisome biogenesis or in one of the metabolic functions of peroxisomes. Diagnosis of patients affected by a certain peroxisomal disorder can be simple if the clinical signs and symptoms of the patient involved are suggestive as in Zellweger syndrome. Through the years, however, we have seen a tremendous increase in the phenotypic variability among patients with a peroxisomal disorder which makes diagnosis on clinical grounds increasingly difficult. The availability of a set of highly sensitive metabolite biomarkers, which can be measured in a small blood sample, followed by enzyme studies and flux analysis of the different peroxisomal pathways in fibroblasts has been of great importance in this respect. Moreover, these biochemical markers and assays remain instrumental for the confirmation of the pathogenicity of DNA variants of uncertain significance identified through whole exome and whole genome sequencing, which have taken over as first-line diagnostic test, at least in several centers around the world. Despite the progress in the clinical and laboratory diagnosis of peroxisomal patients, much less progress has been made with respect to the treatment options. For some disorders there is curative treatment for some aspects of the disease. For instance, the leukodystrophy of XALD responds to hematopoietic cell transplantation (HCT), either heterologous from a matched donor or autologous employing lentiviral gene therapy. Another peroxisomal disorder for which therapeutic options are truly on the horizon is hyperoxaluria Type 1 for which different therapeutic trials are underway.