Arch. Dis. Childh., 1964, 39, 634.

TAY-SACHS DISEASE WITH VISCERAL INVOLVEMENTAND ITS RELATION TO GARGOYLISM

BY

R. M. NORMAN, A. H. TINGEY, C. G. H. NEWMAN, and SHIRLEY P. WARDFrom the Burden Neuropathological Laboratory, Frenchay Hospital, Bristol,

the Institute of Child Health, Birmingham UniversitY, and the Staffordshire General Infirmarv

(RECEIVED FOR PUBLICATION MAY 12. 194)

There is an accumulation of clinical, neuropath-ological, and chemical evidence pointing to the clearseparation of Tay-Sachs disease from other forms ofamaurotic family idiocy. One point of distinction isthe rarity of visceral lipidosis in the infantile form ofthe disease. We have, in fact, only been able to findreference to five cases of Tay-Sachs disease in whichthe neuronal lipidosis was associated with signs of amore generalized storage disease, and in some ofthese the evidence is not very convincing. Davisonand Jacobson (1936) reported foam cells in the spleen,and vacuoles containing sudanophil lipid in the cellsof the liver and renal tubules. Brouwer (1936) alsofound foam cells in the spleen of his case. Marburg(1942) described vacuoles in the liver which werefilled with lipid staining in the same way as that in thenerx c cells. This case was unusual because of thesevere atrophy and fibrosis of some of the otherglandular organs. It is difficult to assess thesignificance of these changes as part of a primarylipidosis, and it is certainly unlikely that the lipid inthe organs of these three cases was chemicallyidentical to that stored in the neurones. The brainin Tay-Sachs disease stores large amounts ofganglioside, and an essential component of thissubstance is neuraminic acid. Neuraminic acid isnot normally present in the spleen, liver, or kidneys,so that an accumulation of ganglioside would not beexpected to occur in these sites as the result ofderanged local metabolism. On the other hand, it iswell known that in certain lipidoses there may bedifferences between the substances or mixtures ofsubstances that are stored in the brain and in theviscera. In gargoylism the nerve cells contain anincreased amount of ganglioside (though usuallymuch less so than in Tay-Sachs disease), while theother affected organs predominantly store poly-saccharides. The latter material is readily diffusable,so that the involved tissues, after ordinary fixation,

are characterized histologically by the presence ofempty vacuoles.

There are two recorded examples of undoubtedTay-Sachs disease, in which a similar change hasbeen found in some of the visceral organs. Turban(1944) described a non-Jewish child who died at theage of 2 years after a progressive neurological illness.The characteristic cherry-red spot at the macula hadbeen noted. Analysis of the cerebral cortex byKlenk showed a fivefold increase in ganglioside, andhistologically the brain was typical of Tay-Sachsdisease. Empty vacuoles were a conspicuous featureof the cells of the liver and renal tubules, and foamcells, also devoid of lipid, were present in thepulmonary alveoli and their walls. More extensivevisceral involvement of the same type was describedby Norman, Urich, Tingey, and Goodbody (1959) intheir case of infantile amaurotic idiocy. This childhad shown typical macular changes and also camefrom a non-Jewish family. There was hepatomegalyand slight enlargement of the spleen. Emptyvacuoles were present in the parenchyma of the liver,kidney, pancreas, and thyroid. Empty foam cellswere numerous in the liver, spleen, lymph nodes,thymus, intestines, bone-marrow, and lungs, both inthe alveoli and their septa.The case to be reported in this paper is a further

example of this unusual combination of neural andvisceral lesions in a chemically verified case ofTay-Sachs disease. Additional interest is given bythe detailed clinical examination which was made ata time when hypotonia was the main neurologicalabnormality.

Case ReportClinical Finding This child (J.C.) was first referred

under the care of Professor D. V. Hubble in December1960, for investigation of motor and mental retardation,first suspected three months previously, at the age of 9months. She was the first child of normal parents, with a

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TA Y-SACHS DISEASE AND GARGO YLISMnegative family history. Delivery was by forceps, fordisproportion. Birth weight, 8 lb. 11 oz. (3,939 g.).The neonatal period was uneventful, but she was noted

to be lethargic before leaving the maternity hospital.There were no feeding difficulties. Vaccination, whoop-ing cough, and diphtheria immunization and B.C.G. weretolerated normally.When seen at the age of I year, her condition was as

follows. Weight was 24 lb. 4 oz. (11 kg.), on the 90thpercentile; length, 32 5 in. (82 5 cm.), above the 97thpercentile; and head circumference, 19 5 in. (49 4 cm.),above the 97th percentile. The skull showed a metopicridge. She was said to respond to her parents, and wasseen to smile, chuckle, and cry. There had been noconvulsions, but twitching affecting all limbs was observedonce.

Sight examination revealed that she followed brightobjects. The pupils were small, but reacted briskly tolight. She blinked in reaction to a loud noise, but showedno other reaction.

Examination of the cranial nerves revealed that the opticdisks appeared normal; the retinae were somewhat pale;the right macula was noted to resemble a Koplik spot, inthat there was a central pale point surrounded by a zonepinker than the adjacent retina. No cranial nerve palsieswere present, but there was a suggestion of ptosis. Therewas a marked hypotonia of neck, trunk, and limbs. Thetendon jerks, however, were brisk, and there wereequivocal plantar responses and positive finger jerks(thumb adduction). Abdominal reflexes could not beobtained. There was also abnormal persistence of someneonatal reactions, such as tonic neck reflexes, palmargrasp, lateral trunk incurvation, and a modified Mororeflex. Voluntary movements were weak, of lowamplitude, and appeared non-purposive. The muscleswere flabby but not wasted. There was no fasciculation.

Painful stimuli produced a weak withdrawal responseand cry.Other findings included two cafe au lait spots on the

trunk.Respiration was normal, and there was no chest

deformity nor other abnormality. There was noapparent enlargement of lymph nodes, liver, or spleen.An ekctroencephalograwn (Dr. B. D. Bower) consisted

mainly of well-organized theta activity which wassymmetrical and of normal amplitude. There was alsolow amplitude fast activity. It was thought that therecord was normal.

Cerebrospinalfluid (lumbar puncture) yielded one whitecell per c.mm.; protein 35 mg./100 ml.; sugar 64 mg./100ml. Cerebrospinal fluid (ventricular puncture) yielded2 lymphocytes, 2 fed cells per c.mm.; protein 20 mg./100ml.; sugar 57 mg./100 ml. Skull radiograph was normalin appearance, as was the air encephalogram (Dr. R.Astley). Urinalysis gave albumin 10 mg./100 ml. only;very occasional dead white cell, and numerous epithelialcells. Amino acid excretion was normal. Negative testfor phenylpyruvic acid. Xanthurenic acid excretion aftertryptophan load (Dr. B. D. Bower) was normal (increaseof 3 -8 mg. over 24 hours). Tests for toxoplasmosis werenegative.

Since the investigations were negative, a provisionaldiagnosis of hypotonic cerebral palsy with mentalretardation and possible special sense impairment wasmade.The later stages of the illness were marked by a rapid

deterioration in the child's clinical condition. Shebecame almost amental, lying motionless, and notfollowing objects with her eyes. There were no tonicspasms. Death occurred from bronchopneumonia whenshe was 2 years old.

Necropsy. External examination revealed a well-nourished female child.

INTERNAL EXAMINATION. The brain was normal in sizebut grossly oedematous with distended dural sinuses andmarked congestion of the vessels of the arachnoid and piamatter. The mucosa of the trachea and bronchi wascongested and covered by thick purulent mucus. Thelung tissue showed patchy bronchopneumonic consolida-tion. The heart was normal. The liver, spleen, andkidneys were congested but otherwise normal and therewas no lymphadenopathy.

FIG. I.-Lung: foam cells in the alveolar septum (H. and E. x 240.)

HIsroLoGy. Numerous foam cells were present both inthe walls and lumina of the lung alveoli (Fig. 1). Exudateand pus cells filled many of the alveoli and small bronchi,and there was inflammatory infiltration of the interstitiallung tissue. T'he lobular pattem of the liver was preserved

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NORMAN, TINGEY, NEWMAN, AND WARD

a W FWZr & -ILFiG. 2.-Liver: lrge singlc vacuoles are present in many of the cells

(H. and E. x 405.)

FIG. 3.-Kidney: vacuolatio of the colecting tubues. (H. and E-x 240.)

'a.

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lte';,_'< Lb; ;-2 ;S

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FIG. 5.-Cerebral cortex: th nere cells are filled with haematoxyphillipid. (Kutschitsky-Pal. x 3 1.)

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FIG. 4.-Pons: nuck-m ccnu-alis.- ballooning of the ncrve ceffs.(Carbol azure. - 240.)

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TA Y-SACHS DISEASE AND GARGO YLISM

FIG. 6.-Psaamen: gla fibrils surround the swotlen nerve cell.(HoIZr. - 267).

and there was marked congestion. Many of the liver cellsshowed a large central vacuole (Fig. 2). There was markedvacuolation of the epithelial cells of the collecting tubulesand of many of the convoluted tubules of the kiwey(Fig. 3). The normal splenic structure was maintained.

Examination of the Brain

Blocks of tissue were available from parts of thecerebral cortex, the anterior part of the corpus striatumincluding the internal capsule and corpus callosum, andfrom the pons. Frozen sections were stained by standardmethods for nerve cells, axis cylinders, myelin, fibrousneuroglia, and lipid.

Nerve Cells. In all parts of the brain that were

available for examination, the nerve cells were greatlydistended with a granular material, the nuclei in pyramidalcells usually being displaced towards the apical dendrite(Fig. 4). Neurofibrils could not be demonstrated in themajority of the cortical nerve cells but in some of the lessswollen ones they were present as a thin marginal ring.Large fusiform dendritic expansions containing similargranular material were occasionally seen. The materialstored in the neurones stained crimson with the periodicacid-Schiff (PAS) method, black with the Kultschitsky-Pal method for myelin (Fig. 5), and the same colour as themyelin with Luxol fast blue. With Sudan IV, Sudanblack, and Nile blue sulphate, there was only a very feeblecoloration. Most neurones contained scanty sudanophil

FiG. 7.--Sectionthrough the anteior Part of the lft crpustriatushowing poverty of myein the internal capsule and cingulate gyrus-

(Kultachitsky-Pal. x 2-4.)

granules. The PAS staining was negative or greatlyreduced in intensity after sections had been kept overnightin cold ethyl alcohol, only a light pink colour remainingin some of the larger cells.

Miroglia. Phagocytes filled with closely packedgranules which stained brightly with PAS, Sudan, andNile blue were scattered diffusely through the grey matter.They were numerous in areas in which nerve cell loss hadoccurred, as in parts of the cerebral cortex, and, particu-larly, the griseum pontis. In contrast to the nerve cells,the PAS staining remained strongly positive after treat-ment with alcohol. Small collections of fat granule cellswere seen around vessels in the white matter.

NeurogUa. Fibrous gliosis was a marked feature of thewhole of the grey matter (Fig. 6). In the white mattergliosis was dense in the poorly myelinated areas, particu-larly the internal capsule (Fig. 8), and in the pes pontis.

MyelU. The cores of the cerebral gyri and the deeperwhite matter showed a diffuse reduction in myelinatedfibres. A more severe loss of fibres was found in theinternal capsule (Fig. 7), transverse fibres of the pons, andthe descending cortical tracts. The corpus callosum andthe tracts in the tegmentum of the brain-stem stainednormally.

Cbe-istThe analytical methods used were those described in

previous papers (Tingey, 1959; Tingey and Edgar, 1963).The brain had been fixed in 10bo formol saline for 14months. Comparison has been made with a normalcontrol (16 month-old child; brain 12 months in formalin),and with our previous case of Tay-Sachs' disease in which

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NORMAN, TINGEY, NEWMAN, AND WARD

FIG. 8.-Internal capsul. Fibrous gliosis in the deenyelinated whitematter. (Holzer. -2- 4.)

visceral involvement had also been found (17 months atdeath; brain 18 hours in formalin, Norman et al., 1959).The results of chemical analysis of the cerebral cortex

and white matter are shown in the Table. The very highlevels of lipid hexosamine and neuraminic acid are themost striking finding and strongly suggest Tay-Sachsdisease. The level of ganglioside may be calculated fromeither of these substances. The chromatogram (Fig. 9)shows that the excessive ganglioside fraction in Case J.C.occupies the position of the monosialo-ganglioside G.M.2described in Tay-Sachs disease by Svennerholm (1963).In normal brains this particular fraction constitutes only340o of the total ganglioside. The greatly increasedtotal lipid hexose reflects the accumulation of thiscomponent. The main differences between Case J.C. andour previously reported case of Tay-Sachs disease lie in

the considerably increased cortical cholesterol and in themuch smaller amount of non-lipid hexosamine.

Fic-. 9.-Thin-layer chromatogram showing excess of ganglioside in

the white matter, compared with a normal neonatal brain (left). Bothrepresent 9 mg. dried tissue. (Solvent: chloroform--ethanol-l0°aq. ammonia (60: 38: 8): spray: 0-2% resorcinol in 5 N. HCI.)

There was not enough cortex available for the chemicalassessment of the neutral hexose (from which cerebrosideis calculated) or the phospholipids. Thin layer chrom-atography, however, showed that cortical cerebroside,sphingomyelin and lecithin appeared to be present innormal amounts.

DuioWhen this child was examined at the age of 12

months there was little to suggest Tay-Sachs diseaseexcept for the marked hypotonia which is a character-istic early sign (van Bogaert, 1962). Macularchanges of the sort seen in this patient's right eye

TABLECOMPOSITION OF CEREBRAL GREY AND WHITE MATTER

Cerebral Cortex Cerebral White Matter

Normal Case J.C. Tay-Sachs Normal Case J.C. Tay-Sachs

Total lipid . .. . 30 6 46-7 28-2 38-0 44-5 37-8Cholesterol free 6-0 8*1 4-3 11-0 7-0 6-2Choksterol ester . . Nil 0-3 0-3 0-2 1-0 0-3Total phospholipid . . 18-7 10-2 16-9Lecithin - 126 7-7 9.4Sphingomyelin . . . 2-6 1-0 1-2Totallipidhexose - -0-75 4-50 3-70 2-00 3-14 3-45Neutral hexose - - - 1-46 0-70 0-27Lipid hexosainue -- 0-124 1 34 0-680 0-075 0-775 0840Neuraminic acid - -0-427 1-45 1-47 0-082 0-854 1-21Non-lipid hexosamine .. 0-466 0-320 0-900 0-425 0-365 0-510Water 86-6 81-9 83-5 75-6 81-5 85-0

All values (except water) in g./100 g. of dry tissue.

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TA Y-SACHS DISEASE AND GARGO YLISM 639

have never been described in the infantile form ofamaurotic idiocy (Danis, Begaux, and Decock, 1957),but there is a single observation by Holmes andPaton (1925) of an apparently similar phenomenonoccurring as the earliest manifestation of the maculardegeneration of Batten's juvenile type of the disease.The fundi in this case were normal except that 'atboth maculae there had appeared a tiny white areasurrounded by an areola of redness, fading off intothe normal retina'. As will be seen, however, ourpatient was certainly not an example of precociousBatten's disease.The neuropathological features were similar to

those described in previous cases of infantileamaurotic family idiocy, particularly as regards thedifferent staining and solubility of the lipids in theneurones and microglia. Histological distinctionsfrom Niemann-Pick's disease are undoubtedlydifficult to draw in the brain, but apart from thechemical findings, the absence of foam cells in thespleen and liver makes this diagnosis untenable.The neuronal changes were unlike those of Batten'sdisease or of gargoylism in which the intracellularlipid is strongly resistant to solvents and is much lesshaematoxyphilic (Bishton, Norman, and Tingey,1956). Nor were the meningeal fibrosis or theperivascular lacunae and networks of gargoylismseen in this brain.The most convincing evidence of a visceral storage

disease was provided by the changes in the lung,though the vacuolation in the liver and kidney maywell be significant in this respect when viewed in thelight of Turban's and our own previous case. Foamcells confined to the alveolar air spaces may be foundin a variety of conditions, but to our knowledge thesecells are widely distributed in the alveolar septa onlyas part of a storage disease. They are commonlyseen, for example, in Niemann-Pick's disease, andhave been noted in infantile Gaucher's disease(Brard-Badier, Payan, and Edgar, 1962), inlipogranulomatosis (Farber, Cohen, and Uzman,1957), and in gargoylism (Henderson, MacGregor,Thannhauser, and Holder, 1952).The chemical analysis of the brain yielded the large

increment of ganglioside appropriate to Tay-Sachsdisease. This substance, however, is also increasedin gargoylism, and Klenk (1955) has reported levelsas high as four to five times the normal. This isabout the same increase as was found in the cortex ofTurban's case and is higher than in our two cases.Tingey (1959), however, has analysed two gargoylebrains using the same methods as in the present caseand found only a small increase of ganglioside in thegrey and white matter. In our opinion, a decisivedifference from gargoylism lies in the tenfold increase

of ganglioside in the white matter of our case, sincelevels of this magnitude have never been reported inthe brains of gargoyles. It is necessary to emphasizethis point because in our previous case of Tay-Sachsdisease there were clinical features suggestive ofgargoylism, namely, the corneal clouding, thedepressed bridge of the nose, the protruding tongue,and the swollen abdomen. The conclusion may bedrawn that the syndrome of Tay-Sachs disease mayoccasionally include visceral changes that resemblethose of gargoylism more closely than any otherstorage disease. This apparent relation may reflecta similarity in the metabolic upset present in thesetwo nosologically distinct diseases. Klenk (1955)has stated that both conditions 'could probably becaused by the same disturbance in the metabolism ofthe brain', while Diezel (1960), in discussing thechemical pathogenesis of the neural and visceralchanges in gargoylism, sees a common factor in thehexosamine component, which is shared by ganglio-side and polysaccharides. Future chemical examin-ation of unfixed tissues in Tay-Sachs disease may beexpected to provide the solution to this problem.

Summary

A female non-Jewish child died at the age of 2years after a progressive neurological illness beginningwith severe hypotonia. Ophthalmoscopic examina-tion showed a white spot surrounded by a red halo atthe right macula. Neuropathologically the changeswere typical of infantile amaurotic family idiocy.Chemical analysis showed that ganglioside (asestimated from the neuraminic acid content) wasincreased three and a half times the normal in thecerebral cortex and ten times in the white matter, thelatter finding being regarded as typical of Tay-Sachsdisease. Examination of the visceral organs showedfoam cells in the alveolar septa, and vacuolation ofthe cells of the liver and renal tubules. Comparisonis made with two previously recorded cases in whichthere has been an association between Tay-Sachsdisease and a visceral storage disease suggesting insome respects that of gargoylism.

We wish to thank Professor D. V. Hubble, Dr. F. J.Pick, Dr. B. D. Bower, and Dr. R. Astley for their kindco-operation.

REFERENCES

Rfrard-Badier, M., Payan, H., and Edgar, G. W. F. (1962). Etudehistologique du systene nerveux central d'un case de maladie deGaucher dans une fratrie. In Proc. 4th Internat. Congr. Neuro-path., Munich, 1961. Vol. 3, p. 102-108. Thieme, Stuttgart.

Bishton, R. L., Norman, R. M., and Tingey, A. (1956). The pathologyand chemistry of a case of gargoylism. J. cin. Path., 9, 305.

Brouwer, B. (1936). The spleen, the liver and the brain. Proc. roy.Soc. Med., 29, 579.

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640 NORMAN. TINGEY. NEWMAN. AND WARDDanis, P., Begaucx, C., and Decock, G. (1957). Bases ophthalmologi-

ques d'une classification des idioties amaurotiques. J. Genet.hum., 6, 91.

Da%ison, C., and Jacobson, S. A. (1936). Generalized lipoidosis in acase of amaurotic familial idiocy. Amer. J. Dis. Child., 52, 345.

Diezel, P. B. (1960). Lipidoses of the central nervous system. InModern Scientific Aspects of Neurology, ed. J. N. Cumings. pp.131-2. Arnold, London.

Farber. S.. Cohen. J.. and Uzman. L. L. (1957). Lipogranulomatosis.J. Mt Sinai Hosp.. 24, 816.

Henderson, J. L., MacGregor, A. R., Thannhauser, S. J., and Holden,R. (1952). The pathology and biochemistry of gargoylism;A report of three cases with a review of the literature. Arch. Dis.Childh., 27, 230.

Holmes, G., and Paton. L. (1925). Cerebro-macular degeneration(the juvenile form of amaurotic family idiocy). Trans. ophthal.Soc. U-K.. 45. 447.

Kienk, E. (1955). The pathologicalchemistry of the developing brain.In Biochemistry of the Developing Nervous System: Proc. 1st int.Neurochem. Symp., Oxford, 19S4, ed. H. Waelsch, pp. 397410.Academic Press, New York.

Marburg, 0. (1942). Studies on the pathology and pathogenesis ofamaurotic family idiocy (Tay-Sachs disease). Amer. J. ment.Defic., 46, 312.

Norman, R. M., Urich, H., Tingey, A. H., and Goodbody, R. A.(1959). Tay-Sachs' disease with visceral involvement and itsrelationship to Niemann-Pick's disease. J. Path. Bact., 78, 409.

Tingey, A. H. (1959). The results of glycolipid analysis in certaintypes of lipidoses and leucodystrophy. J. Veurochem., 3, 230.

-, and Edgar, G. W. F. (1963). A contribution to the chemistry ofthe leucodystrophies. ibid., 10, 817.

Turban, H. (1944). Ober einen familiarer amaurotischer Idiotie vomTyp Tay-Sachs. Thesis, Freiburg i,Br.

Svennerholm, L. (1963). Chromatographic separation of humanbrain gangliosides. J. Neurochem., 10, 613.

van Bogaert, L. (1962). Maladies nerveuses genetiques d'ordremetabolique. Lerons de la Chaire Francqui, Universite de Liege.

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