Tapetoretinal hepato-renal(Zellweger's) · notinfrequently, seizures. Defective liverfunctionis manifested as jaundice and hepatomegaly with, in some cases, hypoprothrombinaemia and

British Journal ofOphthalmology, 1982, 66,422431

Tapetoretinal degeneration in the cerebro-hepato-renal (Zellweger's) syndromeA. GARNER,' A. R. FIELDER,2 R. PRIMAVESI,2 AND A. STEVENS3

From the 'Institute ofOphthalmology, University ofLondon; 2Derbyshire Children's Hospital, Derby;and the 3Department ofHistopathology, University ofNottingham

SUMMARY Electrophysiological and histopathological study of a baby suffering from Zellweger'ssyndrome and presenting progressive retinal dysfunction showed this to be related to degenerativechanges in the photoreceptor cells and pigment epithelium and to defective myelination of the opticnerve. Disturbances of bile acid and lysine metabolism were also demonstrated, lending support tothe concept that Zellweger's syndrome is attributable to a widespread inadequacy of intracellularoxidative function.

The multisystem congenital disorder designated asthe cerebro-hepato-renal syndrome' was first definedas an entity by Zellweger and colleagues in 1964.2Severe dysfunction of the central nervous system isassociated with progressive muscular hypotonia and,not infrequently, seizures. Defective liver function ismanifested as jaundice and hepatomegaly with, insome cases, hypoprothrombinaemia and gastro-intestinal haemorrhage.' Clinical evidence of renalinvolvement in the form of proteinuria is generallyminor, though multiple cortical cysts are a charac-teristic finding at necropsy.3-. A number of otherorgans, including the thymus and pancreas, the lattermanifested as islet cell hyperplasia and hypo-glycaemia,6 may be abnormal, and calcific stippling ofthe bony epiphyses is common.78 Babies affected bythe cerebro-hepato-renal syndrome have a charac-teristic appearance caused by a high forehead and'pear shaped' skull, flat supraorbital ridges,micrognathia, high arched palate, and redundancy ofthe skin of the neck.3 Malformation of the ears,3camptodactyly,3 and other limb deformities are alsowell documented. Death within the first few monthsof life is almost invariable because of progressivecerebral dysfunction, feeding difficulties, and, lessoften, gastrointestinal haemorrhage.3

Ocular disturbance in the cerebro-hepato-renalsyndrome is also frequent and can take a variety offorms. The globes may appear unduly prominent aspart of the overall facial abnormality, enhanced byCorrespondence to Professor A. Gamer, Department of Pathology,Institute of Ophthalmology, 17-25 Cayton Street, London ECIV9AT.

puffiness of the eyelids,3 and nystagmus is a reflectionof brain dysfunction. Defects of the globe per se caninvolve both anterior and posterior segments,presenting variously as corneal clouding, cataract,glaucoma, optic nerve hypoplasia and tapetoretinaldystrophy'" (D. Toussaint, personal communi-cation). However, descriptions of the ocular histo-pathology are relatively few, and in this report wedocument the findings in a baby presenting evidenceof tapetoretinal dysfunction.

Cas history

A female Pakistani baby was born on 2 September1979, the product of a consanguineous marriage.Birth weight was 2340 g following a normal pregnancyand delivery. On the first day an abnormal facialappearance was observed (Fig. 1) due to a high fore-head, epicanthus, and flat supraorbital ridges andbridge of the nose, these latter making the eyesappear to be prominent. Other features includedgross hypotonia, jaundice, hepatomegaly, and pal-pable lobulated kidneys.The eyes were first examined at 3 weeks of age.

Although there was a reaction to light, no followingor optokinetic responses could be elicited. Ocularmovements were full, with jerk nystagmus on lateralgaze. The eyes were of nonnal size, with no discern-ible abnormality of the anterior segments. Pupillaryreactions, intraocular pressures, and optic discs werenormal, but the retinal arteries were attenuated. Ared lesion approximately one-third of the discdiameter in size was seen at the right macula (Fig. 2),

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423Tapetoretinal degeneration in the cerebro-hepato-renal (Zellweger's) syndrome

Fig. 2 Macular region ofthe rightfunduspresentingafocalzone of red pigmentation

dihydroxycoprostanic and trihydroxycoprostanicacids (46% of 5% respectively of the total) andreduced amounts of their related chenodeoxycholicand cholic acid derivatives (7% and 18% respec-

- tively). Liver biopsy showed enlargement of the portaltracts by infiltration with macrophages. Periportalhepatocytes and portal macrophages contained sparse

Fig. I Dysmorphicfacies with high forehead andprominent eyes due to flat supraorbital ridges.

while the left macular region contained a central areaof deep pigment clumping surrounded by a rim ofdepigmentation (Fig. 3).Two siblings, both male, had been born previously. .

The first born in 1973 is alive and well, but the secondborn in 1978 died 5 hours postnatally. Post-mortemexamination revealed renal cysts. There have been no ,miscarriages and there is no further relevant family ':history.

INVESTIGATIONSLiver function tests were consistently abnormal,including serum bilirubin 140 ,tmol/l, lactic dehydro-genase 1346 IU/l, serum glutamic-oxaloacetate trans-ferase 546 IU/I, and serum glutamic-pyruvatetransferase 187 IU/I. Haemoglobin was 20-6 g/dl,white cells 11 7x109/l, and platelets 150xl1O/l. Fig. 3 Macular region ofthe leftfundus with central area ofProthrombin time was normal at 12 s (control 12 s). clumped pigment with a surrounding faint halo ofUrine analysis for bile acids showed the presence of depigmentation.



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A. Garner, A. R. Fielder, R. Primavesi, and A. Stevens

Fig. 4 Electron micrograph of liver biopsy showing punctate intracytoplasmic iron deposits. Uranyl acetate/lead citrate(x6500).

pigment granules. Excess iron was observed inhepatocytes and in portal macrophages (Fig. 4).A pipecolic acid loading test was performed. The

331 ml 24-hour pretest urine specimen contained 24-3mg pipecolic acid, a substance not normally detect-able in urine. Following a 400 mg oral pipecolic acidload the urinary pipecolic acid output increasedbut the a-aminoadipic acid did not, indicatinga metabolic block between pipecolic acid anda-aminoadipic acid.

Ultrasound indicated large cystic kidneys and theintravenous pyelography showed hydronephrosis.With a noncomeal electrode no electroretinogram

(ERG) could be elicited on 3 occasions, whereas witha gold-foil electrode, in contact with the globe, alow-amplitude response was obtained, b wave (a-bpeak to peak) 11 ,uV right and 9 ,uV left. This ERGwas recorded only at 1 month of age, there being nodetectable response at 2 months. The wave form of avisual evoked response (VER) to a flash stimulus at 1month was simple, as compared with that normallyseen at this age (Fig. 5). No consistent VER could beelicited one month later. ERG and VER measure-ments were made with a Medelec MS6 modularelectrophysiological system fitted with a DAV6 digitalyverager.

Over the ensuing 10 weeks the ocular findings, inparticular the red lesion at the right macula, remainedunchanged. The baby failed to thrive, feeding diffi-culties and jaundice persisted, and death frombronchopneumonia occurred at 13 weeks of age.

NECROPSY FINDINGS

Macroscopic abnormalities were seen in the liver,kidneys, and brain. The liver weighed 170 g and had ayellow-green appearance, with histological findingscomparable to those previously described in thebiopsy specimen. Both kidneys were enlarged (com-bined weight 100 g) and had multiple cortical cysts(Fig. 6), which represented mainly markedly dilatedmaldeveloped cortical tubules, as a component of afocally dysplastic renal cortex. The surface of thebrain contained abnormally small and broad gyri(pachymicrogyria) (Fig. 7). The white matter in thecentre of the brain appeared unusually pink. Histolo-gical sections of the brain showed, inter alia, islandsof neurones remaining between the ependyma andcortex, particularly in the temporal lobes; similarchanges of incomplete neuronal migration werepresent in the external granular layer of the cerebel-lum. Myelinisation was less developed for the agethan normal, and in frozen sections of brain stained

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Tapetoretinal degeneration in the cerebro-hepato-renal (Zellweger's) syndrome

FLASH V. E.R.

Fig. 5 Flash VER compared withresults obtainedfrom a normalinfant (lower traces). Thosefromthe case reported here (denoted byCase in thefigure) at 3V2 weeksshow a recognisable waveformwhich is not present at 8 weeks,indicating not only failure ofnormal maturation but alsodeterioration.

I

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Normd v/_both eyes

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with oil red 0 and Sudan black B the commonest cellin the white matter was the swollen astrocyte. Inessence the brain changes were those of delayedneuronal maturation, retarded myelination, andlipid-containing astrocytes.

Ocularpathology. Neither eye showed any externalabnormality, but owing to a delay of several hoursbefore fixation in formalin both showed some pucker-ing and folding of the retina around the macula.

Light microscopy. There was no apparent abnor-mality of the comeoscleral envelope in either eye,and the angles of both anterior chambers were

normally formed and patent. The lens and ciliarybody in both eyes were normal, and the sole finding ofnote in the anterior segments was generalised lacyvacuolation of the pigment epithelium of the iris. Theretinae had suffered considerable autolysis withartefactual detachment, but even in places whereseparation had not occurred there was unmistakableloss of photoreceptor outer segments affecting chieflythe rods (Fig. 8). Atrophic flattening of the retinalpigment epithelium was widespread, with focaldeficiencies and migration of occasional cells away

from their attachment to Bruch's membrane (Fig. 9).Small amounts of necrotic debris were also present

Fig. 6 Multiple cortical cysts in the bisected kidneys.

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A. Gamer, A. R. Fielder, R. Primavesi, and A. Stevens

Fig. 7 The surface ofthe brain ischaracterised by both unusuallysmall and large gyri to create a'cobblestone' appearance.(x0- 125.)

between the degenerate epithelium and photo-receptor cells. The inner layers of the retinae were notnoticeably abnormal and showed a conventionalorganisation. Both optic discs showed an overlyingBergmeister's papilla, while the optic nerve were sitesof extensive demyelination and some gliosis.

Electron microscopy. A piece of retina and choroidfrom the perimacular zone of the right eye was post-fixed in buffered glutataldehyde for transmissionelectron microscopy. Many of the photoreceptor cellswere completely degenerate and were represented by

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Fig. 8 The retina close to the optic disc shows an essentiallynormal organisation, but there is almost total loss ofthephotoreceptor outer segments and migration ofan atrophicpigment epithelium. (Haematoxylin and eosin, x 114.)

sparse debris, some of it in the form of multilaminatedmyelin figures (Fig. 10). Others had shed most, if notall, of their outer segment discs, and the inner seg-ments showed considerable loss of mitochondria withexposure of the ciliary roots. Residual mitochondriain these degenerate cells were frequently swollen withring and other abnormal cristae. No abnormality wasrecognised in other layers of the neuroretina. Thepigment epithelium was flattened and some cells con-tained somewhat less melanin than normal. A generalloss of microvillous processes on the inner surface ofthe epithelium was observed. Some pigment-contain-ing cells were lying free in the subretinal zone andexceptionally included unusually angulated bodiesof moderate electron density presumed to bepremelanosomes (Fig. 11).

Fig. 9 The retinal pigment epithelium isflattened and somemelanin-containing cells are intermingled with necroticphotoreceptor cell debris in the subretinal space.(Haematoxylin and eosin, x 114.)

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Tapetoretinal degeneration in the cerebro-hepato-renal (Zellweger's) syndrome 427

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Fig. 10 Electron microscopy of the degenerate photoreceptor outer limbs reveals multilaminatedresidues and unusual prominence of the ciliary roots (arrow) due to relative sparsity ofmitochondria.(Uranyl acetate/lead citrate, x6685.)



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A. Gamer, A. R. Fielder, R. Primavesi, and A. Stevens

Fig. 11 The retinal pigment epithelium is flattened with absence of villous processes and incipientdetachmentfrom Bruch's membrane. A detached cell on the innersurface ofthe epithelialmonolayercontains several curious angular bodies presumed to be defective and minimally pigmentedmelanosomes. (Electron micrograph, uranyl acetatelead citrate, x6662.)

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Discussion

The combined clinical and pathological findings inour case adequately substantiate the diagnosis ofZellweger's or cerebro-hepato-renal syndrome as

defined in the reports establishing the nosologicalidentity of the condition.`The most extensively studied changes concern the

brain which, to external examination, presents eitheran excessive number of small gyral infoldings (poly-microgyria)5 1617 or a combination of small denselypacked and unusually broad gyri (pachymicro-gyria).39'0 Histological examination shows changessuggestive of arrested maturation manifested asincomplete migration of cortical neurones and defec-tive myelination of nerve fibres in the white matterwith secondary gliosis, which may be associated withthe accumulation of sudanophilic material in thephagocytic elements of the central nervous system. '

The latter have been termed globoid cells, and elec-tron microscopy suggests that they contain multi-laminated cytoplasmic bodies.9 16 Whether thedeficiency of myelin and consequent reduction involume of the white matter is a primary fault insynthesis" or, as is perhaps more likely, a destructiveprocess9 1016 is unresolved. The dysplasia affects thecerebellum and brain stem structures such as themedullary olives9 1 in addition to the cerebrum.The hepatic disturbance can assume a variety of

forms but according to most reports presents as mildenlargement related to diffuse parenchymal celldamage and intralobular fibrosis.8 Cholestasis andportal fibrosis characterise some infants'8 and, as inthe present case, iron deposition may be found.3468The origin of the liver disorder is obscure but ispossibly secondary to metabolic abnormalities818rather than to a primary maldevelopment.

Multiple cysts in the renal cortices are an integralpart of the syndrome, some representing dilatedBowman's spaces around glomerular remnants389 19

with surrounding fibrosis45 and others, as here, beingthe result of tubular dilatation58 caused by focaldysplasia of the cortex.Although the character of the involvement may

vary, ocular involvement in the cerebro-hepato-renalsyndrome is common. Nystagmus features in mostcases and is likely to be neurological rather thanocular in origin, particularly as in our case it was

observed at only 3 weeks of age and then only on

lateral gaze.Abnormalities of the anterior segment include

corneal clouding349I1'1214 which may be associatedwith raised intraocular tension" 12 or iridocornealadhesion and deficiency in the endothelial lining ofDescemet's membrane. 14 Bilateral congenitalcataracts are not uncommon,1349 14 15 1820 and, while

it does not explain their occurrence, their presence inZellweger's syndrome with its attendant articularcartilage calcification invites comparison withchondrodystrophia calcificans congenita (Conradi'ssyndrome), in which lens opacities are usual.2'Alternatively the concomitance of renal tubulardysfunction, brain abnormalities, and cataracts inboth Zellweger's syndrome and Lowe's (oculo-cerebrorenal) syndrome22 may be significant. Arecent report'" suggests that heterozygotes also maydevelop comparable lens opacities. A single report ofBrushfield's spots in the iris3 may be purely coinci-dental, as may the finding of persistent Bergmeister'spapillae in the present case. The pathogenesis of theglaucoma complicating some cases"''-2 is unknown.The vacuolation of the iris pigment we describe hasnot been commented on in other reports, and, thoughcharacteristic of the eye in diabetes mellitus andHurler-Hunter forms of mucopolysaccharidosis, itcan from personal experience sometimes present as anonspecific finding in many states linked withmetabolic dysfunction.With the knowledge of ocular and visual pathway

histopathological findings it is interesting to considerthe possible significance of the electrophysiologicalinvestigations made at various times during life. TheERG (gold-foil electrode) at one month of age with ab wave amplitude of the order of 10 ,uV was grosslyreduced even allowing for age23 and below thesensitivity of the noncorneal electrode, thus explain-ing our failure to demonstrate an ERG using thismethod. The absence of an ERG one month latercould have been due to progression of the patholo-gical process, and it is significant that the ERGs wereabsent in each of4 cases examined by Hittner and hercolleagues'5 after a minimum of 2 months' survival.The VER at 1 month ofage was present but abnormal,and although a large negative wave was always seen at300 ms the preceding positive wave (200 ms), aprominent component of the normal response, was ofreduced. amplitude. One month later no consistentVER could be demonstrated clearly confirming thatin Zellweger's syndrome degenerative features aresuperimposed upon a distinct malformation.The macular regions of the 2 eyes of our case

exhibited different features. It would be interesting toknow whether the pigmentary disturbance we obser-ved at the left macula was the same as the retinal holewithout detachment in the second case reported byOpitz et al.3 The slightly raised red lesion at the rightmacula was assumed to be a haemorrhage, but, unlikea haemorrhage, no change in its shape or colouroccurred over 10 weeks of observation. It should alsobe noted that in our case there was no bleedingdiathesis. Unfortunately due to retinal distortion themacular regions could not be identified histologically.

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Posterior segment abnormalities of the kind seen inthe present case may be an extension of the anomal-ous central nervous system development. The firstreport of sensory disturbance was that of Punnett andKirkpatrick," the child they documented beingunable to follow light at the age of 4 months andpresenting a fundus appearance characterised byhypoplasia of the optic disc and pigmentary disturb-ance. Subsequent authors described attenuation ofthe retinal vasculature'013 and absence of electro-retinogram response.9 13 The first histological descrip-tion of retinal pathology appears to have been that byVolpe and Adams, ' wherein they referred toabnormal clumps of pigment epithelium in theperipheral retina associated with reduced numbers ofphotoreceptor and ganglion cells. Haddad and col-leagues'4 described atrophy and gliosis of the opticnerve and retinal nerve fibre layer as well asdegeneration ofthe photoreceptor cells in the maculararea. The findings in our own case confirm the outerretinal and optic nerve abnormalities. In retrospect itis surprising that the pupillary reactions were pre-served and that there was no dilatation such as iscommonly seen in bilateral optic nerve disease. Thesequence of events at the tapetoretinal level isobscure, but the relative sparing of the pigmentepithelium in a four day old neonate'4 suggests thatthe primary defect is in the neuroretina. Toussaint(personal communication) undertook a detailedexamination of the ocular tissues in an affected babydying at the age of 7 weeks, and here also the degen-erative changes in the photoreceptor outer segmentsappeared to outweigh the disturbance of the pigmentepithelium. The absence of myelin in the optic nerveat the age of 3 months, as pertained in the presentcase, is abnormal and was probably a reflection of thedefective myelination which characterises the brainabnormality in Zellweger's syndrome.The fundamental fault in the cerebro-hepato-renal

syndrome is unknown, but there is increasingevidence of a recessively inherited autosomal genedefect.358 It has been suggested that the same defec-tive gene could, by acting at sequential stages indevelopment, be responsible for both the develop-mental abnormalities and the metabolic disturbancesseen in the syndrome.916The first metabolic derangement to be described

was excessive iron binding by the tissues as demon-strated by electron microscopy in the liver of thepresent case.324 But this is not a constant finding, andmore recently the deposition of iron has beenattributed simply to impaired utilisation in associationwith a failure to thrive and depressed erythropoieticactivity.68 So far as the eye is concerned iron has beendemonstrated in the epithelium of the cornea andciliary body (nonpigmented) by Volpe and Adams,'0

but others, 4 including ourselves, have obtainednegative results.

Accumulation of pipecolic acid in Zellweger'ssyndrome, such as was demonstrated in the presentcase, was first described by Danks and others8 andsince confirmed by Trijbels and colleagues,25 althougha similar disorder presenting a little later in infancyassociated with hyperpipecolataemia had alreadybeen documented.26 Pipecolic acid originates fromthe breakdown of lysine through a subsidiarymetabolic pathway and is normally present in theblood in trace amounts only: its role in the symptoma-tology of Zellweger's syndrome is obscure, althoughan amine derivative, piperidine, can produce braindamage in mice,27 and studies in rats indicate that thepipecolic acid pathway is the principal mode of lysinecatabolism in the nervous system.28

Defective oxidation of bile acid precursors to cholicand chenodeoxycholic acids such that intermediaryproducts are detectable in the serum and urine hasalso been described.'829 The finding of dihydroxy-and trihydroxy-coprostanic acids in the urine of thepresent case, the former accounting for almost halfthe urinary bile acid excretion, is in keeping withthese reports. It is possible that these and other bileacid precursors are toxic to liver cells and account forthe cellular damage in this organ.'8To explain the widespread metabolic disturbances

in Zellweger's syndrome it has been proposed thatthere is a generalised disorder of oxidative functioncaused by defective mitochondrial and peroxisomalactivity, Goldfischer and colleagues30 having earlierdescribed structural and functional anomalies in theseorganelles. Abnormal morphology of mitochondrialcristae was seen in the retinal photoreceptors in thepresent case, but it remains to be seen whether suchalterations are more than a nonspecific degenerativeproduct.

We thank Dr T. L. Chambers, paediatrician in charge of the patient,for permission to publish this report. Our gratitude is due to Dr D. A.Howell of the Derbyshire Children's Hospital for the neuropathologyfindings, to Dr Anne Green of the University of Sheffield forthe pipecolic acid measurements, and to Dr G. M. Murphy of Guy'sHospital, London, for the urinary bile acid analysis. The technicalassistance of Mr R. A. Alexander and Mr R. C. Howes, andsecretarial help provided by Mrs P. Goodwin is also acknowledged.

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3 Opitz JM, Zu Rhein GM, Vitale L, et al. Birth Defects 1969; 5:144-58.

4 Sommer A, Bradel EJ, Hamondi AB. The cerebro-hepato-renalsyndrome (Zellweger's syndrome). Biol Neonate 1974; 25:219-29.

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25 Trijbels JMF, Monnens LAH, Bakkeren JAJM, Van Raay-Selten AHJ, Corstiaensen JMB. Biochemical studies in thecerebro-hepato-renal syndrome of Zellweger: a disturbance inthe metabolism of pipecolic acid. J Inher Metab Dis 1979; 2:39-42.

26 Gatfield PD, Taller E, Hinton GG, Wallace AC, Abdelnow GM,Haust MD. Hyperpipecolatemia: a new metabolic disorderassociated with neuropathy and hepatomegaly. A case study. CanMed Ass J 1968; 99: 1215-33.

27 Kase Y, Miyata T, Kamikawa Y, Kataoka M. Pharmacologicalstudies on alicyclic amines II. Central actions of piperidine,pyrrolidine and piperazine. Jpn J Pharmacol 1969; 19: 300-14.

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29 Hanson RF, Szczepanik-Van Leeuwen P, Williams GC,Grabowski G, Sharp HL. Defects of bile acid synthesis inZellweger's syndrome. Science 1979; 203: 1107-8.

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Tapetoretinal hepato-renal(Zellweger's) · notinfrequently, seizures. Defective liverfunctionis manifested as jaundice and hepatomegaly with, in some cases, hypoprothrombinaemia and