Peroxisomal Disorders: Genotype, Phenotype, Major Neuropathologic Lesions, and Pathogenesis

Neurological dysfunction is a prominent feature of most peroxisomal disorders. Enormous progress in defining their gene defects has been achieved. The genes and gene products, peroxins (PEX), in five of the complementation groups have been defined. These studies confirm that Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD) are a disease continuum. The gene defect in adreno-leukodystrophy (ALD) / adrenomyeloneuropathy (AMN) involves an integral peroxisomal membrane protein. Neuropathologic lesions are of three major classes: (i) abnormalities in neuronal migration or differentiation, (ii) defects in the formation or maintenance of central white matter, and (iii) postdevelopmental neuronal degenerations. The central white matter lesions are those of: (i) inflammatory demyelination, (ii) non-inflammatory dysmyelination, and (iii) nonspecific reductions in myelin volume or staining with or without reactive astrocytosis. The neuronal degenerations are of two major types: (i) the axonopathy of AMN involving ascending and descending tracts of the spinal cord, and (ii) cerebellar atrophy in rhizomelic chondrodysplasia punctata and probably IRD. We postulate that the abnormal fatty acids in peroxisomal disorders, particularly very long chain fatty acids and phytanic acid, are incorporated into cell membranes and perturb their microenvironments resulting in dysfunction, atrophy and death of vulnerable cells. The advent of mouse models for ZS and ALD is anticipated to provide even greater pathogenetic insights into the peroxisomal disorders. Introduction Neurological dysfunction is a prominent feature in 13 of the 15 peroxisomal disorders that have been described (67) (Table 1). Their combined incidence is in excess of 1:20,000. The clinical and neuropathologic details of these diseases have been reviewed numerous times (2, 7, 25, 31, 53, 67-70, 72, 73, 114; 16, 84-86, 108), including in this journal (76). Hence, we will focus this contribution on recent advances in their molecular genetics, the major classes of neuropathologic lesions that typify these diseases and some thoughts regarding their pathogeneses. Peroxisomal disorders are subdivided into two major categories. The first category includes the disorders of peroxisome biogenesis or assembly. In these disorders the organelle is not formed normally, and several peroxisomal functions are deficient. The second category includes at least 10 disorders in which the defect involves a single peroxisomal protein and peroxisome structure is intact. The biochemical defects in all of the disorders listed in Table 1 have been defined and also have been reviewed recently (124-126). In the 13 disorders associated with neurological disturbances the biochemical defects involve various aspects of lipid metabolism. Cell lines from patients with disorders of peroxisome biogenesis have been subdivided into eleven complementation groups (66), which are listed in Table 2. It was postulated that these represented distinct gene defects. Subsequent to the publication of this report it has been shown that group 5 is identical to group 7, and it is likely that groups 4 and 6 are identical to each other (Moser HW, unpublished observation). Poulos et al. (82) have identified an additional complementation group not included in the earlier list. Remarkable progress toward the identification of gene defects has been achieved during the last 5 years, in part because of the methodological advance of homology probing (7). The defects in five of the complementation groups have now been defined and are listed in Table 3. The identification of the human mutants, combined with those previously demonstrated in yeast, has contributed greatly to the clarification of the process of normal peroxisome biogenesis and has been reviewed Brain Pathology 8: 101-120(1998)