foam-cell reticulosis of mice: an inherited resembling

J. med. Genet. (I965). 2, 99.

Foam-cell Reticulosis of Mice: An Inherited ConditionResembling Gaucher's and Niemann-Pick Diseases

MARY F. LYON, E. V. HULSE, and C. E. ROWE*

From the Medical Research Council Radiobiological Research Unit, Harwell, Didcot, Berkshire, and the NationalInstitute for Medical Research, Mill Hill, London N.W.7

An inherited disease, which histologically re-sembles the lipid-storage diseases in man, hasarisen spontaneously in the CBA mice of theRadiobiological Research Unit. The affectedanimals cannot be recognized until they are atleast 3 months old, and do not live long after thedisease has developed. It is difficult to maintaina breeding stock and consequently genetic studieshave been limited. The chemical aspects havealso proved difficult to elucidate, but, as the diseaseis unusual and bears a resemblance to a poorlyunderstood group of human diseases, it has beenthought worth while to put on record the resultswhich have been obtained.

Description of the DiseaseAffected animals became noticeably thin when

10-I4 weeks old. The abdomen lost its normallyslightly rounded contour, and loose folds of skinappeared on the flanks. The animals continuedto lose weight, became hunched, and their activitydecreased. Respiratory movements became undulyobvious and many of the mice made a clickingsound during respiration. Death occurred withina few weeks and none of the animals lived to6 months.

Post-mortem Appearances (Fig. i). In allthe affected animals the thymus and Peyer'spatches were abnormal. The thymus was uniformlyenlarged, and instead of its normal greyish, semi-translucent appearance it was opaque and white.The Peyer's patches were very enlarged and wereobviously infiltrated with the same opaque, whitematerial as the thymus. Most of the increase insize was immediately beneath the peritoneumand there was no evidence of the intestinal lumenbeing encroached upon. In a few instances the

whole of the wall of the terminal ileum was infil-trated with the same material. There was nogeneraiized enlargement of the lymph nodes butthe mediastinal lymph nodes were infiltrated inabout half the affected animals and the mesentericlymph node was infiltrated in about one-quarter.

FIG. I. Post-mortem appearances of an affected mouse, showingenlargement of thymus and Peyer's patches.

Received December 3, I964.* Present address: Department of Physiological Chemistry,University of Birmingham.

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Lyon, Hulse, and Rowe

FIG. 2. Foam-cells in the thymus of an affected mouse. (H. and E.x 900.)

Occasionally the superficial cervical nodes wereinvolved but no other groups of lymph nodeswere affected on naked-eye examination. Theloose connective tissue of the mediastinum and ofthe abdomen was fairly frequently affected. Occa-sionally deposits were found on the peritonealsurfaces of the spleen and liver, but neither organwas enlarged. The uterus was occasionally infil-trated and deposits in the muscles of the scapulawere sometimes seen. Only very occasionallywas there naked-eye evidence of deposits in thelungs, but lung abscesses were a common compli-cation leading to the death of the animal.

HistologyTHYMUS. In advanced cases normal thymic

tissue was replaced by characteristic foam-cellsmeasuring I5 tO 40 j across. Their cytoplasmstained pink with haematoxylin and eosin andusually contained numerous vacuoles of varyingsize in formalin-fixed, paraffin-embedded material(Fig. 2). Sometimes the vacuoles were very smalland occasionally the vacuolated appearance wasreplaced by a mass of fine striae giving a generalizedfibrillary appearance to the cell. The majorityof cells contained a single, irregularly oval, lepto-chromatic nucleus but some bi-nucleate cells werealso present. Small deposits of calcium were foundscattered amongst these cells, particularly near thecentre ofthe gland. Ifany lymphoid tissue remained

FIG. 3. Thymus from a mouse with foam-cell reticulosis. Thethymus is not completely replaced by diseased tissue and somelymphoid tissue is still present at the periphery. (H. and E. x io8.)

it was usually confined to the periphery of the lobule(Fig. 3).

PEYER'S PATCHES. In the early stages foam-cellssimilar to those seen in the thymus were concentratedin a narrow zone immediately beneath the musclelayers and frequently the adjacent lymphocyteswere degenerating (Fig. 4). In the fully developedlesion the lymphoid tissue was completely replacedby foam-cells and sometimes these cells penetratedthe muscle layer and came to lie immediatelybeneath the visceral peritoneum. They were notseen to penetrate the mucosa and no calciumdeposits were found.

LYMPH NODES. Microscopically the mediastinallymph nodes were invariably infiltrated with foam-cells. Similar infiltrations were frequently seen inthe mesenteric and superficial cervical nodes butlymph nodes in other sites were only very rarelyaffected. The infiltration of the lymph nodes wasrarely as complete as that of the thymus or Peyer'spatches and foci of lymphocytes were usuallypresent in affected nodes.

OTHER VISCERA. In addition to the occasionalsurface deposits, histological examination of thespleen and liver regularly revealed small scatteredfoci of two or three foam-cells. Large infiltrationsin the lungs were rare but small perivascularlesions were a very consistent finding. Apart from

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Foam-cell Reticulosis of Mice

FIG. 4. Early lesion on a Peyer's patch showing degeneratinglymphocytes in the lymphoid tissue and foam-cells at the periphery.(H. and E. x 475.)

the animals in which lung abscesses were found a

purulent bronchitis was noted in a few cases.The deposits in the uterus and in muscle consistedof a mass of foam-cells. No foam-cells were foundin the kidneys or the brain and no lesions werefound in bone or bone-marrow.

InvestigationsNone of the evidence suggested that the disease

was infectious or neoplastic. Attempts were madeto transmit it to normal healthy CBA mice bymeans of intraperitoneal or intramuscular injectionsof saline suspensions of affected thymus. Theinjected animals were watched for nine monthsduring which time they remained healthy. Post-mortem examination failed to reveal any evidenceof the foam-cell reticulosis.

Histochemical Investigations. The foamyappearance of the characteristic cells of the diseasesuggested that some material had been dissolvedout of them during histological preparation.

When formalin-fixed material was stained withSudan Black or Oil Red 0 the affected cells wereonly weakly stained, but after fixation in formol-calcium and post-chromation they were stronglypositive with both stains. The affected tissues,usually thymus and Peyer's patches, were, there-fore, subjected to further stains for lipids. Unlessotherwise stated, those methods recommended byPearse (I960) were used.

Baker's acid haematein method for phospholipidswas positive, the dark-blue staining material appear-ing as fine granules in the affected cells. The degreeof staining varied, some cells were packed withpositive granules but in others of similar size andappearance they were much less numerous. AfterBaker's pyridine extraction the cells were uniformlynegative and had the foamy appearance of cellsthat had been paraffin embedded. Okamoto'smercury diphenylcarbazone method, Menschik'sNile blue method for phospholipids, the copperphthalocyanin method, and Rawitz inversionstaining (Przetecka, 1959) were also used and showeda phospholipid distribution similar to that seenwith Baker's acid haematein.

Cholesterol and its esters were tested for usingSchultz's method with and without digitonintreatment, Okamoto's method, the bismuth tri-chloride method, and Adams' (I96I) method, allof which gave negative results.The plasmal reaction, using both Cain's and

Hayes' methods, was positive. Nile blue stainingfor neutral and acidic lipids was weakly positiveand Feyrter's method for acidic lipids was negative.The long Ziehl-Neelsen for acid-fast lipofuscins,Fischler's method for fatty acids, and the performicacid-Schiff method, and U-V Schiff method forlipids containing unsaturated bonds were allnegative. No silvery white secondary fluorescencewas obtained after Phosphine 3R staining. Stainingfor soaps with haematoxylin (Gurr, 1958) was alsonegative.

Chemical Investigations. In view of thehistological similarities with the human lipidstorage diseases, lipid was extracted from thethymus glands of both diseased and normal CBAmice. The extract was analysed for cholesterol andphospholipid classes. Serum cholesterol was alsoestimated. All analyses were performed in dupli-cate.

EXTRACTION OF LIPID. Pieces of mouse thymus ofapproximately i c.mm. were allowed to stand inethanol-ether (2:I by volume: Ioo ml.) overnight.The solvent was decanted and the residue extractedwith 30 ml. boiling ethanol-ether for 3 minutes.

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The residue was recovered by centrifugation andextracted with 30 ml. boiling chloroform methanol(2:I by volume) for 3 minutes. All extracts were

combined and concentrated to dryness using a

rotary evaporator. The residue was extracted threetimes with I ml. of acetone and three times withi ml. ethanol. The ethanol extract was centrifugedto remove insoluble matter. The acetone andethanol extracts were combined and diluted to

IO ml. with ethanol.

ANALYSIS OF PHOSPHOLIPIDS. Extracts containingo 3 ttmole of phosphorus were chromatographed on

silica-impregnated paper using the solvents di-isobutyl-ketone-acetic acid-water as described byMarinetti and Stotz (I956). After development ofthe chromatograms with Rhodamine 6G the sep-

arated phospholipid classes were cut out and elutedfrom the paper with chloroform methanol 2:i, andestimated for phosphorus. The procedure was thatof Berenblum and Chain (1938) except that (i)ashing was achieved with 5 ml. of a mixture of6o% perchloric acid and sulphuric acid (I:I'5 byvolume); (ii) 5 ml. of isobutyl alcohol was used forextraction; and (iii) O IO ml. stannous chloridesolution (40% w/v in concentrated hydrochloricacid) was added to the extract in isobutyl alcoholafter washing. For each phospholipid class a pieceof blank chromatogram identical in area anddistance from the origin was cut out and extractedin an identical manner to give a blank phosphorusestimation.The components were identified (i) by their

positions on the chromatogram relative to eachother, and to both egg lecithin and commercialsphingomyelin (California Biochemicals Corpn);and (ii) by their fluorescence in ultraviolet radiationafter treatment of the chromatogram with Rhoda-mine 6G. Phosphatidyl ethanolamine and phos-phatidyl serine were detected by their purplecolour when the chromatogram was sprayed withninhydrin and heated at Iio0C. for IO minutes.Choline-containing phospholipids, e.g. lecithin andsphingomyelin, were detected by treatment of thechromatogram with phosphomolybdic acid followedby reduction (Chargaff, Levine, and Green, 1948).

Cholesterol was measured by the method ofBloor (I9I6).

RESULTS. The total phospholipids in the thymustissue from diseased and normal mice were thesame (Table I). There was, however, a differencein the distribution of phospholipid classes. Thediseased tissue contained an additional componentnot found in normal thymus. This component,though not conclusively identified, had the chrom-

TABLE ICHOLESTEROL AND PHOSPHOLIPID CONTENT OFPOOLED THYMUS GLANDS AND CHOLESTEROLCONTENT OF POOLED SERUM FROM DISEASED AND

NORMAL MICE OF SAME AGE

Diseased NormalMice Mice

Total cholesterol (free plus esterified)(g moles/g. wet tissue) 34 9.8

Serum cholesterol (free plus esterified)(mg-/trll) I.5 1.4

Thymus phospholipid(,u moles phosphorus/g. wet tissue) I I 10

atographic and staining properties of lysolecithin(Table II).The diseased tissue had an abnormally high

content of cholesterol (free plus esterified) (Table I).The level of serum cholesterol in the serum ofdiseased mice has the same as that in the serum ofnormal mice.

Genetics. The circumstances in which theoriginal affected animals were found, among theprogeny of two pairs with common ancestors 2-3generations back, suggested that the disease mightbe due to an autosomal recessive gene. Since thecharacter did not become obvious until the micewere 3-4 months old, and since the affectedanimals died shortly thereafter, it was not possibleto plan a genetic programme. Animals had to bepaired before it was known whether they werenormal or affected, and the affected ones left veryfew progeny.

In view of these difficulties, the possible waysof testing the hypothesis of an autosomal recessivegenetic basis were as follows:

(I) To observe the proportions of affected youngin the offspring of the various types of matingsamong normal and affected parents.

(2) To note what proportion of normal youngbred as though heterozygous for the postulatedgene and what proportion as homozygous normal.

All the matings were made within the sublineof CBA/H in which the mutation occurred, with

TABLE IIPHOSPHOLIPID COMPONENTS AS % OF TOTAL LIPIDIN THYMUS GLANDS FROM DISEASED AND NORMAL

MICE OF SAME AGE

Diseased Mice Normal Mice

Lysolecithin 36-2 0Sphingomyelin g-o 7.3Lecithin 37-1 68-9Phosphatidyl serine I3A239Phosphatidyl ethanolamine 6.5

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TABLE III

SEGREGATION OF ANIMALS AFFECTED WITH FOAM-CELL RETICULOSIS (fm) AMONG PROGENY OF PAIRS OFVARIOUS TYPES

Parents Offspring

Phenotype Cross No. Postulated Genotype No. of Pairs Normal Affected

Both affected I fmfm x fmfm I9 3 68Normal x affected 2 + fm x fmfm 26 go 82

3 +±+ x fmfin 2 24-4 + fm? x fmfm 6 13 -

Normal x normal 5 + fm x + fm 26 350 1346 + + x + fm I3 240 -

or++ x ++7 +fn? x+fm? 8 44-

no outcrosses to other stocks, and in most, but notall, cases the mated animals were sibs. The name

foam-cell reticulosis, symbol fm, is used to denotethe postulated recessive gene concerned.The possible types of pairs were: normal x

normal, normal x affected, and affected x affected.If the disease were indeed due to a recessive genesome of the normal animals would be expected tobe homozygous for the wild-type allele, and in linewith this some matings of normals threw no affectedyoung. In Table III the results from these crosses

(Nos. 3 and 6) are shown separately from thosethat did give affected offspring. In addition, therewere other crosses (Nos. 4 and 7) which producedvery small numbers of young (less than 7 youngper mating in cross 4, and less than ii in cross 7),so that it was not certain whether the unaffectedparent was heterozygous or homozygous normal.The Table shows that the results from the segre-gating matings (crosses 2 and 5) were in good agree-ment with the expected I:I and 3:i ratios. Forcross 2 X2 was 0-37 for i degree of freedom (p >o 5o) and for cross 5 it was i-86 (p > otIo). Thedata will have been slightly biased in favour ofaffected animals by the exclusion of the pairs incrosses 4 and 7, since in some at least of thesepairs the normal parent will have been a heterozy-gote which by chance produced no affected off-spring. Even if all the progeny of crosses 4 and 7are included with those of 2 and 5, however, the

figures would still show no significant deviationfrom the expected ratios. The single unexpectedfact in the data of Table III is the occurrence of 3normal animals among the offspring of matings oftwo affected parents (cross i). Thus on the wholethese data support the hypothesis of a single reces-sive gene, but are not adequate to establish it.

Further support was obtained from tests of thegenotypes of the normal offspring. Normals fromnormal x affected matings should all be heterozy-gotes and throw affected offspring, whereas somenormals from normal x normal matings should behomozygous wild-type. Forty-six normal offspringof normal x affected parents produced enoughyoung to establish their genotype, and all provedthemselves heterozygous (Table IV). On the otherhand, of the normals from presumed + fm x + fmmatings, 2 out of IO gave no affected progeny whenpaired with affected mates, and I4 out of 25 behavedsimilarly when paired with normal mates. In thislatter case, one of the normal animals of the paircould have been heterozygous, and therefore theseI4 animals are shown in Table IV as of the geno-

type + fm?The data of Table III were further analysed to

test for sex-linkage of the gene concerned. Thefigures from those matings which gave informationon this point are shown in Table V; %2 for deviationfrom independent segregation (calculated byFisher's scoring method (Green, I963)) was 2-25

TABLE IVTHE GENOTYPE, ESTABLISHED BY BREEDING, OF NORMAL OFFSPRING FROM PAIRS OF VARIOUS TYPES

Parent Mating Genotypes of Normal Offspring Mated With:

Normal Mate Affected MatePhenotypes Postulated Genotypes

+ + + fm + fm? + + + fm

Normal x affected + fm x fmfm - 22 - - I2+ + xfifm - 9 - 3

Normal x normal + fm x + fm - II I4 2 8

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TABLE VTEST FOR SEX-LINKAGE OF THE POSTULATEDRECESSIVE GENE CONCERNED IN FOAM-CELL

RETICULOSIS

Phenotypes of OffspringParents __ - Score I*

+ fm ±d'fm d __

+fm V x +X/fmY 4 88 42 98 3 +28-6 345-3+fm Y xfmX/+Yc 9 1I 3 2 - 6-o 20o0fmfm V x +X/fmY d I 3 4 2 + 8-o 40 0

Total +30-6 415'3

* Information.

for i degree of freedom, so there was no evidence ofsex-linkage.Thus, all the evidence pointed to the disease

being due to the action of an autosomal recessivegene, except for the 3 normal offspring frommatings of affected parents. The first obviousexplanation to postulate for these three anomalousanimals is incomplete penetrance. In that case theanomalous animals should have been homozygousfor the gene concerned and should have beenindistinguishable in breeding behaviour fromaffected animals. Offspring were obtained fromtwo of the animals, when mated to affected sibs.One produced 3 normal, 3 affected, and the other6 normal, 7 affected, i.e. both bred like heterozy-gotes rather than homozygotes. However, thisevidence is not critical since it was possible thatgenetic modifiers lowering the penetrance of thegene had accumulated in these particular pairs.One of the two animals left only one further pairof descendants, but the other left several latergenerations (Table VI), including 3 pairs of affectedx affected, which produced 9 affected and no nor-mal young, and a mating of normal x normaJ, oneof whose normal offspring proved to be homozygousfor the wild-type allele. The existence of thisnormal descendant proves that the anomalousnormal ancestor must have carried the wild-typeallele of the gene, and the progeny of the affecteddescendants show that the penetrance of the genewas high. Thus, of the three anomalous animals,one was certainly and another probably heterozygous,and no animal was shown to be a non-manifestinghomozygote.

There are various possible ways of explaininghow heterozygous offspring could be derived fromsupposedly homozygous recessive parents.

(i) One of the supposed homozygous parentscould in fact have been heterozygous and eitherwrongly classified as affected or was the result ofrare heterozygous expression of the gene. Thisexplanation is possible but unlikely, as the propor-

TABLE VISEGREGATION OF FOAM-CELL RETICULOSIS AMONGOFFSPRING OF VARIOUS TYPES OF PAIRS DESCENDED

FROM AN ANOMALOUS NORMAL ANIMAL

Parents Offspring

Postulated No. ofNomlAfcePhenotypes Genotypes Pairs Normal Affected

Both affected fmfm x fmfm 3 - 9One affected + fmxm 4 12 i6Both normal + fm x +fm 5 67 18

++ x +fm I I

tion of affected offspring thrown by these parentswas higher than would be expected from heterozy-gotes.

(2) There could have been clerical error inascribing the three normal animals to the wrongparents. This again seems unlikely, as the fre-quency of errors would have to be deplorably high,and such a bad record of mistakes is not found inother stocks in this laboratory. However, this possi-bility cannot be ruled out.

(3) Back-mutation of the mutant to the normalallele could have occurred. This would imply aremarkably high rate of back-mutation and hencethat the mutant allele was unstable. As the possi-bility of error cannot be ruled out, mutation cannotbe proved.

It is not possible to decide which of these threeexplanations is the correct one, but it is clear thatthe three anomalous animals do not rule out thehypothesis of a single autosomal recessive gene.The penetrance of the postulated gene fm is

high in the CBA/H stock, but no crosses to otherstocks have been made, nor any linkage tests otherthan that for sex-linkage.

DiscussionThe pathological and histochemical findings

indicate that this foam-cell reticulosis, which hasbeen observed in an inbred strain of mice, can beclassified as a lipid-storage disease. The lymphoidtissue of the thymus and Peyer's patches is replacedby cells which store lipoid material in their foamycytoplasm. Other tissues may also be affected butrarely to the same extent. The disease is not neo-plastic.

In spite of the chemical investigations and num-erous histochemical tests, it is impossible to bedogmatic about the nature of the stored lipid in thisdisease. In some ways the chemistry and histo-chemistry appear to be contradictory. Histo-chemically the foam-cells contained phospholipid.The chemical investigations did not show an increasein the proportion of phospholipid in diseased tissue,

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but they did reveal the presence of a remarkablyhigh proportion of a component with the propertiesof lysolecithin which was in a i :i ratio with lecithin.Moreover, the sum of this component and lecithinin the diseased tissue was approximately equal tothe amount of lecithin found in normal tissue. Itwould be expected that lysolecithin, which is acomparatively polar molecule and has only onehydrocarbon chain, would be more easily extractedinto aqueous solvents than would other phospho-lipids. It is not surprising, therefore, that fixationin formol-calcium and post-chromation was neces-sary when staining sections for fat. The proportionof cholesterol and cholesterol ester was high bychemical examination, but unless the cholesterol wasso complex as to prevent successful histochemicaltests, it was presumably not sufficiently high to givepositive histochemistry. The ratio of cholesteroland cholesterol ester to phospholipid is 3 in thediseased mice as compared with i in the normalmice. These findings make it possible that thediseased mice are storing some complex or com-plexes containing cholesterol and lysolecithin.

This disease of mice has no exact counterpartamongst the lipid-storage diseases of man, but thesimilarities are sufficiently close to make compari-sons worth while. Chemical estimations revealedthree times as much cholesterol in the affectedtissues but anatomically the disease is least like thexanthomatoses. The mouse disease was more orless generalized and the serum cholesterol wasnormal so that only the Hand-Schiller-Christiangroup need to be considered. However, the micewere free of any lesions in bone which could corres-pond to the characteristic lesions in the humandiseases, and the lesions in the mice were at nostage infiltrated with eosinophils. The foam-cellsin the mice were not unlike the histiocytic cells ofthe older lesions of Hand-Schuiller-Christiandisease and eosinophilic granuloma of bone, butthe multinucleate giant cells, typical of the humandiseases, were not present in the mice.There are closer similarities with Gaucher's

disease and Niemann-Pick disease. In Gaucher'sdisease the lipid is the sphingogalactoside cerasinand in Niemann-Pick disease it is a mixture ofsphingomyelin and cholesterol and its esters. Thecombined storage of cholesterol and a phospholipidin the mouse disease suggests that, chemically, ithas a greater affinity with Niemann-Pick disease,but the storage of lysolecithin has no counterpart inman. However, Niemann-Pick disease is nearlyalways a disease of infants and in this respect themouse disease is more like Gaucher's disease, whichbegins later in life. In both human diseases the

reticulum cells of the lymphoid tissue are affectedin a similar way to those of the mice. The charac-teristic cell of the mouse disease is more like theNiemann-Pick cell, which has foamy, vacuolatedcytoplasm, than the Gaucher cell, which is largerand has a wrinkled fibrillary cytoplasm. In somedetails the mouse disease is different from both ofthe human diseases. The splenomegaly, withmassive lipid deposition, which gives one of thecharacteristic clinical signs in the human diseases,was not present in the mouse. Lipid storage in thebone-marrow and the deposits of haemosiderin,both of which are seen in the human diseases, werenot present in the affected mice. Lipid storage innerve cells, which occurs in Niemann-Pick diseaseand which is an essential pathological feature ofTay-Sachs disease and other forms of amauroticfamily idiocy, did not occur in the mouse disease.

Genetically, too, the mouse disease resemblesGaucher's and Niemann-Pick diseases in man.In both of these, and also in Tay-Sachs disease,the majority of cases show an autosomal recessivemode of inheritance, like that found for foam-cellreticulosis in this paper, whereas Hand-Schiiller-Christian disease is not inherited (Herndon, 1954).Recent evidence, however, suggests that all threeof the inherited human diseases may be geneticallyheterogeneous. In Gaucher's disease, though mostpedigrees show recessive inheritance, there aresome in which an autosomal dominant gene seemsresponsible (Fredrickson and Hofmann, I960;Hsia, Naylor, and Bigler, 1959). In Niemann-Pickdisease, on the other hand, the heterogeneity con-cerns the time of onset. Typically the disease isone of infancy and is usually detected in the firstyear of life, but a few cases have been detected inadults, the first well-estabJished instance being thatof Pfandler (I953), who described two brothers whodied of the disease at ages 29 and 33. Two survivingbrothers of these cases had marked hepatospleno-megaly, and Pfandler considered that this familycarried a genetically distinct adult form of thedisease. Similarly, amaurotic idiocy, of whichTay-Sachs disease is the infantile form, is knownalso in juvenile and adult forms, which occur inseparate pedigrees and are therefore considered tobe genetically distinct (Herndon, I954; Fredrickson,1960).Thus, considering the histological, chemical, and

genetic evidence together, the human disease whichfoam-cell reticulosis of mice most resembles maybe an adult form of Niemann-Pick disease.The stock is available to those interested in

making further studies and comparisons of the twodiseases.

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SummaryAn inherited lipid-storage disease has occurred

in CBA mice. Lipid-containing foam-cells replacethe lymphoid tissue of the thymus and Peyer'spatches and may occur in smaller numbers inother tissues. Chemical and histochemical investi-gations suggest that the lipid may be a complex oflysolecithin and cholesterol. The disease appearsto be inherited via a single autosomal recessivegene for which the name and symbol foam-cellreticulosis, fm, are suggested. It is concluded thatthis foam-cell reticulosis of mice is very similar toNiemann-Pick disease in man.

The authors are very grateful to Mrs. H. Bowker,Mr. Albert Jackson, and Mr. R. Faulkes for technicalassistance.

REFERENCES

Adams, C. W. M. (I96I). A perchloric acid-naphthoquinonemethod for the histochemical localization of cholesterol. Nature(Lond.), 192, 33I.

-Berenblum, I., and Chain, E. (1938). An improved method forthe colorimetric determination of phosphate. Biochem. J., 32,295.

Bloor, W. R. (I9I6). The determination of cholesterol in blood.J. biol. Chem., 24, 227.

Chargaff, E., Levine, C., and Green, C. (1948). Techniques forthe demonstration by chromatography of nitrogenous lipideconstituents, sulphur-containing amino acids and reducingsugars. ibid., 175, 67.

Fredrickson, D. S. (I960). Infantile amaurotic family idiocy.In The Metabolic Basis of Inherited Diseases, ed. J. B. Stanbury,J. B. Wyngaarden, and D. S. Fredrickson, p. 553. McGraw-Hill,New York.-, and Hofmann, A. F. (I960). Gaucher's disease. ibid., p. 603.Green, M. C. (I963). Methods for testing linkage. In Methodology

in Mammalian Genetics, ed. W. J. Burdette, pp. 56-82. Holden-Day, San Francisco.

Gurr, E. (i958). Methods of Analytical Histology and Histochemistry.Leonard Hill, London.

Herndon, C. N. (0954). Genetics of the lipidoses. Res. Publ. Ass.nerv. ment. Dis., 33, 239.

Hsia, D. Y., Naylor, J,, and Bigler, J. A. (i9g9). Gaucher's disease:report of two cases in father and son and review of the literature.New Engl. J7. Med., 26I, I64.

Marinetti, G. V., and Stotz, E. (I956). Chromatography of phos-phatides on silicic acid impregnated paper. Biochim. biophys.Acta (Amst.), 21, I68.

Pearse, A. G. E. (I96o). Histochemistry, Theoretical and Applied,2nd ed. Churchill, London.

Pfindler, U. (I953). Nouvelles conceptions sur l'heredite et lapathog6nie de la maladie de Niemann-Pick. Helv. med. Acta,20, 2x6.

Przetqcka, A. (I959). A study of Rawitz's 'inversion staining'.Quart. J. micr. Sci., 100, 231.

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