Peroxisomal Disorders

Abstract Peroxisomes are essential organelles for normal cellular function and are responsible for performing over 50 metabolic reactions, most of which consume or generate molecular oxygen. They are highly versatile, with both anabolic and catabolic functions, many of which are induced only under appropriate conditions. Many reactions, such as β-oxidation of VLCFAs, take place exclusively within peroxisomes. Other reactions, such as β-oxidation of long-chain fatty acids, occur in other compartments within the cell, but the peroxisomal pathway is highly inducible and allows for fine-tuning of the metabolic environment. For many pathways, such as the first steps in plasmalogen synthesis, essential portions of the reactions take place within peroxisomes and intermediates are shunted to other cellular organelles for additional processing. Much of what has been learned about peroxisomes stems from the search to understand diseases where one or more peroxisomal functions are deficient. Peroxisomal diseases were hence divided into (1) disorders of peroxisomal assembly or biogenesis, where peroxisomes are characteristically deficient in size and number (although “ghost” organelles may be present) and (2) disorders where only single enzymatic functions of peroxisomes are defective and (3) contiguous gene syndromes. Peroxisomal membrane and matrix proteins are synthesized on free ribosomes and transported into existing peroxisomes, which bud and divide to form new peroxisomes. The mechanism of peroxisomal biogenesis involves specific targeting of proteins by peroxisomal targeting signals (PTS) within the amino acid sequence that direct the importation of the protein into the peroxisomes. These PTSs occur at either the carboxy-terminal end of the peptide (PTS1) or the pre-sequence at the amino-terminus (PTS2), or they can be inherent in the sequence itself. Defects of the peroxins genes, which mediate this import, have been identified in patients with the Zellweger spectrum and RCDP. Much is yet to be discovered about the transportation into peroxisomes of proteins and substrates for metabolic reactions. The clinician should suspect a disorder or peroxisomal biogenesis, such as the Zellweger spectrum (ZS, NALD, or IRD) or RCDP type 1, in patients who present early in life with features that are characteristic for these disorders (Table 44.4). The most widely used laboratory test for the diagnosis of children suspected of having a disorder of peroxisomal biogenesis is the measurement of levels of VLCFAs in plasma. However, VLCFA levels are not elevated in RCDP. Other assays that help in the detection and classification of these disorders include measurement of plasma levels of phytanic acid, pristanic acid, pipecolic acid, plasmalogens, and bile acid intermediates. Phytanic acid and plasmalogens levels are age-dependent and may not be abnormal in older children with Zellweger, NALD, and IRD. Most of these disorders have ocular or visual system findings, including cataract, glaucoma, retinal degeneration, optic atrophy, and leukodystrophy leading to cortical blindness. Retinopathy cannot be presumed to be absent in infancy without a normal ERG. The ophthalmologist must consider the possibility of a peroxisomal disease whenever findings suggestive of this class of disorders are encountered.