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Reviews in Medicine, Alan Sugar, Editor SURVEY OF OPHTHALMOLOGY VOLUME 35. NUMBER 5 * MARCH-APRIL 1991 REVIEWS IN MEDICINE, ALAN SUGAR, EDITOR The Peroxisome and the Eye STEVE J. FOLZ, B.S., AND JONATHAN D. TROBE, M.D. The W.K. Kellogg Eye Center, and Departments of Ophthalmology and Neurology, University of Michigan Medical Center, Ann Arbor, Michigan Abstract. Several childhood multisystem disorders with prominent ophthalmological manifesta- tions have been ascribed to the malfunction of the peroxisome, a subcellular organelle. The peroxisomal disorders have been divided into three groups: 1) those that result from defective biogenesis of the peroxisome (Zellweger syndrome, neonatal adrenoleukodystrophy, and infan- tile Refsum’s disease); 2) those that result from multiple enzyme deficiencies (rhizomelic chon- drodysplasia punctata); and 3) those that result from a single enzyme deficiency (X-linked adrenoleukodystrophy, primary hyperoxaluria type 1). Zellweger syndrome, the most lethal of the three peroxisomal biogenesis disorders, causes infantile hypotonia, seizures, and death within the first year. Ophthalmic manifestations include cornea1 opacification, cataract, glauco- ma, pigmentary retinopathy and optic atrophy. Neonatal adrenoleukodystrophy and infantile Refsum’s disease appear to be genetically distinct, but clinically, biochemically, and pathological- ly similar to Zellweger syndrome, although milder. Rhizomelic chondrodysplasia punctata, a peroxisomal disorder which results from at least two peroxisomal enzyme deficiencies, presents at birth with skeletal abnormalities and patients rarely survive past one year of age. The most prominent ocular manifestation consists of bilateral cataracts. X-linked (childhood) adrenoleu- kodystrophy, results from a deficiency of a single peroxisomal enzyme, presents in the latter part ofthe first decade with behavioral, cognitive and visual deterioration. The vision loss results from demyelination of the entire visual pathway, but the outer retina is spared. Primary hyperoxaluria type I manifests parafoveal subretinal pigment proliferation. Classical Refsum’s disease may also be a peroxisomal disorder, but definitive evidence is lacking. Early identification of these disor- ders, which may depend on recognizing the ophthalmological findings, is critical for prenatal diagnosis, treatment, and genetic counselling. Sure Ophthalmol 35:353-368, 1991) Key words. infantile Refsum’s disease l neonatal adrenoleukodystrophy l peroxisome l peroxisomal disorders l primary hyperoxaluria type l Refsum’s disease l rhizomelic chondrodysplasia punctata l Zellweger syndrome As the result of recent developments in cellular I. The Peroxisome biochemistry, a group of childhood diseases with prominent ophthalmological manifestations can A. HISTORICAL PERSPECTIVE now be attributed to the malfunction of a subcel- While observing mouse kidney cells in 1954, lular organelle called the “peroxisome.” Discov- Rhodin noted a single membrane-bound organelle ered in 1954, the peroxisome is known to harbor a with a granular matrix measuring about one-half large number of important catabolic and anabolic micrometer which he called simply a “microbody.“1’2 reactions, among them the degradation of very- A few years later, de Duve et a12’ discovered that this long-chain fatty acids. The build-up of these very- microbody oxidized certain substrates by utilizing long-chain fatty acids and characteristic ocular molecular oxygen (0,) and producing hydrogen abnormalities are principal markers of the peroxi- peroxide (H202), leading them to designate this or- somal disorders. ganelle the “peroxisome.” 353 354 Surv Ophthalmol 35 (5) March-April 1991 FOLZ, TROBE Peroxisomes are believed to be present in nearly VLCFA Beta-Oxidation all human cells, including those of the eye,g0 but their abundance and distribution vary depending , upon the developmental stage of the tissue. Most abundant in liver and kidney cells, they are also R-CH, -CH, -OH - present during the first two weeks of life in neurons of the cerebrum and cerebellum.* They are espe- cially numerous in oligodendrocytes, which are re- sponsible for myelin formation within the central nervous system. B. BIOGENESIS Peroxisomal enzymes are encoded by nuclear genes and are synthesized on cytoplasmic poly- somes. 68 The enzymes then enter preformed per- oxisomes post-translationally.6a~‘1 With one known exception (beta-ketoacyl-CoA thiolase), peroxisom- Fig. 1. Peroxisomal very-long-chain fatty acid degrada- tion pathway. Electron micrograph 32,000)of human al enzymes have been shown to be synthesized in ( x peroxisome of a hepatocyte (Adapted from Sternlieb et their final form, not requiring proteolytic cleavage a1’42 with permission of the authors and the United States for activation.80 Once formed, peroxisomes are be- and Canadian Academy of Pathology, Inc.). lieved to grow to a certain size and then split in two. In those childhood disorders ascribed to imperfect biogenesis of peroxisomes, many enzymes cannot acyl-CoA ligase, acyl-CoA oxidase, bifunctional pro- be incorporated into the peroxisomes. Stranded in tein (acyl-CoA hydratase and acyl-CoA dehydro- the cytosol, these enzymes and the “ghost” peroxi- genase), and beta-ketoacyl-CoA thiolase.4g*55,81Mal- somes are rapidly degraded.‘24 function of this pathway leads to a build-up of very long-chain fatty acids, the chief biochemical clue to C. CATABOLIC REACTIONS the diagnosis of peroxisomal disorders. The best understood catabolic reaction of the peroxisome is the oxidative degradation of long- 2. Pipecolic Acid chain fatty acids, those with 16 or more carbon In primates, the peroxisome is responsible for atoms. Very-long-chain fatty acids, those with 22 or the catabolism of L-pipecolic acid, which is, in turn, more carbon atoms, are oxidized exclusively in the formed from the catabolism of the amino acid ly- peroxisome.‘30 The organelle is also involved in sine.43,54,60*61It has been suggested that the L-pipe- pipecolic acid metabolism in primates,70~7g cellular colic acid synthetic pathway may be the major oxidation reactions generating H202*‘, and possibly degradative pathway of lysine in the rain.*‘,” All phytanic acid metabolism. disorders of peroxisomal biogenesis give rise to ab- normally high serum levels of pipecolic acid.‘.70~78*‘52 1. Very-long-chain Fatty Acid Degradation The shorter-chain fatty acids enter the mitochon- 3. HZOZ-forming Oxidation drion by a carnitine acyl transferase carrier system The peroxisome gets its name from its ability to and are catabolized by a process known as beta- oxidize a number of substrates utilizing 0, and oxidation, which consists of the repeated removal of forming hydrogen peroxide (H202) in the proc- two carbon fragments in the form of acetyl-CoA ess.*’ The formed H,O, is converted to H,O by the from the carboxyl end of the fatty acid molecule. peroxisomal enzyme catalase, the main histochemi- The acetyl-CoA then enters the tricarboxylic acid cal marker of this organelle. When the peroxisomes (Krebs) cycle and generates energy for the cell. are poorly formed, catalase is found in the cytosol Very-long-chain fatty acids, as well as fatty acids rather than in the peroxisomes. consisting of 14 or more carbons, are oxidized by a similar process, but predominantly in peroxisomes, 4. Phytanic Acid Degradation by enzymes which are distinct from their mitochon- Whether the peroxisome is involved in the ca- drial analogs 8*13o(Fig. 1). Another difference is that tabolism of phytanic acid remains a debated issue. A very long-chain fatty acids enter the peroxisome via branched 20-carbon fatty acid of dietary origin, a non-carnitine acyl transferase carrier system.75 phytanic acid undergoes beta-oxidation after an The peroxisomal enzymes involved in very long- initial alpha-oxidation step.‘43,‘53 Evidence for a chain fatty acid oxidation have been identified as peroxisomal role comes from the work of Van den THE PEROXISOME AND THE EYE 355 Branden et al, ‘55 who showed that administration of TABLE 1 phytol, a precursor of phytanic acid, induces per- Peroxisomul Disorders as Recorded at the Kenned Institute oxisomal proliferation and leads to a five-fold in- from 1981-l 988 (Adapted from Moser’ J) crease in peroxisomal acyl-CoA oxidase levels. Fur- Disorder No. Cases thermore, an elevated serum phytanic acid level is X-linked adrenoleukodystrophy found in the peroxisomal biogenetic disorders. hemizygotes 575 X-linked adrenoleukodystrophy D. ANABOLIC REACTIONS heterozygotes 504 Anabolic reactions that take place in the peroxi- Zellweger Syndrome 105 Neonatal adrenoleukodystrophy 54 some include ether lipid synthesis (a plasmalogen Rhizomelic chondrodysplasia punctata 18 precursor),45 bile acid synthesis,g5 and possibly cho- Infantile Refsum’s disease 12 lesterol synthesis. 66 Peroxisomal biogenetic disor- Classical Refsum’s disease 4 ders leave these substances in deficit or pile up ex- Primary hyperoxaluria type 1 Not monitored cessive intermediates. Insufficient information for classification 55 Others (including hyperpipecolic 1. Ether Lipids acidemia and isolated defects of very Peroxisomes prepare ether lipids, the major pre- long chain fatty acid metabolism) 18 cursors for plasmalogen synthesis, from dihydroxy- Total 1.345 acetone phosphate. Plasmalogens comprise up to 20% of mammalian cell membranes135 and 15% of myelin lipids. ” Whereas conventional phospholip- ids contain an ester-linked fatty acid at the first posi- tact peroxisome structure, and those that appear to tion of the glycerol backbone,
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