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 manifestations 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 infantile Refsum’s disease); 2) those that result from multiple enzyme deficiencies (rhizomelic chondrodysplasia 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, glaucoma, pigmentary retinopathy and optic atrophy. Neonatal adrenoleukodystrophy and infantile Refsum’s disease appear to be genetically distinct, but clinically, biochemically, and pathologically 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) adrenoleukodystrophy, 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 disorders, 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 especially numerous in oligodendrocytes, which are responsible 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 peroxisomes post-translationally.6a~‘1 With one known exception (beta-ketoacyl-CoA thiolase), peroxisom- Fig. 1. Peroxisomal very-long-chain fatty acid degradation 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 a1’42with 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, ‘55who 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, plasmalogens contain result from one faulty enzyme.*’ The relative fre- a 1,2 unsaturated long-chain vinyl ether linkage at quency of the various peroxisomal disorders has the first position. The predominant plasmalogen in been reported for 1981-1988 from the Kennedy most tissues is phosphatidylethanolamine, although Institute8’ (Table 1). heart and liver cell membranes contain predomi- A. PEROXISOME BIOGENESIS DISORDERS nantly phosphatidylcholine.53 The final synthetic (TABLE 2) reactions of plasmalogen synthesis occur in the endoplasmic reticulum.47 Defective plasmalogen syn- The peroxisomal disorders that result from ab- thesis may be partially responsible for some of the normal biogenesis of the organelle include Zell- neurologic manifestations of peroxisomal disorders. weger (Cerebro-hepato-renal) syndrome, neonatal adrenoleukodystrophy, and infantile Refsum’s dis- 2. Bile Acids ease. Disorders of peroxisome biogenesis all share a Certain steps of bile acid synthesis occur in the panel of ultrastructural or biochemical abnormali- peroxisome which accounts for the proportionally ties,87 which include: 1) absent or reduced numbers higher levels of bile acid intermediates observed in of peroxisomes; 2) catalase present in the cytosol patients with peroxisome biogenesis disorders.g5 (instead of in the peroxisome); 3) reduced tissue Two bile acid precursors, dihydroxycoprostanic levels of plasmalogen; 4) defective oxidation and acid and trihydroxycoprostanic acid, are detectable accumulation of very long-chain fatty acids; 5) defi- clinically and may aid in the diagnosis. cient oxidation and age-dependent accumulation of phytanic acid; 6) defects in certain steps of bile acid 3. Cholesterol synthesis and accumulation of bile acid intermediates; 7) defective oxidation and accumulation of Peroxisomes may possess a pathway for choles- L-pipecolic acid; and 8) increased urinary excretion terol synthesis’46 that is distinct from the better of dicarboxylic acids due to inadequate H,O,-based known microsomal pathway. Disruption of the per- oxidation. oxisomal pathway may lead to the low plasma cho- Genetic analysis of the peroxisomal biogenesis lesterol levels observed in some patients with per- disorders has shown that at least five complementa- oxisomal disorders.” tion groups (genes) exist.‘5.“* Alteration of any of three different genes may result in Zellweger syn- II. Peroxisomal Disorders drome. Likewise, there are two separate genes The peroxisomal disorders have been divided whose disruption will yield neonatal adrenoleuko- into three groups: those that result from defective dystrophy, and one which can result in infantile biogenesis of the organelle, those resulting from Refsum’s disease. Because the complementation more than one enzymatic abnormality but with in- group which encompasses infantile Refsum’s dis- 356 Surv Ophthalmol 35 (5) March-April 1991 FOLZ, TROBE

Fig. 2. Z@: Infant with Zellweger syndrome, showing severe craniofacial dysmorphic features: high forehead, hypertelorism, and hypoplastic supraorbital ridges (Reprinted from Smith et al134 with permission of the authors and the CV Mosby Co.) Right: Infant with Zellweger syndrome exhibiting milder dysmorphic features: hypertelorism and hypoplastic supraorbital ridges (courtesy of James McManaway, Ill, MD. Hershey, PA).

ease is also one of the three complementation 1. Zellweger Syndrome (Cerebro-hepato-renal groups for Zellweger syndrome, the disruption of Syndrome) one gene may produce either Zellweger syndrome In 1964, Bowen et al” first described a severe or infantile Refsum’s disease. The factors which de- neonatal disorder with distinctive craniofacial dys- termine which of the two diseases will occur are morphism marked by a high forehead, epicanthal currently unknown. folds, hypoplastic supraorbital ridges and nasal

TABLE 2 Peroxisomul Disorders with Ocular Manifestations Neonatal Zellweger Syndrome Adrenoleukodystrophy Infantile Refsum’s Disease Inheritance Autosomal Recessive Autosomal Recessive Autosomal recessive Age at onset Neonatal Neonatal First decade Peroxisomal Imperfect biogenesis Imperfect biogenesis Imperfect biogenesis Defect

Peroxisomes Markedly reduced or absent Markedly reduced or absent Markedly reduced or absent Ophthalmologic Pigmentary retinopathy and Pigmentary retinopathy and Pigmentary retinopathy and Findings retinal arteriolar attenuation retinal arteriolar attenuation retinal arteriolar attenuation Optic atrophy Pigment epithelial clumping Optic atrophy Cornea1 clouding Optic atrophy Extinguished ERG Glaucoma Extinguished ERG Cataract Extinguished ERG

Other Craniofacial dysmorphism Adrenal cortical atrophy Deafness Clinical Seizures and hypotomia Seizures and hypotomia Psychomotor retardation Findings Psychomotor retardation Psychomotor retardation Renal cysts

Biochemical Plasma: VLCFA Plasma: VLCFA Plasma: VLCFA Diagnostic Pipecolic acid Pipecolic acid Pipecolic acid Tests Phytanic acid Phytanic acid Phytanic acid Bile acids Bile acids Bile acids RBC: Plasmalogen RBC: Plasmalogen RBC: Plasmalogen *VLCFA = Very-long-chain fatty acids THE PEROXISOME AND THE EYE 357 bridge, micrognathia, high arched palate, and hyper- are attended by perivascular macrophages laden telorism (Fig. 2). The externally apparent ocular ab- with inclusions which, on electron microscopy, are normalities include corneal clouding,12*44,g3*10,‘05~‘36*144 found to consist of two electron-dense leaflets sepa- CataraCtS 56,‘X69,~,‘W’~6,‘~and g~aucoma.‘2,104,105,1~ rated by a lucent space. 94 These inclusions have Zellweger syndrome babies also have seizures, been identified as cholesterol esters of very-long- psychomotor retardation, severe hypotonia, talipes chain fatty acids. equinovarus, limb contractures with limited finger Several reports have now characterized the oph- extension (camptodactyly), hepatomegaly, severe thalmic pathology. Anteriorly, cornea1 epithelial hearing impairment, ventricular septal defects, jaun- edema,22*44 posterior embryotoxon, cataract,44,56*6g dice, and hypoprothrombinemia.36,H~‘34*145 Death oc- and glaucoma have been inconsistently document- curs within a few months. ed. The cause of the cornea1 clouding is uncertain, As globes were inspected after death, it became as no pathologic inclusions have been found in the evident that the posterior ocular segment is also cornea. The cataracts, of variable density, appear to affected, with narrowed retinal arterioles,35~‘3g”57 be caused by vacuolations of cortical lens fibers. Al- retinal pigment clumping,“‘j and optic disc pallor though anterior chamber angle anomalies have and hypoplasia. 22,‘06~13gMost observers have noted been described, ” the pathogenesis of glaucoma is that the abnormal dispersion of retinal pigment not definite. lacks the perivascular “bone spicule” pattern associ- The posterior segment abnormalities are far ated with typical retinitis pigmentosa.22s35 The ex- more severe (Fig. 3). Most striking is a loss of pho- tensive retinal abnormalities were foretold by the toreceptors, 35,44,6g.‘56but all retinal neurons are re- finding of extinguished electroretinograms in all duced in number, including retinal pigment epi- cases.56*‘3g thelium and ganglion cells.44,156 Scattered through The brain pathology of Zellweger syndrome con- the retina and the subretinal space are humerous sists of a failure of neuronal migration and patchy macrophages containing pigment and nonpig- demyelination. 28,32*g3~‘56The areas of demyelination mented cytoplasmic bileaflet inclusions identical to

TABLE 2 Peroxisomul Disorders with Ocular Manifestations (continued) khizomelic X-linked Primary hyperoxaluria Chondrodysplasia Punctata Adrenoleukodystrophy Type 1 Classical Refsum’s Disease Autosomal recessive X-linked Autosomal recessive Autosomal recessive Neonatal First decade First or second decades First to fourth decades Plasmalogen synthesis VLCFA* oxidation Glyoxalate metabolism Phytanic acid oxidation Phytanic acid oxidation (deficient lignoceroyl- (deficient alanine : glyox- (deficient phytanic acid Thiolase processing CoA ligase) alate aminotransferase) alpha-hydroxylase) Present Present Present Present Cataract Optic atrophy Black parafoveal ringlets Pigmentary retinopathy Normal ERG Anterior and posterior visu- with or without white fi- and retinal arteriolar at- al pathway demyelina- brous material deep to tenuation tiun the lesion Night blindness Normal ERG Optic atrophy Optic atrophy Reduced ERG Shortening of proximal Adrenal cortical atrophy Renal failure Chronic polyneuropathy extremities Dark skin pigmentation Osteodystrophy Ataxia Dermatitis Emotional lability hydrocephalus Hearing loss Psychomotor retardation Cognitive decline Increased CSF protein Radiographic epiphyseal Hearing loss Cardiopathy stippling Incoordination and Anosmia spasticity Plasma: Phytanic acid Plasma: VLCFA Urine: Organic acids Plasma: Phytanic acid RBC: Plasmalogen RBC: VLCFA Liver: Alanine : glyoxalate Fibroblasts: Phytanic acid Fibroblasts VLCFA aminotransferase in per- cutaneous biopsy 358 Surv Ophthalmol 35 (5) March-April 1991 FOLZ, TROBE

The diagnosis of Zellweger syndrome should be considered in a severely hypotonic infant with seizures, craniofacial dysmorphism, narrowed retinal arterioles, retinal pigment dispersion, and optic disc pallor. Cornea1 clouding and cataract are not necessary features. With these findings, Zellweger syndrome can be distinguished from intrauterine infections, Lowe’s syndrome, galactosemia, and ly- sozomal storage abnormalities by finding elevated plasma very-long-chain fatty acids and reduced plasmalogen levels. If these tests are not normal, pipecolic acid and bile acids may be measured for confirmation. These specialized tests, which are still available only in a small number of medical centers, have now been extended to prenatal diagnosis.” Because Zellweger syndrome is an autosomal recessive disorder,Q3 genetic counseling of families that Fig. 3. Midperipheral retina in case of Zellweger syn- have had an affected offspring is critical. Unfortu- drome, showing loss of photoreceptors and ganglion nately, there is yet no treatment available. cells. An aggregate of pigmented macrophages (arrow) is present in the subretinal space (hematoxylin and eosin, 2. Neonatal Adrenoleukodystrophy by in situ hybridization in neuronal cells in a latently Neonatal adrenoleukodystrophy was first de- x 290; reprinted from Cohen et al’* with permission of the authors and The Ophthalmic Publishing Co., Chica- scribed in 1978 by Ulrich et a1.15* They observed a go, IL). severely hypotonic infant who developed seizures at 4 days and died at 20 months. Because their patient had adrenal cortical atrophy and patchy those seen in the brain. These inclusions are also brain demyelination reminiscent of the already well found in the retinal pigment epithelium. The optic known X-linked adrenoleukodystrophy, they chose nerve is profoundly demyelinated, its axons inter- to label the disease neonatal adrenoleukodystro- leaved with the familiar inclusion-bearing macro- phy. It subsequently became clear that neonatal phagesuQ The posterior vitreous contains enough adrenoleukodystrophy is an autosomal recessive of these bileaflet-bearing macrophages to appear disorder which is clinically, pathologically, and bio- hazy in some cases.” One may speculate that the chemically much closer to Zellweger syndrome accumulation of very-long-chain fatty acids kills the than to X-linked adrenoleukodystrophy. neurons and the myelin-forming oligodendrocytes, Neonatal adrenoleukodystrophy may look exact- and that the macrophages scavenge the debris. ly like Zellweger syndrome and cause death within In 1973, Zellweger syndrome became the first the first year, but more commonly the disease is human disease to be linked to the peroxisome. By milder than Zellweger syndrome, with patients man- utilizing histochemical staining procedures, Gold- ifesting no dysmorphic features and living an aver- fischer et a13’ were able to show that tissues from age of four years - some even into the second dec- Zellweger syndrome patients lacked catalase-con- ade.85,‘“8 patients typically have adrenal cortical taining particles (peroxisomes). Using more sophis- atrophy, but rarely manifest adrenal insufftciency.67 ticated techniques, Santos et al”’ have recently Anterior ocular segment abnormalities are uncom- been able to demonstrate that membrane struc- mon, but retinal pigmentary degeneration and op- tures similar to peroxisomes are present in Zell- tic atrophy are disabling and diagnostically impor- weger syndrome patients, but do not contain the tant.63 normal complement of enzymes. Subsequent stud- We have had the opportunity to perform oph- ies confirmed that many peroxisomal enzymes are thalmological examinations on two of the longest- synthesized normally in Zellweger syndrome but surviving patients with neonatal adrenoleukodys- are not assembled into the organelle and many are trophy - brothers aged 12 and 15. In both boys, therefore quickly degraded in the cytoplasm.25~‘5Q visual acuity was 20/200 OU. The older brother had Zellweger syndrome shares the biochemical pro- a comitant 30 prism diopter right exotropia, while file common to all peroxisomal biogenetic disor- the younger brother’s motility examination was ders, but may be biochemically distinct in having normal. Both patients demonstrated smooth ocular the highest very-long-chain fatty acid accumulation movements without nystagmus. The pupils of both and lowest level of plasmalogens. patients reacted moderately, but sluggishly to light, Fig. 4. Fundus photographs from right eye (left) and left eye (right) of a 15-year-old boy with Neonatal Adrenoleukodys- trophy. Note marked retinal arteriolar attenuation, optic disc pallor, and loss of pigment epithelium especially evident in macular area.

White Flash Dark Adapted - $W

“Rod Response” Dim Blue Flash Dark Adapted - - JiT=

“Cone Response” White Flash Light Adapted - - w

Patient BM Patient RM Normal 12 y/o WM 15 y/o WM

Fig.5. Electroretinograms (ERGS) from two boys with neonatal adrenoleukodystrophy, showing extinguished responses.

Fig. 6. L.@ Retina from patient with neonatal adrenoleukodystrophy, showing loss of photoreceptor and ganglion cells, similar to that seen in Zellweger Syndrome (hematoxylin and eosin, x 100). Right: Electron micrograph x 27,000 of a vitreous macrophage displaying inclusion (arrow). Inset ( x 95,000)shows that inclusion consists of two electron-dense leaves separated by a central lucent zone. (Reprinted from Glasgow et aIs with permission of the authors and O#th&zelogy.)

359 360 Surv Ophthalmol 35 (5) March-April 1991 FOLZ, TROBE

Fig. 7. Retina from patient with X- linked adrenoleukodystrophy. Note loss of ganglion cells but preservation of photoreceptors. There is postmortem artifactual detachment of the photoreceptor layer (Hematoxylin and eosin, x40; Reprinted from Wray et a1’66 with permission of the authors and the Ophthalmic Publish- ing Co., Chicago, IL).

and there were no other anterior segment abnor- fuscinosis.g6~‘50 When hearing loss is present, they malities. The optic nerves exhibited waxy pallor may be labelled “Usher’s syndrome.” The correct with marked attenuation of the retinal vessels (Fig. diagnosis can now be made, as with Zellweger syn- 4). Pigment was clumped and scattered through- drome, by demonstrating the plasma abnormalities out the retinal mid-periphery; the perifoveal area shared by the peroxisomal biogenetic disorders. was markedly depigmented. The electroretinogram 3. Infantile Refsum’s Disease showed the cone and rod responses to be decreased 95 to 98% (Fig. 5). Infantile Refsum’s disease is the least severe of The pathologic findings of neonatal adrenoleu- the peroxisome biogenesis disorders, and was first kodystrophy in the central nervous system are simi- described in 1982 by Scotto et a11z6and Boltshauser lar to those of Zellweger syndrome.’ Ocular patho- et al.” They observed patients presenting in the logic findings are confined to the posterior segment first year of life with pigmentary retinopathy, neu- but otherwise are identical to those described in rosensory deafness, growth and mental retarda- Zellweger syndrome22~38 (Fig. 6A). Characteristic bi- tion, hepatomegaly, and mild facial dysmorphism leaflet inclusions are present in the adrenal cortex, consisting of epicanthal folds, flat nasal bridge, and pigment epithelial cells, photoreceptor cells, and retinal and vitreous macrophage? (Fig. 6B). The link to the peroxisome came first in 1982, when Brown et alI4 demonstrated deficient peroxisomal very-long-chain fatty acid oxidation in tissues from neonatal adrenoleukodystrophy patients. Then in 1985, Goldfischer et a14’ discovered that peroxisomes are significantly reduced in number and size in neonatal adrenoleukodystrophy patients. It has since been learned that neonatal adrenoleukodystrophy patients share the biochemical aberrations found in Zellweger syndrome patients, except that neonatal adrenoleukodystrophy shows increased serum levels of saturated very-long-chain fatty acids,63 but normal or reduced levels of mono-unsaturated very-long-chain fatty acids.67 Neonatal adrenoleukodystrophy should be re- garded clinically as a mild form of Zellweger syndrome. Patients frequently survive the years of infancy, show no dysmorphic features, and have Fig. 8. Fundus photograph from a 2% year old girl with markedly diminished vision. Because of the retinal Primary hyperoxaluria Type 1 demonstrating confluent, findings, they may initially be diagnosed as having black, subretinal parafoveal ringlets and white fibrosis “Leber’s congenital amaurosis”” or suspected of (Reprinted from Small et a1’33 with permission of the having the infantile form of neuronal ceroid lipo- authors and the American Medical Association). THE PEROXISOME AND THE EYE 361

low set ears. Increased serum levels of phytanic acid 1. Rhizomelic Chondrodysplasia Punctata led them to surmise that these patients suffered In 1914, Conradi described chondrodysplasia from an infantile form of Refsum’s disease, despite punctata as a condition marked by stippling foci of the fact that adult patients with Refsum’s disease do calcification in the epiphyses.24 In 1971 Spranger et not have facial dysmorphism or cognitive impair- al”’ delineated the rhizomelic form of chondrodys- ment. plasia, known as rhizomelic condrodysplasia punc- Although microphthalmia, strabismus, and nys- tata, characterized by autosomal recessive inheri- tagmus have been described, the most consistent tance, shortening of the proximal extremities, ophthalmic abnormalities are retinal arteriolar at- dermatitis, psychomotor retardation, cataracts, and tenuation and mottled pigmentation of the retina death usually before the end of the first year. Rhizo- with prominent loss of perifoveal pigment.‘“’ The melic chondrodysplasia punctata was shown to be a electroretinogram demonstrates severely reduced peroxismal disorder by Heymans et a1.52 They not- rod and cone mediated responses. ed the striking clinical similarities of rhizomelic The pathologic manifestations of infantile Ref- chondrodysplasia punctata to Zellweger syndrome, sum’s disease have been documented in only one then discovered a deficiency of plasmalogen synthe- case study by Torvik et al, 14’who noted micronodu- sis and elevated levels of phytanic acid which are lar liver cirrhosis and hypoplastic but nonatrophic indicative of peroxisome dysfunction. adrenal changes. The central nervous system Rhizomelic chondrodysplasia punctata is to be showed severe hypoplasia of the cerebellar granu- distinguished from Conradi-Hunermann chondro- lar layer and reduction of axons and myelin in var- dysplasia, which is an autosomal dominant disease ious areas including the optic nerves. Large num- with a normal life span and normal intellect. It is bers of perivascular macrophages with bilamellar not a peroxisomal disorder. inclusions were present in these areas, but no active Ocular findings in patients with rhizomelic chon- demyelinative process was seen. There was neuro- drodysplasia punctata include alternating esotro- nal loss in all layers of the retina. pia, lateral gaze nystagmus, and wandering eye Shortly after infantile Refsum’s disease was first movements. 74 However, cataracts are the most described, further biochemical studies indicated prominent and debilitating ophthalmologic mani- that phytanic acid accumulation was not the only festation_3*48*74*11g abnormality. Excessive tissue amounts of very-long- A characteristic radiographic manifestation of chain fatty acids, pipecolic acid, and bile acid inter- rhizomelic chondrodysplasia punctata is irregular mediates were discovered,‘6*gs*gg overlapping those calcification (stippling) of the cartilage of the ex- of the biogenetic peroxisomal disorders, Zellweger tremities.9’37’197 Primary ossification centers may be syndrome and neonatal adrenoleukodystrophy, absent in the lower femur, and histologically abnor- but much less severe. Several investigators have mal chondrocytes are observed.“’ Clefting of verte- now reported a deficiency of peroxisomes in tissues bral bodies, cerebral hypoplasia, and reduced neu- from infantile Refsum’s disease patients.6*g”“5*‘5s rons in the cerebrum, cerebellum, medulla, and spinal cord have also been reported.74 Ocular pathologic features consist of bilateral B. PEROXISOMAL DISORDERS RESULTING anterior capsular cataracts containing acid muco- FROM MORE THAN ONE ENZYME DEFICIENCY polysaccharides, posterior lenticonus, posterior Rhizomelic chondrodysplasia punctata is cur- embryotoxon, and hypoplasia of the choroid and rently the only disorder in this category. There is ciliary body. 74The cataracts are believed to be histo- defective plasmalogen synthesis, phytanic acid oxi- chemically similar to the usual anterior capsular dation, and abnormal processing of the peroxisom- cataract.48*74*“g Hypoplasia of retinal ganglion cells, al enzyme thiolase. Unlike the peroxisome biogene- nerve fibers, and optic nerve may also be present.74 sis disorders, peroxisomes are present but may be C. PEROXISOME DISORDERS RESULTING abnormal.5’ Due to perturbed synthesis, plasmalogen levels FROM A DEFICIENCY OF A SINGLE ENZYME are profoundly reduced and are lower than in Zell- X-linked adrenoleukodystrophy and primary hy- weger syndrome. 5p,57Phytanic acid levels are in- peroxaluria type 1 appear to result from a deficien- creased and are comparable to those seen in classi- cy of a single peroxisomal enzyme. Although classical Refsum’s disease.5’ However, pipecolic acid, bile cal Refsum’s disease is also frequently attributed to acid intermediates, and very long chain fatty acid a single peroxisomal enzyme deficiency, definitive levels are normal in rhizomelic chondrodysplasia evidence is lacking. punctata, indicating that some peroxisomal func- The biochemical perturbation observed when the tions are intact. peroxisome disorder is caused by a single faulty en- 362 Surv Ophthalmol 35 (5) March-April 1991 FOLZ, TROBE

zyme is much more limited than in the peroxisome disorders, X-linked adrenoleukodystrophy shows biogenesis disorders. One such example is the very- very severe and focal demyelination, most marked long-chain fatty acid build-up in X-linked adrenoleu- in the parietal and occipital lobes. Perivascular lym- kodystrophy because of deficient lignoceroyl-CoA phocytes are abundant; neurons appear normal. synthetase (an acyl-CoA ligase).50~73~‘2g~‘60~162Primary There are characteristic striated inclusions in hyperoxaluria type 1 results from a deficiency of Schwann cells, testis, brain, and adrenal cortex the peroxisomal enzyme alanine: glyoxylate amino- which represent cholesterol esters of very-long- transferase and manifests increased serum levels of chain fatty acids.62,10',1O2~103~122 glyoxalate and oxalate. 26*86Classical Refsum’s dis- Because these changes are occurring in children ease results from defective phytanic acid oxidation, who are old enough to have myelinated their cere- a consequence of deficient phytanic acid alpha-hy- brum, the contrast between normal and abnormal droxylase.31f5g However, this reaction has not yet areas is striking. It can be imaged with CT and MRI, been localized to the peroxisome. which vividly demonstrate forward progression, from occipital to frontal lobes, of areas of low signal 1. X-Linked Adrenoleukodystrophy intensity surrounded by a “torch-like” rim of high In 1923 Siemerling and Creutzfeldt first recog- signal intensity, reflecting breakdown of the blood- nized a disorder that manifested adrenal hypofunc- brain barrier.g” Impressed by the intensity of this tion and cerebral demyelination.1”8 Because the surrounding inflammatory response, observers have children appeared tanned due to adrenal dysfunc- wondered if some other disease mechanism besides tion, and their post-mortem brains and spinal cords metabolic dysfunction is at work. showed demyelination with gliosis, the authors Ocular pathologic studies show loss of the gangli- called the condition “bronzed sclerosing encepha- on cell layer151~166(Fig. 7), and atrophy and gliosis of lomyelitis.” The condition was later named “adre- the nerve fiber layer and optic nerve.” Bileaflet- noleukodystrophy,” and was found to have X- bearing macrophages have been found in the optic linked inheritance.77*85z86 nerve in one case. 23 Unlike the peroxisomal biogen- There are two predominant phenotypes associat- etic disorders, the outer retina remains histological- ed with X-linked adrenoleukodystrophy: a child- ly normal. hood form, in which visual loss is a prominent fea- Although X-linked-adrenoleukodystrophy is the ture, and an adult form, called adrenomyeloneurop- most common peroxisomal disorder, it was not un- athy, in which color vision deficits have been the til 1976 that Igarshi et a16* demonstrated that there only reported ophthalmologic disturbance.12’ In is an accumulation of very-long-chain fatty acids the childhood form, the first symptoms usually be- present as cholesterol esters in the brain and adre- gin mid-way through the first decade, with emo- nal tissues from X-linked adrenoleukodystrophy tional lability and hyperactivity. “Attention deficit patients. The definitive connection came in 1984, disorder” is usually diagnosed, but cognitive de- when Singh et al 130,‘3’showed that very-long-chain cline soon sets in, followed by loss of sight and hear- fatty acid oxidation is localized to the peroxisome ing, incoordination, and spastic quadriparesis. Ad- and that X-linked adrenoleukodystrophy results renal hypofunction is present in nearly all cases, but from its interruption. Since then, the specific bio- may precede or follow neurologic signs.‘23 Death chemical defect has been identified as a deficiency usually supervenes within a decade of onset. of the peroxisomal enzyme lignoceroyl-CoA synthe- The visual loss in X-linked adrenoleukodystro- tase,50 the first enzyme in the very-long-chain fatty phy appears to result from demyelination of any or acid oxidative pathway, and one that is embedded all portions of the visual pathway, from optic nerve in the peroxisomal membrane. This leads to very- to visual cortex.‘65*166 A delayed, broad, low ampli- long-chain fatty acid accumulation, the only distin- tude visual evoked response that becomes extinct guishing biochemical abnormality of X-linked with time and a normal electroretinogram15’,‘65 are adrenoleukodystrophy. The pile-up of very-long- consistent with neural visual pathway damage that chain fatty acids, as dramatic as it is, may not be the spares the outer retina. explanation for neurologic dysfunction, since the The central nervous system pathology of X-linked degree of dysfunction is poorly correlated with the adrenoleukodystrophy bears superficial resemblance levels of very long chain fatty acids.*‘j to that seen in Zellweger syndrome and neonatal X-linked adrenoleukodystrophy should be sus- adrenoleukodystrophy, but there are fundamental pected in boys aged under ten years who exhibit differences.67s123 As in the biogenetic peroxisomal hyperactive behavior and psychomotor regression disorders, there are macrophages filled with bileaf- together with visual loss. Ophthalmologic findings let inclusions scattered throughout the demyelinat- include cortical blindness and optic atrophy. The ing regions. But unlike the biogenetic peroxisomal diagnosis is made definitively by finding elevated THE PEROXISOME AND THE EYE 363 plasma levels of very-long-chain fatty acid. TABLE 3 The current treatment of childhood X-linked Pigmentary Retinopathy in Inborn Errors of Metabolism of adrenoleukodystrophy consists of replacement of Infancy or Childhood (Adapted from Batemun et a15) adrenal steroids and dietary restrictions of fatty Lysosomul disorders acid intake. It has been shown that plasma levels of Mucopolysaccharidosis very-long-chain fatty acid can be reduced to nor- Mucolipidosis mal levels by special dietary manipulation,629”3 but Fucosidosis Neuronal ceroid lipofuscinosis there is no evidence that this will induce improve- Abetalipoproteinemia ment or even stabilization of the disease. Immu- Aminoacidopathies nosuppression, used in an attempt to reduce the Cystinosis “inflammatory” component of X-linked adrenoleu- Gyrate atrophy kodystrophy, has been ineffective.” Aubourg et al4 Organic acidopathies Methylmalonic acidemia have reported reversal of neurologic deficits and Multiple sulfatase deficiency brain MRI abnormalities in an eight-year-old boy Mitochondrial disorders treated with bone marrow transplantation. They Kearns-Sayre syndrome hypothesize that the transplanted marrow cells Peroxisomal disorders crossed the blood-brain barrier and supplied the Zeliweger syndrome Neonatal adrenoleukodystrophy missing peroxisomal functions. Infantile Refsum’s disease Classical Refsum’s disease 2. Primary hyperoxaluria Type 1 Primary hyperoxaluria type I There are two types of genetically determined primary hyperoxaluria. Type 1 is an autosomal recessive disorder which results from a deficiency of the peroxisomal enzyme alanine : glyoxylate aminotransferase.26*sg Accumulation of glyoxylate and its conversion to oxalate result in the deposition of cases. oxalate in various tissues, including the eye. Prima- The pathologic features of primary hyperoxal- ry hyperoxaluria type 1 usually becomes manifest uria type 1 consist primarily of renal deposition of during early childhood or adulthood and patients oxalate which causes nephrolithiasis and nephro- present with renal failure or nephrolithiasis.‘33 In- calcinosis. Osteodystrophy has been reported and fantile onset is correlated with more severe features may result in pathological fractures with mild trau- and death due to renal failure. Primary hyperoxal- ma. I3 H Ydrocephalus and mental retardation are uria type 2 results from a deficiency of D-glycerate also rarely seen. 13’ dehydrogenase and is not a peroxisomal disorder. Ocular pathologic findings in patients with pri- Primary hyperoxaluria type 1 causes in a distinc- mary hyperoxaluria type 1 consist of calcium oxa- tive retinal pigmentary disturbance secondary to late crystal deposition in the retinal pigment epithe- deposition of oxalate. Findings are confined to the lium, ciliary body, retina, and ocular muscles.33,42,76, posterior pole and are bilaterally symmetric. Mild ‘*‘Jo’ Crystals of oxalate have also been documented cases show small parafoveal subretinal black ring- in the wall of retinal vessels and all vascularized lets with a bright white or yellow center48,“g,‘33 (Fig. ocular tissues, including the conjunctiva, iris, inner 8). More advanced cases show single large, black, retinal layers (especially ganglion cell layer), optic well-circumscribed central macular lesions with white disc, choroid, and episclera.“j The black pigmented fibrous material deep to the black area and below lesions of primary hyperoxaluria type 1 are be- the sensory retina. These lesions are believed to be lieved to represent retinal pigment epithelium hy- nonprogressive. Surprisingly, visual acuity tends to pertrophy and/or hyperplasia in response to irri- be unaffected by these lesions.‘33 tation by oxalate crystal deposition.76 The white The other manifestation of primary hyperoxal- fibrosis has been postulated to represent subretinal uria type 1 is optic disc pallor which may be secon- neovascularization. Diffuse optic atrophy secondary dary to increased intracranial pressure or to retinal to papilledema may be caused by impeded cerebro- arteriolar occlusion.“’ Of 24 cases followed at a sin- spinal fluid drainage due to oxalate crystal deposi- gle institution, three were noted to have optic disc tion, in as much as Scowens et al’*’ demonstrated pallor. Two of these cases previously had enlarged elevated calcium oxalate levels in the cerebrospinal ventricles, papilledema, and increased intracranial fluid of a patient with primary hyperoxaluria type 1. pressure. ‘33The third had retinal arteriolar attenu- In the past, patients with primary hyperoxaluria ation believed secondary to oxalate deposition in type 1 succumbed to renal failure at an early age. the vessel walls.‘32 Visual acuity was subnormal in all However, renal transplantation is prolonging sur- 364 Surv Ophthalmol 35 (5) March-April 1991 FOLZ, TROBE viva1 and more patients are living long enough to prominent. demonstrate ocular lesions. III. Peroxisomal Disorders and the 3. Classical Refsum’s Disease Ophthalmologist Classical Refsum’s disease, or “heredopathia atac- The peroxisomal disorders must be added to the tica polyneuritiformis” was first described in 1945 list of conditions with inborn errors of metabolism by Refsum, who noted night blindness, pigmentary that present in infancy or childhood with multior- retinopathy, hearing loss, peripheral neuropathy gan dysfunction and retinal abnormalities (Table and ataxia.“‘*‘l’ Other features are an increase in 3). The three peroxisomal biogenesis disorders - the CSF protein level with a normal cell count, car- Zellweger syndrome, neonatal adrenoleukodystro- diopathy, skeletal malformations primarily of the phy, and infantile Refsum’s disease - will manifest metatarsals and metacarpals, and skin changes re- a noncorpuscular pigmentary retinopathy and op- sembling ichthyosis.4’,‘06.‘O7,lOg~~lI,148 tic atrophy. The only peroxisomal disorder caused Classical Refsum’s disease may have its onset by multiple enzyme abnormalities - rhizomelic from the first to the third decade, either with night chondrodysplasia punctata - will present ophthal- blindness, extremity weakness, or ataxia.“’ It runs mologically with cataract. Of the three disorders an indolently progressive course with death often attributable to a single enzyme defect, X-linked caused by cardiac arrhythmia. Present in all cases of adrenoleukodystrophy will usually manifest optic classical Refsum’s disease, the pigmentary retinop- atrophy but the retina will appear normal; primary athy is granular rather than corpuscular, but other- hyperoxaluria type 1 has distinctive posterior pole wise quite like typical retinitis pigmentosa in having retinal findings of black parafoveal ringlets sur- narrowed retinal arterioles, visual fields that show rounding yellow-white patches; classical Refsum’s ring scotomas and progressive constriction, and disease manifests a pigmentary retinopathy similar electroretinography that indicates marked loss of to that of Zellweger syndrome and neonatal adren- rod and cone function.‘06,1’0,148 oleukodystrophy. The ophthalmologist should be The nervous system pathology of classical Ref- aware of the genetic implications of these disorders, sum’s disease involves principally the peripheral that biochemical tests now exist for rapid, even pre- nerves, the spinal cord, and the retina.‘7”8*34’108The natal, diagnosis, 19.46,72.82,64,114,116,117, 125,157,161 and that rods and cones are almost entirely absent, the outer in two disorders (classical Refsum’s disease, X-linked nuclear and outer plexiform layers are completely adrenoleukodystrophy) treatment is available. atrophic, the ganglion cells are reduced in number, the inner nuclear layer is thinned, and the nerve References fiber layer is thickened due to gliosis.‘4s Retinal ves- 1. Arneson DW, Tipton RE, Ward JC: Hyperpipecolic acidemia: Occurrence in an infant with clinical findings of the sels are narrowed and occluded, their walls swelled cerebrohepatorenal (Zellweger) syndrome. Arch Nemo1 39: by lipid material. 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