The gangliosidoses

The gangliosidoses

Reviews The Gangliosidoses* LARRY SCHNECK, M .D ., BRUNO W. VOLK, M .D . and ABRAHAM SAIFER, PH .D . Brooklyn, New York Reviewed herein is a histo...

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Reviews The Gangliosidoses* LARRY SCHNECK, M .D ., BRUNO W. VOLK, M .D . and ABRAHAM SAIFER, PH .D . Brooklyn, New York

Reviewed herein is a historic survey of the various types of amaurotic idiocy and the biochemical technics of isolation, identification, quantification, structure and metabolism of gangliosides . The clinical, pathologic and biochemical features of two established gangliosidoses, Tay-Sachs disease (TSD) and systemic late infantile amaurotic idiocy, are described in detail . The problem of precise identification and classification of the various gangliosidoses is discussed . It is recommended that until the specific enzymatic defect is established, identification and classification be based upon combined clinical, pathologic and biochemical criteria .

(Table I), Suzuki and Chen [12] have proposed that these two disorders be called "G M, and GMa gangliosidosis," respectively . None of the other forms can as yet be considered bio chemically verified examples of ganglioside storage disease. Reviewed herein is the history of amaurotic idiocy, the biochemistry of gangliosides, and the clinical, pathologic and biochemical features of the two established ganglioside storage disorders-

ANGLIOSIDE is the trivial name for a group of sphingoglycolipids that contain N-acetyl-neuraminic acid (NANA) (sialic acid) . Ganglioside storage disease is an inborn error of ganglioside metabolism resulting in an absolute increase in the tissue concentration of ganglioside . Amaurotic idiocy refers to a group of hereditary disorders characterized by progressive psychomotor and visual deterioration . The six major forms of amaurotic idiocy include congenital amaurotic idiocy [11, infantile amaurotic idiocy .[2,3], the late infantile type [4,5], the systemic late infantile group [6-8], the juvenile variety [9,101 and adult amaurotic idiocy [II] . Ganglioside storage disease is a biochemical classification and amaurotic idiocy is a clinical description but the two terms have often been used interchangeably . However, only two classes of amaurotic idiocy are biochemically proved ganglioside storage diseases . These are infantile amaurotic idiocy [2,3] and the systemic late infantile variety [6,7] . Since the predominant stored ganglioside fraction in the infantile form is a G MI ganglioside (Table I), and the predominant fraction in the systemic late infantile variety is a G M1 ganglioside

G

HISTORIC

Warren Tay in 1881 observed cherry-red macular degeneration in a twelve month old child with marked weakness of the trunk and limbs [2] . Subsequently he reported two additional cases in the same family [13] and a third case from another family [1 .1] . 111 1887 Bernard Sachs published his clinical and pathologic observations on a child with arrested cerebral development [3] . Several years later he had collected additional cases, all occurring in Jewish children [15] . He named the syndrome complex "amaurotic family idiocy," and concluded that the disease was a "heredodegenerative disorder occurring in infancy, and marked by arrested mental development, gen-

• From the Isaac Albert Research Institute and Department of Pediatrics, Kingsbrook Jewish Medical Center, Brooklyn, New York. This study was supported by grants from the NIH (B-2977), Hartford Foundation and National Tay-Sachs Association . Requests for reprints should be addressed to Bruno W- Volk, M .D ., Isaac Albert Research Institute of the Kingsbrook Jewish Medical Center, 86 East 49th Street, Brooklyn, New York 11203 . Manuscript received January 15 1968 . . VOL .

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eralized paralysis and blindness associated with a cherry-red spot in the macula and optic atrophy ." In recognition of the pioneer work of these two investigators, the infantile form of amaurotic idiocy is commonly known as Tay-Sachs disease (TSD) . By 1962, over 500 cases of TSD had been recorded, 296 of which had been studied at the Kingsbrook Jewish Medical Center [16] . Peterson [17], Hirsch [18] and Schaffer [19,20] described the pathologic changes in the central nervous system . The disorder was characterized by ubiquitous neuronal degeneration, ballooned-out nerve cells containing lipid granules, and severe demyelination . The cherry-red spot in the macula is believed to be the end result of ganglion cell degeneration of the maculas which unmasks the underlying red vascular choroid [21-23] . In the early 1900's several cases were published which superficially seemed to be variants of TSD occurring in older children . Batten [24] described a juvenile variety of this disease which appeared in children five to six years of age . The retina in his case did not show the characteristic cherry-red spot . Vogt [9] in 1905 and Spielmeyer [10] in 1906 described the pathologic condition in a clinically similar case . This form of amaurotic idiocy was subsequently known as the juvenile form of TSD, or Vogt-Spielmeyer-Batten disease . Juvenile amaurotic family idiocy becomes clinically apparent between five and ten years of age . The first clinical signs are usually those of progressive mental deterioration and decreased visual acuity . Within a few years after onset the children are akinetic, dystonic and have focal and generalized convulsions [25] . Optic atrophy and retinitis pigmentosa are the typical retinal lesions [261 . Vacuolated lymphocytes have been reported to be present in the heterozygote [27] as well as the homozygote [28,29] . The neurologic changes are essentially similar to but less marked than those seen in TSD [30] . Jansky [41 and Bielschowsky [5] reported a form of amaurotic idiocy in which overt clinical signs and symptoms emerged at the age of two to three years. The typical clinical syndrome is one of generalized convulsions and myoclonic fits, cerebellar disorders of gait, psychomotor deterioration, and blindness associated with optic atrophy and retinitis pigmentosa [31], Seitelherger [32] suspected that

el al .

the Jansky-Bielschowsky form of amaurotic idiocy was similar if not identical to the myoclonic variant of cerebral lipidosis . In the latter disorder he reported that the severe atrophic changes in the cerebellum, cerebral hemispheres and brain stem were associated with two types of storage material . The granular inclusion bodies were protein-bound glycolipids, whereas the spheroid myoclonic bodies were essentially protein . Epstein [33] in 1917 described a congenital form of "TSD" in which the clinical picture became evident within the second week of lifeNorman and Wood [1] and Hagberg et al . [34] described other cases considered to be examples of congenital forms of amaurotic idiocy . In the neonatal period these infants have evidence of severe diffuse neurologic impairment . The pathologic findings are characterized by severe brain atrophy and diffuse neuronal destruction. Kufs [11] in 1925 published his observations on an adult with "amaurotic idiocy ." The clinical manifestations [35] in the adult form appear after puberty and the disease may last for several decades. The initial symptoms are mainly those of mental deterioration, dyskinesia, dystonia and seizures . Although this condition is classified as a form of amaurotic idiocy, visual disturbances and retinal changes are rare . Pathologically, there is evidence of neuronal deterioration as well as storage of pigmented lipid [36] . A number of case reports have appeared of infants in whom the clinical course resembled that in the infantile form of amaurotic idiocy . However, the frequent hepatosplenomegaly and roentgenographic findings simulating Hunter-Hurler disease, together with visceral foam cells, differentiate this disorder from the classic infantile form of amaurotic idiocy . Cases reported as "variants of Hurler's syndrome" [37], "TSD with visceral involvement" [38], "pseudo-Hurler's disease" [39], "neurovisceral lipidosis" [6], "biochemically special form of infantile amaurotic idiocy" [40], "systemic late infantile lipidosis" [8] and "generalized gangliosidosis" [7] may all have been examples of this disease entity . The psychomotor and visual deterioration resemble the pattern seen in TSD. Pathologically, the cerebral degeneration is associated with ballooned ganglion cells [6,8,41] . These variants of classic infantile amaurotic AMERICAN JOURNAL ON MEDICINE



The Gangliosidoses-Schneck idiocy differed from TSD with regard to racial predilection, age of onset, rate of progression, and degree and extent of pathologic findingsCommon to all was evidence of an autosomal recessive inborn error of metabolism producing progressive psychomotor deterioration and neuronal destruction associated with or resulting from the storage of lipid-like material in cells of the central nervous system . By implication, therefore, these forms were often thought to show a common metabolic defect [42] . Klenk's fundamental studies on gangliosides [43-47], which appeared between 1939 through 1945, revealed that the brain in TSD contains a marked absolute increase in the concentration of ganglioside- Glohus' Unitarian theory that the various types of amaurotic idiocy were age-dependent varieties of the same disease process gained credence from the observations that the stored lipids in other types of amaurotic idiocy often had histochemical or staining properties similar to gangliosides [48,49] . It is now generally accepted that the staining reaction of a stored substance, in lieu of qualitative and quantitative biochemical analysis and identification, cannot be relied upon [50,51] . In 1960 Terry and Korey [52] reported that the neurons in TSD exhibit intracytoplasmic membranous bodies . These bodies were shown to contain gangliosides [53] . However, similar inclusion bodies are now known to occur in other forms of cerebral lipidosis [8,32,54-57] . With improved chromatographic technics, it was established that the ganglioside isolated by Klenk comprised a heterogeneous mixture of sialic acid-containing sphingoglycolipids (Table I) . The ganglioside which accumulated in TSD was shown to be a monosialo-ceramide trihexoside G MZ [58] which in normal brains comprises a minor percentage of the total monosialoganglioside fraction [59] . The ganglioside stored in excess in the systemic late infantile form is G MI [7], the ganglioside which is the major monosialoganglioside in the normal brain . Suzuki and Chen [12] therefore proposed that TSD be known as a G K , ganglioside storage disease and the late infantile form as a G ., ganglioside storage disease . The congenital, the nonsystemic late infantile and/or myoclonic varieties, the juvenile and the adult forms of amaurotic idiocy are not biochemically proved ganglioside storage VOL .

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diseases [34,60-65] . Jatzkewitz and colleagues [66] have reported increases of specific tissue ganglioside fractions in the formalin-fixed brain specimens from patients with juvenile and adult forms of amaurotic idiocy . However, their results must be interpreted with some caution since Suzuki [67] found that formalin alters ganglioside patterns . BIOCHEMISTRY OF GANGLIOSIDES

Gangliosides have both hydrophobic and hydrophilic properties . The former is due to the ceramide moiety which consists of a C 18 or Czo dihydroxyamino alcohol, sphingosine, which is in acid amide linkage to a long-chain fatty acid . The oligosaccharide unit, which by definition contains one or more moles of sialic acid, is hydrophilic and acidic [68-71] . The weight of experimental evidence supports Kuhn and Wiegandt's hypothesis [72] of a common basic structural unit for at least the four major ganglioside fractions (Fig . 1), but Gal(1-3)GaINAc(1-4)Gal(I-4)Glu (1-1) Cer / I\

NANA Flr . l . Structure of major monosialoganglioside of nor . mal brain-Gm, .

the structure of the trisialogangliosides is still in doubt [70] . Molecular differentiation and nomenclature are generally based on the oligosaccharide unit . The proposed structural formulas, different nomenclature and percentage distribution of the common brain gangliosides are given in Table I . The confusing multiplicity of names points up the urgent need for a standardized system of ganglioside designation . Without prejudging the merits of any one system, we shall use Svennerholm's designations . Gangliosides are usually extracted from tissue by the chloroform-methanol system of Folch and co-workers [73] . Modifications of this system are frequently employed to increase the purity or quantitative yields of various ganglioside fractions [74-77]. Preliminary separation of gangliosides from the other extracted lipids is often achieved by either solvent partitioning [77-80] or column chromatography [81-84] . Silica gel thin layer chromatography is commonly used for further frac-





The Gangliosidoses-Schneck et at .

248 SUMMARY

OF

TABLE I STRUCTURES, NOTATIONS AND DISTRIBUTION

Or

BRAIN GANGLIOSIDES

Designations* according to

Structure NANA(2-3)Gal(1-4)Gluc(1-1)Cer GaINAc(1-4)Gal(1-4)Gluc(1-1)Cer

NAN A Gal(1-3)Ga1NAc(1-4)Gal(1-I 4)Gluc(1-1)Cer

Korey, Svenner- Gonaholm tas, et al. Suzuki GMI Gx2

Gs Gs

Johnson, McCluer

Klenk et al .

FM

Kuhn et al .

% of Total Penick, GangliMcCluer oside

Gr, aot GO, GNTrII

HG-C

1 .0

HG-D

6 .0

Gm,

G,

1-G

A2

G,

HG-1

25 .0

NANA Gal(1-3)GaINAc(1-4)Gal (1-4)Gluc (1-1)Ccr

G DI .

Gi

2-G

B,

Gu

HG-2

60 .0

NANA NANA Gal(1-3)GaINAc(1-4)Gal(1-4)Gluc(1-1)Cer

Gli b

G,

3-G

Gu,

HG-4

3 .0

GT,

G,

4-G(?)

G1v

G)

(2)

c!~

NANA NANA Gal(1-3)Ga1NAc(1-4)GaI(1-4)Gluc(1-1)Cer

(2)

(2~

NANA

NANA(2-8)NANA

5 .0

* Based upon tables by Schettler, G . and Kahlke, W. (p . 215 [50]) and MCCLUER, R. H . and PENICK, R . J . Isolation and structural analyses of brain ganglintides In : Inborn Errors of Sphingoloid Metabolism, p. 242 . Edited by Aronson, S. M. and Volk, B . W . New York, 1967 . Pergamon Press, Inc . donation and identification of the ganglioside mixture [85-89] . Quantitative analysis of gangliosides is generally performed by estimation of the sialic acid content [90] . An elegant quantitative micromethod has been developed by Suzuki [911 . He utilized the descending system of Korey and Gonatas [88] for fractionation, and then directly determined the concentration of each ganglioside fraction on the silica gel by a modification of the resorcinol method of Svennerholm . Gas-liquid chromatography is an excellent micro-analytical tool for sphingosine, fatty acid and carbohydrate analysis [92-94] . Immunochemistry is another technic that can be utilized for identification and structural analysis [95] . Histochemical methods have been used for cellular identification and localization of ganglioside or ganglioside-like complexes [961

(Table it) . However, these histochemical staining reactions reflect the physicochemical state of aa substance rather than its structure or concentration . Electron microscopy of brain specimens from patients with TSD reveals membranous cytoplasmic bodies which were initially considered to be specific storage formations in TSD [50] (Fig. 3) . Similar bodies are now known to occur in other disorders too [8,32,5457] . Isolation and chemical analysis of the membranous cytoplasmic bodies in TSD showed them to contain about 57 per cent gangliosides, 22 per cent cholesterol and 11 per cent phospholipids [53] . Structural analysis of gangliosides has failed to reveal any significant structural differences between the various fractions found in brain specimens from normal subjects and those AMERICAN JOURNAL

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249

The Gangliosidoses-Schneck et al . from patients with disorders of ganglioside metabolism [97] . The stereochemical configuration of these compounds has not yet been firmly established . There have been several recent studies on the metabolic pathways for ceramide synthesis . Brain sphingosine was synthesized by the condensation of palmitaldehyde with serine (98,99] . The conversion of sphingosine to ceramide may involve a reaction between sphingosine and a long-chain fatty acid thiolester of coenzyme A [100] . Gatt [101] has been able to isolate and partially purify the enzyme ceraminidase which catalyzes both the synthesis and hydrolysis of ceramide. For greater detail, the reader is referred to reviews by Rossiter [102] and Burton [103] . The chemistry of sialic acid has been described by Gottschalk [104] and Warren [105] . It has been demonstrated that the N-acetylneuraminic acid (NANA) which is in 2-3 glycoside linkage to the internal galactose is relatively more resistant to hydrolysis by neuraminidase than the other NANA residues [106J . Thus, the NANA in GM1 and GM_ appears to be protected by N-acetyl galactosamine . Kanfer and Brady [107] and Kaufman, Basu and Roseman [108] have developed and studied in vitro models of ganglioside synthesis . They have proposed a sequential synthesis of gangliosides from ceramide disaccharide by the step-wise addition of monosaccharide units . Both groups of investigators caution that their in vitro system may not be identical with the metabolic events occurring in vivo . In vivo studies by Suzuki and Korey [109] on ganglioside synthesis, using D-(U-C 14) glucose, indicate that the four major brain gangliosides are synthesized at about the same rate. They suggest that the four major gangliosides are formed simultaneously rather than sequentially . Wiegandt [110] found brain gangliosides concentrated in the microsomal fractions of nerve terminals and he demonstrated a direct correlation between acetylcholine esterase activity and ganglioside concentrations . Gangliosides have also been isolated from nonneural tissue [111,112] . Little is known about the physiologic role of gangliosides . The severe neurologic disturbances resulting from inborn errors of ganglioside metabolism implicate these compounds as vOL .

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TABLE 11 HISTOCHEMICAL REACTIONS OF GANGLIOSIDES

Method Sudan Black Periodic acid-Schiff

Substance Shown

Lipids Glycolipids and glycoproteins, (glycosaminoglycans), lipid pigments Biat Neuraminic acid Cresyt violet-acetic Red-gangliosides, acid metachromasia brown-sulfatides Luxol Fast Blue Lipids containing choline and/or phosphates (e .g., sphingomyelin)

Ganglioside Reaction + +

+ + + -

essential to normal nerve physiology . Mclllwain [1131 investigated the effect of ganglioside on cortical response to electrical stimulation . Ganglioside modulates water and potassium ion distribution in brain tissue [114] . Bogoch [115] and van Heyningen and Miller [116] described the protective action of gangliosides against certain viruses and bacterial toxins, and Gottschalk [117] studied sialic acid and its role in myxovirus-erythrocyte interactions. It has been shown that there are qualitative and quantitative differences in the ceramide and oligosaccharide units of gangliosides which are dependent upon age, species and tissue . Thus, Rosenberg [118] reported that although both C 18 and C2n sphingosine are present in mature brain, C 26 sphingosine is virtually absent in neonatal brain . Furthermore, although the ceramide unit of gangliosides from normal fetal and newborn brain contains more than 90 per cent stearic add, with increasing age the percentage of stearic acid decreases and that of palmitic acid increases . Suzuki [119] has also reported quantitative symmetrical regional variations in brain gangliosides . Quantitatively, the highest concentrations of gangliosides were found in cerebral cortex, the lowest concentrations were obtained from the white matter of the centrum semi-ovale and corpus callosum . The uncal area had a much higher percentage of the less polar gangliosides than other cortical areas . Variations of the ratios of polar and nonpolar



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The Gangliosidoses-Schneck et al .

gangliosides were also found in the diencephalon . He also reported that at birth the molar ratios of GT and GD I , approach unity. With increasing age, GD 1 , declines and GT increases. Therefore, when comparing ganglioside data from different laboratories one must realize that results will vary according to (1) whether the tissue is preserved by cold or formalin ; (2) the type of lipid extraction procedure used, e .g ., ratios of chloroform-methanol utilized ; (3) the solvent partitioning method employed to separate the gangliosides from other extracted lipids ; and (4) the stage of maturation and the area of tissue being analyzed . The term ganglioside storage disorder should he reserved for primary disorders of ganglioside metabolism with an absolute increase of total ganglioside concentration . Only the infantile and the systemic late infantile forms of amaurotic idiocy meet these criteria . There are several other diseases which are not primary disorders of ganglioside metabolism but which are nevertheless associated with total quantitative and/or qualitative alterations of ganglioside concentrations (Table in) . C

M2

GANGLIOSIDOSIS (TAY-SACHS DISEASE)

Clinical . The clinical recognition of TSD is based upon a typical and predictable pattern of signs and symptoms [15,42,128-130] . The clinical picture is dominated by the appearance, during infancy, of psychomotor deterioration, blindness, "cherry-red spot" in the

macula and an exaggerated extension response to sound ("hyperacusis" or "startle reaction") . The exaggerated extension response to sound, which has erroneously been labeled hyperacusis, is one of the earliest clinical signs to appear . Sudden sharp, not necessarily, loud noise will elicit a sudden extension of the upper extremities and a startled facial expression . The motor reaction resembles decerebrate posturing and myoclonus . In a recent study twelve of fifteen children with TSD showed this acousticomotor reaction within the first two months of life [130] . The frequency and amplitude of this acousticomotor reaction often decreases in the terminal stages of the disease . Cherry-red macula is the clinical sign most frequently equated with TSD . The sign is said to be due to the degeneration of ganglion cells at the macula which results in the unmasking and framing of the underlying vascular choroid [21-23] . It may not be present during the perinatal period [130] . Blindness, which becomes noticeable between the twelfth to eighteenth months of life, is of central rather than peripheral origin [130] . Although the child may not show any affective response to visual stimuli, the pupils will often react to light . The pupillary response to light persists well into the terminal vegetative state . The electroretinogram, which measures the reaction of rods and cones, becomes abnormal late in the disease [130] . Optic atrophy is evident by two years of age . It may precede or follow the blindness [130]-

TABLE III DISEASES WITH SECONDARY DISTURBANCES IN GANGLIOSIDE METABOLISM

Primary Disorder

Disease Gargoylisrn and variants Niemann-Pick disease Infantile metachromatic leucodystrophy Subacute sclerosing leucoencephalitis Infantile Gaucher's disease

Total Ganglioside Content

Increased Fractions

References

Mucopolysaccharidc

Increased

GM, GM, GM,

[120-122]

Sphingomyelin Sulfatide

Cerebroside

Normal

Gml GM2 Gma Ga, * G, : GM, Gms C,, Gxa Gma Gma Gma Gma

[723,124] [121,12.5]

Viral?

Increased Increased (white matter) Normal

[126] [727]

* According to Suzuki, the minor fractions G, :, and C,, have Rf values between Grub and GD,e and Gma and GM,, respectively . Because their structure has not been established, they cannot be translated into Svennerholm's nomenclature . AMERICAN JOURNAL OF MEDICINE



251

The Gangliosidoses-Schneck et al . Jampel [131] has described the evolution of ophthalmologic signs in the various stages of the disease . Failure to sit by six to seven months is the symptom most likely to bring the child to the attention of the pediatrician or neurologist . However, many parents report that before this period the infant appeared apathetic and had decreased spontaneous motor activity . Rarely, a child with TSD may sit without support, or even crawl . By one year, the retardation in motor activity is obvious . The child no longer sits, and is unable to hold or transfer objects . By two years of age there is little or no spontaneous motor activity . Hypotonia, especially of the pectoral girdle, may be present before four months and often persists into the vegetative state . Spasticity is another early and consistent sign . Seizures are rare before the first year [132] . The first epileptic manifestation is usually associated with periods of abnormal laughter and paroxysmal episodes of autonomic dysfunction . The electroencephalogram [132,133] usually appears normal during the first year of life . The second year is associated with paroxysmal discharges of high voltage slow wave activity with single and multiple spike and sharp wave complexes . During this period focal and generalized convulsions and myoclonic seizures are common . Terminally, there is a decrease in both spike discharges and convulsive seizures . Except for the development of megalocephaly during the second year [134] there are few gross physical defects or anomalies . Signs of precocious puberty may appear after the age of two and probably reflect hypothalamic involvement. Electrocardiographic abnormalities have been reported in the older children [135] . Wallace et al . [136] presented electron microscopic evidence and Svennerholm [127] biochemical data suggesting ganglioside storage in the liver . However, hepatomegaly is absent and liver function tests are normal . Occasional vacuolated lymphocytes are seen in TSD by light microscopy [137,138] but no lipid cytosomes were found by electron microscopy [138] . No specific roentgenographic abnormalities have been noted in TSD . Early and marked elevation of serum glutamic oxaloacetic transaminase (SCOT) and

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lactic dehydrogenase (LDH) activity [139], and decrease in serum fructose- l-phosphate aldolase (F-1-PA) activity is characteristic of this disorder [140] . A decrease in serum F-I-PA activity is found in the heterozygote also [141] . Clinical signs of fructose intolerance nevertheless are absent [142] . Recent studies of serum LDH isoenzymes suggest an elevation in the ratio of the third to fifth fraction [143] . It may be difficult to diagnose TSD in the perinatal period . The cherry-red macula is not specific for this disease and may even be absent in the perinatal period [130,135] . A transitory hyperextension response to sound may be found in a small percentage of normal infants [130] . A perinatal elevation of SGOT and LDH can reflect nonspecific brain damage or liver immaturity [144] . A decrease in F-1-PA is found in the heterozygote as well as the homozygote . Psychomotor retardation may not be obvious before four months . The electroencephalogram is usually normal until the age of one year . TSD is transmitted as an autosomal recessive trait . It is found predominantly but not exclusively in eastern European (Ashkenazi) Jews [145-147] . The carrier rate in this ethnic group is 1 :30 . In Sephardic Jews the carrier rate is 1 :100 whereas in Yemenite Jews and in non-Jews it is 1 :300 . Demographic studies indicate epicenters in northeast Europe . The augmented gene frequency of TSD in Jews suggests that TSD heterozygotes enjoy a small, subtle, but distinctive survival advantage during the reproductive period [148] . Pathology Brain . During the progression of the disease the striking increment in brain weight and volume results in significant megaloencephaly . The increase in brain dimensions becomes particularly pronounced after twentyfour months and averages over 40 per cent of the expected normal brain weight [149] . Light Microscopy . Histologically there is a marked and ubiquitous distortion of the cytoarchitecture, without predilection for any specific cortical layer. There is generalized involvement of the neurons of the central nervous system, although the degenerative process is not uniformly distributed. The ganglion cells, especially in the early stages of the disease, are markedly distended,

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Fm . 2 . Section from frontal cortex of Tay-Sachs brain showing ballooned neurons with shrunken nuclei displaced to the axonal bases . The Nissl bodies are diminished in number and localized around the nuclei . Nissl stain, original magnification X 125 . and as time progresses become ballooned-out (Fig. 2) . The cytoplasm appears pale and spongy. The Nissl bodies gradually decrease until only a small zone around the nucleus remains . Eventually even this disappears, leaving in its wake a dust-like halo of a granular substance (Fig . 2) . The nuclei are frequently displaced to the periphery and may show varying degrees of disintegration . In protracted cases there is a distinct loss of neurons and the surviving cells present a ghost-like appearance and are devoid of nuclei . The axis cylinders, in various stages of disintegration, eventually become reduced in number . In general, the greatest decrease of axons occurs in the cerebral cortex, whereas the optic radiation and the brain stem show comparatively little decrease of axons or significant evidence of tract degeneration . In silver preparations the axons frequently show fusiform swellings with marked disturbance of the fibrillary structure . These swellings (also called "torpedoes") are rarely seen during the early stages of the disease . They exhibit the same histochemical reaction as the material deposited within neurons . Demyelination may become quite extensive, and in some cases involves almost the entire white matter [150152] . During later stages the glial response increases and eventually mobile microglial cells are present in abundance . These cells are distended and are densely filled with large granules which show qualitatively staining properties similar to those seen in the neurons .

astrocytes which at times aggregate in large clusters . Some are multinucleated and numerous granules adherent to the base of the processes are frequently seen . Cerebellum : In general, the cerebellum participates in the neuronal storage process . In contrast to the brain, its weight and volume fails to increase. There is shrinkage of the folia, the cells of the external granular layer are decreased in number, and there is a marked loss of Purkinje cells . Those remaining show a considerable irregularity in distribution, size and shape . In many instances the Purkinje cells are distended with lipid material and eventually disappear . However, compared to the cerebral hemispheres, the axons are only slightly decreased in number, and there is only a mild microglial and astrocytic reaction [149] . Spinal cord : The cells of the spinal cord show changes similar to those observed elsewhere in the central nervous system . The cells of the anterior horn are more extensively affected than those of the posterior or lateral horns [149] . Autonomic nervous system : The neurons of the autonomic nervous system, including those of the sympathetic ganglia, the myenteric plexus of the bowel, ganglion cells of the pancreas, adrenal gland, and in the wall of the urinary bladder, all show morphologic and tinctorial changes which are quite similar to those noted in the neurons of the central nervous system . Nakai and Landing [153] suggested that a study of the myenteric plexus neurons obtained by rectal biopsy might be a useful adjunct in the diagnosis of neurolipidoses . The feasibility of this procedure has been confirmed by others [154,155 . Electron Microscopy . Central nervous system : Terry, Korey and their co-workers [156, 1571 observed in electron microscopic studies of cerebral biopsy specimens that most of the distended neurons contained membranous cytoplasmic bodies which measured 0 .5 to 2 .0 l, . (median 1 .0 µ) in diameter. These bodies are composed of closely packed, frequently concentrically arranged membranes (Fig 3) . Many of these concentric membranes surround a homogeneous or finely granular central zone . The axis cylinders and the ballooned-out dendrites may also contain similar membranous cytoplasmic bodies_ The aggregates observed in the axis cylinders probably correAMERICAN JOURNAL OF MEDICINE

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Fic. 3 . Electron photomicrograph of portion of a neuron from a cortical biopsy specimen from a child with Tay-Sachs disease . The cell cytoplasm contains numerous large membranous cytoplasmic bodies characteristic for the disease. Osmium fixation, methacrylate embedding, original magnification X 34,200 . spond to the "torpedoes" seen by light microscopy . Liver : Studies of the fine structure of the liver reveal no obvious anatomic abnormalities [158] . Some of the liver cells contain membrane-filled structures near the bile canaliculi [158] . These structures often consist of either oval-shaped, membrane-bound bodies containing parallel membranes or of lipofuscin bodies with parallel or concentrically arranged membranous inclusions. Congeries of lipid bodies may be seen (Fig . 4) . Occasional structures resemble the membranous cytoplasmic bodies found in the brain of patients with TSD . Myenteric plexus : In biopsy specimens from the rectal wall, unusual cellular inclusions occur in neurons as well as in the interstitial cells of the myenteric plexus [159] . The ganglion cells contain large concentrically lamellated membranous cytoplasmic bodies similar to those found in cortical neurons, as well as many granular dense bodies containing few membranes and some small vesicles . Histochemistty Light Microscopy . The intraneuronal material in TSD stains weakly or not at all with VOL .

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Sudan to or iv, moderately black with Sudan black B, gives a positive Smith-Dietrich and Baker reaction for phospholipids, stains blue with the Nile blue technic for acid fats and fatty acids, and the periodic acid-Schiff reaction is intensely metachromatic [49,96,160] . The storage material reacts strongly with the orcinol-sulphuric acid test for carbohydrates and gives a positive Okamoto test for sphingolipids [161] . Diezel [162] found that the Bial reaction for neuraminic acid was negative in ganglion cells but positive in glial cells . This suggested that the material in ganglion cells is a glycolipid bound to protein, whereas in glial cells the sialic acid containing glycolipid is protein . free . These histochemical findings have been confirmed by other investigators [163] but, as Svennerholm has pointed out, the free translation of staining reactions into biochemical structural data is of questionable validity [164] . In 1955 Franceschetti, Wildi and Klein (165] observed large amounts of acid phosphatase in neurons of patients with TSD . Lazarus et al . [166] confirmed these observations and found this enzyme activity also in glial cells . The distribution of acid phosphatase in

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The Gangliosidoses-Schneck et al .

FIG . Electron photomicrograph of portion of hepatocyte of patient with Tay-Sachs disease showing two congeries (arrows) consisting of concentrically lamellated inclusions similar to membranous cytoplasmic bodies as well as small vacuoles. Original magnification X 4,320 .

neurons of patients with TSD corresponds to the intracytoplasmic periodic acid-Schiff, Luxol fast blue positive and sudanophilic material that is observed by light microscopy [1671 . Electron Microscopy . Using electron microscopy, Wallace et al . [168] studied the fine structural localization of acid phosphatase and thiolacetate esterase activities in biopsy specimens from the cerebellum of children with TSD . It was observed that acid phosphatase and organophosphorus-resistant esterase activities are localized largely in membranous cytoplasmic bodies of Purkinje cells and stellate or basket cells of the molecular layer, as well as in macrophages and astrocytes of the granular cell layer (Fig . 5) . Hypertrophic astrocytes in the granular layer also contained numerous spherical dense bodies which were acid phosphatase positive. Acid phosphatase activity was also noted within the various lipid cytosomes of hepatocytes [158,159] . Biochemistry . TSD is biochemically identified with abnormally high concentrations of G M, in the central nervous system [46,58,59,75, 169-171] . No significant structural differences (exclusive of sterochemistry) have been found between ganglioside in TSD and its counter-

part in normal brain [1721 . Abnormal concentrations of G, 1 _ have also been found in the liver and spleen of patients with TSD [127] . Svennerholm [171] reported that the ceramide moiety of the GM2 ganglioside in liver and spleen contained equal amounts of C rs and C22_24 fatty acids. He suggested that the C ls ganglioside, the ganglioside usually found in brain specimens from people with TSD, was transported from the central nervous system to the liver. The C_2_24 ganglioside, on the other hand, appeared to be synthesized in situ . If the reported increased concentration of G M2 in liver and spleen [164] and the presence of membranous cytoplasmic bodies in the liver in TSD [158,159] is substantiated, TSD should be considered a systemic disorder of ganglioside metabolism. There are also significant alterations in the other cerebral lipids of white matter [127] . In TSD, the total lipids in white matter may be reduced to half of the normal . The marked decrease in total cholesterol and total phospholipids and the associated increase in the cholesterol esters is indicative of a demyelinating or myelinoclastic process . There is also biochemical evidence for delayed or impaired AMERICAN JOURNAL OF MEDICINE



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Porton of Purkinje cell layer from a ten month old child with TaySachs disease (glutaraldehyde fixation and incubation for acid phosphatase activity) . The reaction product is localized consistently within membranous cytoplasmic bodies (arrows) in granule cell . Original magnification X 12,300-

Fit . 5 .

myelination, The persistence of a relatively high concentration of C, s sphingosine in the TSD ganglioside [118] and the abnormally high water content in white matter [127] are reminiscent of fetal brain . The enzymatic defect in TSD is still unknown . The three enzyme systems that have been implicated are neuraminidase, galactosyltransferase and galactosaminidase (Fig . 6) . The high concentration in TSD brain of the corresponding asialo or sialic acid free derivative of TSD ganglioside [12,173] indicates neuraminidase activity in TSD brain. Kaufman et al . [108] suggested that the accumulation of large quantities of TSD ganglioside may be due to decreased activity of a galactosyltransferase system . One would, if this were correct, expect a marked absolute reduction in the concentration of GM , in TSD as compared to normal but this was not the case for TSD brains analyzed by Suzuki [119] . Nacetyl galactosaminidase is the third enzyme system that has been implicated in the pathogenesis of TSD [127] . However, the comparatively slight increase in concentration of ceramide dihexosides [121, together with the relatively low concentration of the ceramide tetrahexosides (GMI ), vitiates this hypothesis . VOL .

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Girt GANGLIOSIDO5IS (LANDING'S DISEASt) (SYSTEMIC LATE INFANTILE LIPMOSIS)

A number of cases reported in the literature as "familial neurovisceral lipidosis" [5], "variant of Hurler's syndrome" [37], "Tay-Sachs disease with visceral involvement" [38,41], "pseudo-Hurler's disease" [39], "Landing's disease" [174], "systemic late infantile gangliosidosis" [8], "a biochemically special form of infantile amaurotic idiocy" 140], probably are all examples of the specific disease entity G M1 gangliosidosis. However, only a few of these reported cases have been biochemically analyzed for increased concentrations of G Mr ganglioside in nonformalin fixed tissue [1,7,8, 41,174,1751 . Clinical. The clinical features delineating

this disorder are the roentgenographic findings resembling Hunter-Hurler syndrome, (3)

} Gal .

Cer: Glue .-Gal . < GaINAc'~ G„, 7 NA~ "t NANA 1 Asialo derivative of G,,, Fm . 6 . Biosynthetic pathways-G, (1) N-acetylneuraminidase . (2) Calactosyltransferase. (8) N-acetylgalactosaminidase .

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The Gangliosidoses-Schneck el al .

hepatomegaly and,/or splenomegaly, psychomotor deterioration, foam cells in reticuloendothelial tissue, and vacuolated lymphocytes [39,172] . Most or all of these features were found in the thirteen cases so far described [174] . This familial disorder appears to be due to an autosomal recessive gene with no apparent racial predilection . Clinical signs are present within the first six months of life and the patient rarely survives beyond the age of two. The immediate cause of death is usually pneumonitis . Because of the frequent cardiac involvement, congestive heart failure is a potentially fatal complication [1741 . The roentgenographic picture resembling Hunter-Hurler disease is described in detail by Landing et al. [6] . The characteristic roentgenographic changes in Hunter-Hurler disease are mainly found in the head, trunk and upper extremities . The skull is large, the calvariant dense and the pituitary fossa is shallow and "J"-shaped . In the trunk, the ribs are widened and the cortices thin . The vertebral bodies, especially those in the dorsolumbar region, have a typical beaked appearance . The humerus shows a peculiar widening of the midshaft with tapering at both ends . Metacarpal and phalangeal abnormalities are also common . The osseous abnormalities, which increase with age, were found in the overwhelming majority of cases studied . The coarse, thickened facial features and thick, large tongue are similar to those ascribed to gargoylism . Hepatomegaly and/or splenomegaly is usually present, and peripheral edema is common . Psychomotor retardation, which is apparent during infancy, exhibits a pattern of regression similar to that seen in TSD . However, amaurosis and "hyperacusis" are rare . Cherryred maculas were seen in about 20 per cent of the recorded cases, and corneal opacities were found in two of the eight cases reported by Landing [39] . Foam cell histiocytes resembling NiemannPick cells may be seen in biopsy specimens of bone marrow, liver or rectal tissue . In a compilation of thirteen cases vacuolated lymphocytes were found in nine [174] ; they were either absent or not noted in the remaining four . Abnormal leukocyte granulations (-A1der/Reilly bodies) may also be present . Unlike TSD there is no marked elevation of SGOT and LDH or depression of F-I-PA activity

[8,174] . Only in one case [175] has there been an apparent increase in urinary mucopolysaccharities . Pathology . The brain weight is usually moderately increased . The neurons are ballooned-out and resemble those seen in TSD [8,39,172,173] . There is moderate astrocytosis . The Purkinje cells show both cytoplasmic and axonal swelling and the cerebellar granular layer is hypocellular. The white matter also shows microgliosis and moderate demyelination . The anterior horn, the sympathetic ganglia and the neurons of the myenteric plexus exhibit changes similar to those in TSD. A marked hepatosplenomegaly is common . There is cytoplasmic vacuolization of the respiratory gland epithelium, of the acinar and ductular cells of the pancreas and of the hepatocytes . Swelling of the glomerular epithelium and vacuolization of the cytoplasm of the renal tubules is similar to that seen in Fabry's disease . Histiocytes with foamy cytoplasm have been found in reticuloendothelial tissue of various organs . Histochemically, the stored material is soluble in alcohol, is sudanophilic and gives a positive reaction with the periodic acid-Schiff, Bial, Hale's and Alcian blue reagents [6,121] . Enzyme histochemistry reveals variable activities for acid phosphatase and esterase within the neurons . In one biochemically undefined case of visceral neurolipidosis [176], metachromatic material was found in vacuoles of glomerular epithelium of renal complex polysaccharide . A biopsy specimen of rectal tissue, however, failed to reveal distended neurons with storage material . No biochemical studies were carried out in this case, nor were other tissues examined histologically . Electron microscopic studies [8,175] showed rounded, oval membranous cytoplasmic bodies in neurons similar to those seen in TSD (Fig . 7) . In addition, bodies which contain parallel arrays of membranes are also seen . Astrocytes contain large numbers of membranebound circular or oval bodies surrounding linear or circular densities, as well as an amorphous material of high density . The reaction for acid phosphatase is present in these membrane-bound bodies, whereas membranous cytoplasmic bodies show little or no reaction . In the liver, the hepatocytes, Kupffer cells and vascular epithelium contain large vacuoles filled with a dense granulofibrillar material [8] . AMERICAN JOURNAL OF MEDICINE

The Gangliosidoses-Schneck et al .

257

Portion of neuron (N) of patient with G s„ gangliosidosis (systemic late infantile lipidosis) . It is filled with numerous cytosomes (arrows) which are quite similar to the membranous cytoplasmic bodies of Tay-Sachs diesase . A satellite glial cell (SC) contains a different type of abnormal cytoplasmic lipid bodies composed of many small vesicular myelin figures and of packed straight or curved lamellar structures . Extremely pleomorphic organelles are found in the cytoplasm of an astrocyte (A) . (Published through the courtesy of Dr. Kinuko Suzuki, Albert Einstein College of Medicine, New York) . Original magnification X 9 .300 . Fm . 7 .

Biochemistry . Chemical analysis of brain, liver and spleen in systemic late infantile amaurotic idiocy indicates storage of a ganglioside whose Rf value, carbohydrate content, structure and sequence, and fatty acid ratios are identical with G Mt of normal brain [7,12, 120,174,175] . This ganglioside, in G, gangliosidosis, may comprise more than 70 per cent of the total N-acetyl-neuraminic acid in cerebral gray matter . GMe and GM „ are also increased [118], as is a ceramide tetrahexoside chemically related to the asialo derivative of G Mr [12] . Brain cerebroside sulfate and sphingomyelin were found to be equivalent to control values, and white matter cholesterol concentrations were slightly diminished [7] . In the case studied by O'Brien et al . [71 the concentrations of G stt in liver and spleen were 2.1 and 2 .3 per cent of total lipids, far in excess of normal concentrations . This increased concentration of visceral ganglioside may not be the sole chemical abnormality responsible for the "pseudo-Hurler" syndrome . Many of the clinical and pathologic findings resemble a mucopolysaccharide storage dis, VOL .

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ease even though there was no obvious increase in the urinary excretion of mucopolysaccharides in most of the cases studied . However, Attal and co-workers [175] reported a case of gangliosidosis with increased concentration of G M2 in brain and a positive urinary reaction for mucopolysaccharides . The primary enzymatic defect in this disorder is not known . The term gangliosidosis should be limited to primary disorders of ganglioside metabolism with an absolute increase of tissue ganglioside concentration . Until the specific enzymatic defect for each type of ganglioside storage disease is established, identification of these various disease entities should be based upon combined clinical, biochemical and pathologic criteria . ADDENDUM

After this paper was submitted, several studies were published which further support these conclusions. The report of a lipid in TSD heart with an R£ value similar to G Mz ganglioside is further evidence for systemic



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The Gangliosidoses-Schneck et al .

storage case

of GM2

ganglioside in

TSD [177] . A

of systemic G m, gangliosidosis was de-

scribed with electron microscopic and clinical features similar to late infantile amaurotic idiocy [178] . It has been suggested that Gut gangliosidosis be divided into type I and type

u.

Type I would be systemic GM, gangliosidosis with visceromegaly and skeletal changes on the roentgenogram, whereas type it would be those cases of GM , neuronal lipidosis in which these changes did not take place [179] . Finally, Suzuki [180] found that GM, gangliosidosis appears to be a combined cerebral gangliosidosis and visceral mucopolysaccharidosis . REFERENCES 1 . NORMAN, R . M . and WOOD, N . A congenital form of amaurotic family idiocy . J. Neurol. Neurosurg . & Psychiat ., 4: 175, 1941 . 2 . TAY, W. Symmetrical changes in the region of the yellow spot in each eye of an infant . Tr . Ophth . Soc . U. Kingdom, 1 : 155, 1881 . 3 . SACHS, B . On arrested cerebral development with special reference to its cortical pathology . J . Nerv, 6, Ment. Dir ., 14: 541, 1887 . 4. JANSKY, J . fiber einen noch nicht beschriebenen Fall der familiaren amaurotischen Idiotic mit Hypoplasie des Kleinhirns . Ztschr . f.d . Erforsch. and Behandl. jugendl . Schwachsinns, 3 : 86, 1909.1910. 5 . BlrtscHOwsxY, M . fiber spatinfantile familiare amaurotische Idiotic mit Kleinhirnsymptomen . Deutsch . Ztschr . Nervenh ., 50 : 7, 1914. 6. LANDING, B . H., SILVERMAN, F. N ., CRAtc, J . M ., JACOBY, M. D., LAHEY, M . D . and CHADWICK, D . L . Familial neurovisceral lipidoses . Am . J . Dis . Child ., 108 : 503, 1964 . 7 . O'BRIEN, J . S., STERN, M . B ., LANDING, B . H ., O'BRtEN, J . K . and DONNELL, G . N . Generalized gangliosidosis . Am . J. Dis . Child., 109 : 338, 1965 . 8 . GONATAS, N . K . and GONATAS, J . Ultrastructure and biochemical observations on a case of systemic late infantile lipidosis and its relationship to Tay-Sachs disease and gargoylism . J. Neuropath . & Exper . Neurol., 24 : 341, 1965. 9 . VOGT, H . fiber familiars amaurotische Idiotic and verwandte Krankheitsbilder, Monatsschr . Psychiat . It. Neurol, 18 : 161, 1905 . IO . SPIELMEYER, W . fiber familiare amaurotische Idiotien. Neurol. Centralbl ., 24: 620, 1905 . 11 . Ku m, H . Ober eine Spatform and ihre heredo . familiaren Grundlagen . Ztschr, ges. Neurol, & Psychiat ., 95 : 169, 1925 . 12. SuzuKt K. and CHEN, G . C. Brain ceramide hexo. sides in Tay-Sachs diesease and generalized gangliosidosis (G,,,,-gangliosidosis) . J . Lipid Res, S : 105, 1967 . 13 . TAY, W. Third instance in same family of sym . metrical changes in the region of the yellow spot in each eye of an infant closely resembling those of embolism . Tr. Ophth . Soc . U . Kingdom, 4 : 158,1884 .

14 . TAY, W . A fourth instance of symmetrical changes in the yellow spot region of an infant closely resembling those of embolism . Tr. Ophth . Soc . U. Kingdom, 7 : 125, 1892 . 15. SACHS, B. A family form of idiocy. New York J. Med, 63 : 697, 1898 . 16. VOLK, B . W ., SCHNEmt, L., SAIFER, A . and ARONSON, S. M . In : Tay-Sachs Disease. Edited by Volk, B . W . New York, 1964 . Grune & Stratton, Inc. 17 . PETERSON, F . A case of amaurotic family idiocy with autopsy. J . Nerv. & Ment . Dis., 25 : 529, 1898 . 18 . HIRScB, W . The pathological anatomy of a fatal disease of infancy with symmetrical changes in the region of the yellow spot . J. Nerv . & Ment . Dis, 25 : 538, 1898 . 19. SCHAYFER, K. Zur Pathogenese der Tay-Sachs'schen Idiote . Neurol . Centralbf., 24 : 386, 1905 . 20 . SCHAFFER, K . Pathogenesis of amaurotic idiocy . Arch . Newel, 24 : 765, 1930. 21 . COLLINS, T. Sciatic nerves ; occular changes . Med .Chir. Tr., 80 : 101, 1897 . 22. POYNTON, F . J., PARSONS, J. H. and HOLMES, G. A contribution to the study of amaurotic family idiocy. Brain, 29 : 180, 1906. 23 . GREENFIELD, J, G. and NEVIN, S . it. Amaurotic family idiocy: study of a late infantile case . Tr . Ophth . Soc. 11. Kingdom, 53: 170, 1933 . 24 . BATTEN, F. E. Cerebral degeneration with sym . metrical changes in the maculae in two members of a family . Tr. Ophth . Soc . U. Kingdom, 23: 386, 1902-1903 . 25 . SJSGREN, T . Die juvenile amaurotische Idiotic . "Klinische and erblichkeits-medizinische Untersuchungen." Hereditas, 14 : 197, 1931 . 26- MAYOU, M . S . Cerebral degeneration with symmetrical changes in the maculae in three memhers of a family . Tr. Ophth . Soc . U . Kingdom, 24: 142, 1904 . 27 . VAN BACH, K . and HORTLINC, H. Blodfynd vid juvenil amaurotisk idioti . Nord Med, 38 : 1072 . 1948 . 28 . RAYNER, S . Juvenile amaurotic idiocy : diagnosis of heterozygotes . Acta genet ., 3 : 1, 1952 . 29 . HARLEM, O . K . Juvenile cerebroretinal degeneration (Spielmeyer-Vogt) : blood and EEG findings in a family of 10 members . Am . J. Dis . Child ., 100 : 918, 1960 . 30 . Scams, F . G . K . fiber die amaurotische Idiotic . Fortschr . Med ., 28 : 1912 . Zur pathologischen Idiotic. Ztschr. ges. Neurol. & Psychiat„ 10 : 303, 1912 ; 46, 1919 . 31 . SEITELBERGFR, K, VoGEL, G . and STEPAN, H. Arch . Spatinfantile amaurotische Idiotic. Psychiat ., 196 : 154, 1957 . 32 . SEITELBERGER, F ., JACOB, H . and SCHNABEL, R . The myoclonic variant of cerebral lipidosis . In : Inborn Disorders of Sphingolipid Metabolism, p . 43 . Edited by Aronson, S . M . and Volk, B . W . New York, 1967 . Pergamon Press, Inc. 33 . EPSTEIN, J . Amaurotic family idiocy . New York J . Med ., 106 : 887, 1917 . 34 . HACBERG, B ., HOLTQurST, G, OHMAN, R. and AMERICAN JOURNAL OF MEDICINE



The Gangliosidoses-Schneck et al . SVENNERHOLM, L . Congenital amaurotic idiocy . Acta paediat . scandinav ., 54 : 116, 1965 . 35 . HALLERVORDEN, J . Spatform der amaurotischen Idiotic unter dem Bilde der Paralysis agitans . Monatsschr . Psychiat . U . Neurol., 99 : 74, 1938 . 36 . MOSCHEL, R . Amaurotic Idiotic mit enter hesonderen Form von Pigmentablagerung . Deutsche Ztschr . Nervenh ., 172 : 102, 1954 . 37 . CRAIG J. M., CLARKE, J . T. and BANKER, B . Q . Metabolic neurovisceral disorder with accumulation of unidentified substance : variant of Hurler's syndrome% Am . J . Dis . Child ., 98 : 577, 1959 . 38. NORMAN, R. M ., URICH, H ., TINGEY, A . H . and GOODBODY, R . A . Tay-Sachs disease with visceral involvement and its relationship to NiemannPick disease, J. Path . & Beet., 78 : 634, 1964. 39. LANDING, B . H . and RUBINSrEIN, J . H . Biopsy diagnosis of neurologic diseases in children with emphasis on the lipidoses . In : Cerebral Sphingolipidoses. A Symposium On Tay-Sachs Disease and Allied Disorders, p . 1 . Edited by Aronson, S . M . and Volk, B . W . New York, 1962, Academic Press, Inc . 40. JATZKEWITZ, H . and SANDHOFF, K . On a biochemically special form of infantile amaurotic idiocy . Biochim . et biophys, acta, 70 : 354, 1963 . 41 . FARKAS-BARGETON, E . Idiotic amaurotique infantile avec surcharge viscErale . In : Proceedings of the 5th International Congress on Neuropathology, p . 135 . Edited by LOthy, F . and Bischoff, A . 1965. Excerpta Medica Foundation . 42 . GLOBUs, J . H . Amaurotic family idiocy . J . Mt . Sinai Hosp ., 9 : 451, 1943. 43 . KLENR, E . Beitrage zur Chemie der Lipoidosen . Niemann-Picksche Krankheit and amaurotische Idiotic . Ztschr . Physiol . Chem ., 262 : 128, 19391940 . 44. KLENK, E . Beitrage zur Chemie der Lipoidosen . Ztschr. Physiol. Chem, 267 : 128, 1940 . 45. KLENK, E . Neumminsaure, das Spaltprodukt eines neuen Gehirnlipoids . Ztschr . Physiol . Chem ., 268 : 50, 1941 . 46 . KLENK, E . Vber die Ganglioside des Gehirns bei der infantilen amaurotischen Idiotic vom Types Tay-Sachs . Ber. deutsch . chem . Gesellsch ., 75 : 1632, 1942 . 47 . KLENK, E . Vber die Ganglioside, eine neue Gruppe von zuekerhaltigen Gehirnlipoiden . Ztschr . Physiol . Chem ., 273 : 76, 1942 . 48 . DIEZEL, P . B . Die Stoffwechselst6rungen der Sphingolipoide ; ein histochemische Studie an den primaren Lipoidosen and den Entmarkungskrankeiten des Nervensystems . Heidelberg, 1957 . Springer-Verlag. 49, DIEZEL, P . B. In : Modern Scientific Aspects of Neurology, p . 98 . Edited by Comings, J . N . London, 1960. Edward Arnold & Co . 50 . ScesnLER, C . and KAHLKE, W . Gangliosidoses . In : Lipids and Lipidoses . p . 213 . Edited by Schettler, G . New York, 1967 . Springer-Verlag . .51, EDGAR, C . W . F . Anatomo-chemical research in demvelinating conditions and inborn errors of metabolism . In : Proceedings of 5th International Congress on Neuropath . Edited by LOthy, F . and VOL . 46, FEBRUARY 1969

259

Bischoff, A . Amsterdam, The Netherlands, 1966 . Exerpta Medica Foundation . 52 . TERRY, R . D . and KoREY, S. R . Membranous cytoplasmic granules in infantile amaurotic idiocy . Nature, 188 : 1000, 1960 . 53 . SAMUELS, S ., KOREY, S . R ., GONATAS, J ., TERRY, R . D. and WEBS, M . The membranous granules in Tay-Sacks disease . In : Cerebral Sphingolipidoses. A Symposium on Tay-Sachs Disease and Allied Disorders, p . 309 . Edited by Aronson, S . M ., and Volk, B . W . New York, 1962 . Academic Press, Inc. 51 . VOLK, B . VV., WALLACE, B . J ., ScHNECR, L . and SAIFER, A . Late infantile amaurotic idiocy . Arch . Path ., 78 : 483, 1964. 55 . ALEU, F . P ., TERRY, R . D. and ZELLWEGER, H . Electron microscopy of two cerebral biopsies in gargoylism . J . Neuropath . & Exper. Neural, 24 : 304, 1965 . 56 . WALLACE, B . J ., KAPLAN, D ., ADACHI, M ., SCHNECK, L. and VOLK, B . W . Mucopolysaccharidosis type In . Morphologic and biochemical studies of two siblings with Sanfilippo syndrome . Arch . Path ., 82 : 462, 1966 . 57 . DIEzEL, P . B . Juvenile form of amaurotic idiocy. In : Inborn Disorders of Sphingolipid Metabo . lism, p . 23 . Edited by Aronson, S. M. and Volk, B . W ., New York, 1967. Pergamon Press, Inc . 58 . KLENK, E ., VATER, W . and BARTSCH, G . Storage of gangliosides in nervous tissue in Tay-Sachs disease and changes in material preserved in formalin . J. Neurochem ., 1 : 203, 1957 . 59 . SAWER, A ., ROBIN, M . and VOLK, B . W . Chromatographic studies of normal and Tay-Sachs ganglioside (peptide-strandin) . J . Neurochem ., 10 : 577, 1963. 60 . TINGEY, A . The results of glycolipid analysis in certain types of lipidosis and leucodystmphy. .1. Neurochem ., 3 : 230, 1950 . 61 . JERVIS, G . A . Juvenile amaurotic idiocy . Am . J. Dis Child ., 97 : 663, 1959 . 62 . CONATAS, N . K ., TERRY, R. D ., WINKLER, R ., KOREY, S . R, GOMEZ, C . J . and STEIN, A . A case of juvenile lipidosis : the significance of electron microscopic and biochemical observations of a cerebral biopsy . J. Neuropath . v Exper. Neural ., 22 : 557, 1963 . 63 . SVENNERHOLM, L . Chromatographic separation of human brain gangliosides . J . Neurochem ., 10 : 613, 1963. 64 . SVENNERHOLM, L . and SOURANDER, P . Investigations on brain autopsy material in Bpidoses . In : Proceedings of 5th International Congress on Neuropathology, p 342 . Edited by L6thy, F . and Bischoff A . Amsterdam, The Netherlands, 1966. Exerpta Medica Foundation . 65 . EDGAR, G, W . F . and VAN BOGAERT, L . Anatomochemical study of white matter . In : Inborn Disorders of Sphingolipid Metabolism, p . 75 . Edited by Aronson, S . M . and Volk, B . W . New York, 1967 . Pergamon Press, Inc . 66. JATZKEWITZ, H ., Paz, H . and SANOHOFF, K. Quantitative Bestimmungen von Gangliosiden and ihren neuraminosaurefreien Derivaten bei infantilen, juvenilen and adulten Formen der

260

The Gangliosidoses-Schneck et al .

amaurotischen Idiotie and einer spatinfantilen biochemischen Sonderform . J . Neurochem., 12: 135, 1965 . 67 . SUZUKi, K . The pattern of mammalian brain gangliosides. II. Evaluation of the extraction procedures, post mortem changes and the effect of formalin preservation . J. Neurochem ., 12 :629, 1965 . 68. SAIFER, A . The biochemistry of Tav-Sacks disease . In : TaySachs Disease, p . 68 . Edited by Volk, B . W . New York, 1964 . Grune & Stratton, Inc . 69 . SYENNERHOLM, L . The gangliosides . J. Lipid Res ., 5 : 145, 1964 . 70 . LEDEEN, R . The chemistry of gangliosides . A review, J . Am . Oil Chem. Soc., 43 : 57, 1966 . 71 . STOFFEI ., W . The chemistry of mammalian lipids. In : Lipids and Lipidoses, p . 1, Edited by G . Schettler. New York, 1967 . Springer-Verlag . 72, KUHN, R . and WIEGANDT, H . Die Konstitution der Ganglio-N-tetraose and des Gangliosids G 1 . Chem . Ber., 96 : 866, 1963 . 75 . FoLdH, J ., ARsova, S . and MEATH, J . A . Isolation of brain strandin . A new type of large molecule tissue component. J . Biol. Chem-, 191 : 819, 1951 . 74 . ROSENBERG, A ., HowE, C . and CHARGAFF, E . Inhibition of influenza virus haemagglutination by a brain lipid fraction . Nature, 177 : 234, 1956. 75 . BERMAN, E . R . and GATT, S . Chemical pathology of glycolipids in brain tissue of Tay-Sachs disease . In : Cerebral Sphingolipidoses . A Symposium on Tay-Sachs Disease and Allied Disorders, p . 237 . Edited by Aronson, S . M . and Volk, B . W . New York, 1962 . Academic Press, Inc . 76, Boorn, D . A . The isolation and assay of gangliosides and their interactions with basic proteins . J. Neurochem ., 9 : 265, 1962 . 77 . FOLCH, J. LEES, M . and SLOANE-STANLEY, G. M . A simple method for the isolation and purification of total lipids from animal tissue . J. Biol. Chem ., 226: 497, 1957 . 78 . GATT, S . and BERMAN, E . R. A new glycolipid in Tay-Sachs brain . Bioehem . & Biophys . Res. Commun ., 4 : 9, 1961 . 79 . TRAMS, E . G . and LAUTER, C . J . On the isolation and characterization of gangliosides . Biochim . et biophys .acta, 60 : 350, 1962 . 80 . Moans, C . J . O . R . and Moats, P . Experimental methods of partition chromatography . In : Separation Methods in Biochemistry, p . 402 . New York, 1963 . Interscience Publishers . Inc . 81 . O'BRIEN, J. S . and RousER, G. The fatty acid composition of brain sphingolipids . Sphingomyelin ceramide, cerebroside and cerebroside sulfate. J . Lipid Res ., 5 : 339, 1964 . 82 . SAMBASIVARAO, K . and MCCLUER, R . H . Lipid components of gangliosides . J. Lipid Res ., 5 : 103, 1964 . 83 . SVENNERHOLM, L . The distribution of lipids in the human nervous system. I . Analytical procedure . Lipids of foetal and newborn brain . J . Ncurochem ., 11 : 839, 1964. 84 . RousER, G., KRITcHEvsRV, G ., GALLI, C . and HEL-

LER, D . Determination of polar lipids : quantitative column and thin layer chromatography . J . Am . Oil Chem . Soc., 42 : 215, 1965 . 85 . STAHL, E. Dunnschicht-Chromatographic . It . Standardisierung, Sichtbarmachung, Dokumcntation and Anwendung . Chemiker-Ztg., 82 : 323, 1958. 86 . MANGOLD, H . K . Aliphatische Lipide, 5 .141 . In Dunnschicht-chromatographic . Edited by Stahl, E . Heidelberg, 1962 . Springer-Verlag . 87 . WAGNER, H . Neuere Ergebnisse auf dem Gehiet der Isolierung and Analytik von Phosphatiden and Glykolipiden . Fette, Selfen, Anstrichmittel, 62 : 1115, 1960. 88 . KOREY, S. R. and GONATAS, J . Separation of till man brain gangliosides . Life Sc., 5 : 296,196389 . PADLEY, F . B . Thin-layer chromatography of lipids. In: Thin-layer Chromatography, p . 86 . Edited by Merrini-Bettolo, G . B . Amsterdam, 1964 . Elsevier Publishing Co. 90 . SVENNERBOLM, L . Quantitative estimation of sialic acids . u . A colorimetric resorcinol-hydrochloric acid method . Biochim - et biophys . acts, 24 : 604, 1957 . 91 . SUZUKI, K . A simple and accurate micromethod for quantitative determination of gangliosidc patterns . Life Sc ., 3 : 1227, 1964 . 92 . HORNING, E . C ., AHRENS, E . H ., LIPSKY, S . R ., MAWsoN, F. H ., MEAD, J . F,, TURNER, D . A, and GOrmvAWx, W. H . Quantitative analysis of fatty acids by gas-liquid chromatography . J. Lipid Res., 5 : 20, 1964. 93 . WELLS, W . S ., SwEELEY, C . C . and BENTLEY, R . Gas chromatography of carbohydrates . In : Bin chemical Application of Gas Chromatography, p . 169. Edited by Szymanski, H . A . New York, 1964 . Plenum Press, Inc . 94, VANCE, E . V . and SWEELEY, C . C . Quantitative determination of the neutral gycosyl ceramides in human blood . J . Lipid Res-, 8 : 621, 1967 . 95 . PASCAL, T, A ., SALVER, A . and GITLIN, J . Comparative studies of normal human and TavSachs gangliosides-an immunochemical approach . In : Inborn Disorders of Sphingolipid Metabolism, p . 289 . Edited by Aronson, S . M . and Volk, B . W . New York . 1967 . Pergamon Press, Inc . 96. DIEZEL, P . B . Histochemischer Nachweis des Gangliosids in Ganglien- and Gliazellen be! Amaurotischer Idiotic and Isolierung der lipoidspeichernden Zellen nach der Methods von M . Behrens . Deutsche Ztmhr . Nervenh ., 171 : 344, 1954 . 97 . LEDEEN, R . Structure of Tay-Sachs ganglioside . Biochemistry, 4 : 2225, 1965 . 98 . BRADY, R . O . and KOVAL, G . J . The enzymatic synthesis of sphingosine, J. Biol. Chem ., 233 : 26, 1958 . 99 . BRADY, R . O ., FORMICA, J . V . and KOVAL, G . J . The enzymatic synthesis of sphingosine II . Further studies on the mechanism of the reaction . J. Rinl . Chem ., 233 : 1072, 1958 . 100 . SRIBNEY, M . and KENNEDY, E . P . The enzymatic synthesis of sphingomyelin . J . Blot. Chem ., 233 : 1315, 1958 . AMERICAN JOURNAL

OF

MEDICINE



The Gangliosidoses-Schneck el al. 101 . GAIT, S. Comparison of four enzymes from brain which hydrolyze sphingolipids . In : Inborn Disorders of Sphingolipid Metabolism, p . 261 . Edited by Aronson, S . M. and Volk, B . W . New York, 1967 . Pergamon Press, Inc. 102 . Rosstraa, R. J . Metabolism of phosphatides. In : Metabolic Pathways, p . 357 . Edited by GreenBerg, D . M . New York, 1960 . Academic Press, Inc . 103 . BURTON, R . M . Biochemistry of sphingosine containing lipids . In : Lipids and Lipidoses, p . 122. Edited by Schettler, G, New York . 1967 . Springer-Verlag . 104 . Gorrsmuts, A . Neuraminic acid : the functional group of some biologically active muroproteins . Yale J . Biol . & Med., 28 : 525, 1956 . 105 . WARREN, L The metabolism of sialic acids . In : Inborn Disorders of Sphingolipid Metabolism, p. 251 . Edited by Aronson, S . M . and Volk, B . W . New York, 1967 . Pergamon Press, Inc . 106 . LICOVAC, K. and ROSENBERG, A : The mechanism by which sialic acid in the gangliosides is rendered immune to sialidase, p . 135. Strasbourg, France, 1967 . First International Meeting of the International Society on Neurochemistry . 107 . KANFER, J . N . and BsABY, R . O. Studies on the biosynthesis of gangliosides . In : Inborn Disorders of Sphingolipid Metabolism, p . 187 . Edited by Aronson, S. M . and Volk, B . W. New York, 1967 . Pergamon Press, Inc. 108 . KAUFMAN, B., BASU, S. and ROSEMAN, S . Studies on the biosynthesis of gangliosides . In : Inborn Disorders of Sphingolipid Metabolism, p . 193 . Edited by Aronson, S . M . and Volk, B. W . New York, 1967 . Pergamon Press, Inc. 109 . Suzunl, K. and KOREY, S . R . Incorporation of D . (C-') glucose into individual gangliosides . Biochem . et biophys . acta, 78 : 388, 1963 . 110. WIECANDr, H . The subcellular localization of gangliosides in the brain . J. Neurochem ., 14 : 671 . 1967 . 111 . YAMAKAwA, T . and SuzUKi, S . The chemistry of the lipids of posthemolytic residue on stroma of erythrocytes. I . Concerning the ether-insoluble lipids of lyophilized horse blood stroma . J . Biochem ., 38 : 199, 1951 . 112 . SVENNERHos .M, L, Isolation of the major gangliosides of human spleen . Acta them, scandinav ., 17 : 860, 1963 . 113 . MCILLwAtN, H . Characterization of naturally occurring materials which restore excitability to isolated cerebral tissues, Biochem . J, 78 : 24, 1961 . 114. DAwsoN, J . and BONE, A . The effect of thiols and gangliosides on the alterations in water sodium and potassium distribution in brain slices by vasopressin and prolamine . J . Neurochem ., 13 : 257, 1966 . 115 . BoraGE, S . Demonstration of serum precipitin to brain ganglioside . Nature, 185 : 392, 1959. 116. VAN HEYNINCEN, W, E . and MILLER, P . A . The fixation of tetanus toxin by ganglioside . J . Gen . Micro blot, 24 : 107, 1961 . A . Neuraminidase : the specific 117. GorrscHALR, enzyme of influenza virus and vibrio cholerae . Biochem . et biophys. acta, 23 : 645, 1957.

VOL .

46,

FEBRUARY

1969

261

115 . RosENarac, A . The nature of the lipophilic portions of the brain gangliosides . In: Inborn Disorders of Sphingolipid Metabolism, p . 267 . Edited by Aronson, S . M . and Volk, B . W . New York, 1967 . Pergamon Press ., Inc . 119 . SUZUKI, K . Ganglioside patterns of normal and pathological brains. In : Inborn Disorders of Sphingolipid Metabolism, p . 215 . Edited by Aronson, S . M. and Volk, B. AV . Now York, 1967 . Pergamon Press, Inc . 120 . BRANTE, G . Chemical pathology in gargoylism . In : Cerebral Lipidoses, p . 164 . Edited by van Bogaert, L ., Comings, J . N . and Lowenthal, M . Oxford, 1957 . Blackwell Scientific Publications . 121, LFDEEN, R ., SAIZMAN, K ., GONATAS, J . and TACHAVY, A . Structure comparison of the major monosialogangliosdes from brains of normal human, gargoylism, and late infantile systemic lipidosis . J. \'europath v Exper . Neurol., 24 : 341, 1965 . 122 . Boast, P . F ., HooctiwINKEL, G . J . M . and Enc.AR, G. W . F . Brain ganglioside pattern in three forms of amaurotic idiocy and in gargoylism . J. Neurochem ., 13 : 1249, 1966 . 123 . KLENK, E . Uber die Verteilung der Neuraminsaure im Cehirn bei der familiaren amaurotischen Idiotic and bei der Niemann-Pick'schen Krankheit (Beitrage zur Chemie der Lipoidosen, 6 . Mitteilung) . Hoppe-Seylers Ztschr . Physiol. Chem ., 282 : 84, 1947 . 124 . CuNrmcs, J . N . Abnormalities in lipid metabolism in two members of a family with Niemanm Pick disease . In : Cerebral Sphingolipidoses . A Symposium on Tay-Sachs Disease and Allied . Edited by Aronson, S . M. and Disorders, p. 171 Volk . B . W . New York, 1962 . Academic Press, Inc . 125 . AUSTIN, J . H . Medical Aspects of Mental Retardation, p . 768 . Edited by Carter, C . Springfield, Ill ., 1965. Charles C Thomas, 126 . NORTON, W . T . S ., PoDnsco, S . and SUzuas, K. Abnormal myelin, ganglioside pattern and lipid values in a subacute sclerosing Mowencephalitic brain . Fed. Proc., 24 : 492, 1965 . 127 . SVENNERHOLM, L. Metabolism of gangliosides in cerebral lipidosis . In : Inborn Disorders of Sphingolipid Metabolism, p . 169 . Edited by Aronson, S . M . and Volk, B . W . New York, 1967 . Pergamon Press, Inc . 128. VAN BOr.AERr, L. Les Idiocies Amaurotique. Maladies Neurveuses Gen6tiques d'ordre Mdtabolique . LBcons de la Chaire Francqui UniversitB de Liege, Belgium, 17, 1962 . 129 . KAN0F, A ., ARONSON, S. M. and VOLK, B . W. Clinical progression of amaurotic family idiocy . Am, J. Dis. Child ., 91 : 656, 1959 . 130 . SCHNECK, L . The clinical aspects of Tay-Sacks disease, p . 16. In : Tay-Sachs Disease. Edited by Volk B. W . New York, 1964 . Grune & Stratton, Inc 131 . JAMPEL, R . S. Eye movements in Tay-Sachs disease . Neurology, 14 : 1013, 1964. 132. SCHNECK, L. The early electroencephalopathie and seizure characteristics of Tay-Sacks disease. Acta neural . scandinav., 41 : 163, 1965 .



262

The Gangliosidoses-Schneck el al.

133 . MORRLL, F . and Tonars, F . Electrophysiological analysis of a case of Tay-Sachs disease . Brain, 83 : 213, 1960, 134. Aronson, S. M ., LEWITAN, A ., RABINER, A. M ., EP . STEIN, N . and VOLK, B . W. The megalencephalic phase of infantile amaurotic familiar idiocy . Arch, Neural . & Psychiat ., 79 : 151, 1958. 135 . SCHNECK, L. and VOLK, B . W . Clinical manifestations of Tay-Sachs disease and Niemann-Pick disease . In : Inborn Disorders of Sphingolipid Metabolism, p. 403, Edited by Aronson, S . M. and Volk, B . IV . New York, 1967 . Pergamon Press, Inc . 136 . WALLACE, B . J . LAZARUS, S . S . and VOLK, B . W. Electron microscopic and histochemical studies of viscera in lipidoses. In : Inborn Disorders of Sphingolipid Metabolism, p . 107 . Edited by Aronson, S . M, and Volk, B . W . New York, 1967 . Pergamon Press, Inc . 137. SPIECEL-ADOLF, AL, BAIRD, H . W ., COLEMAN, H, S . and SZEKELY, G . Vacuolized blood lymphocytes in the lipidoses and other central nervous system diseases with special reference to histo . chemical studies . In : Cerebral Sphingolipidoses . A Symposium on Tay-Sachs Disease and Allied Disorders, p . 129 . Edited by Aronson, S . M . and Volk, B . W. New York, 1962 . Academic Press, Inc. 138 . LAZARUS, S . S., VEFIIAMANY, V . G ., SCHNECK, L . and VOLK, B . W . Fine structure and histochemistry of peripheral blood cells in Niemann Pick disease . Lab . Invest ., 1 .7 : 155, 1967 . 139 . ARONSON, S . M ., SAIFHR, A ., KANOF, A . and VOLK, B . W . Progression of amaurotic family idiocy as reflected by serum and cerebrospinal fluid changes . Ain . J. Med ., 24 : 390, 1958. 140, VOLK, B . W ., ARONSON, S . M . and SALTER, A . Fruc. tow-l-phosphate aldolase deficiency in TaySachs disease . Am . J . Med ., 36 : 481, 1964. . ARONSON, S . M ., PERLE, G ., SAIFHR, A . and VOLK, 141 B . W . Biochemical identification of the carrier state in Tay-Sachs disease . Proc . Soc . Ex per . Blot & Med ., 111 : 664, 1962 . 142 . SCHNECK, L ., PERLE, G . and VOLK, B . W . Fructose tolerance in Tay-Sachs disease . Pediatrics, 36: 272, 1965 . 143 . SAIFHR, A . . SCHNECK, L ., PERLE, G . and VOLK . B . W . Lactate dehydrogenase isoenzyme distribution in the cerebral sphingolipidoses and other neurological disorders . J . Neurochem ., in press. 144 . LENDING, M ., SLOBODY, L . B ., STONE, M. D ., HeEACH, R . E . and MesrERN, J . Activity of glutamic. oxaloacetic transaminase and lactic dehydro. genase in cerebrospinal fluid and plasma of non mal and abnormal newborn infants . Pediatrics, 24 : 378, 1959. 145 . ARONSON, S . M ., VALSAMIS, M. P_ and VOLK, B . W, Infantile amaurotic family idiocy (occurrence, genetic considerations and pathophysiology in the non-Jewish infant) . Pediatrics, 26 : 229, 1960. 146. MYRIANrHOPOULos, N . C . Some epidemiologic and genetic aspects of Tay-Sachs disease . In : Cerebral Sphingolipidoses : A Symposium on Tay . Sachs Disease and Allied Disorders, p . 359 . Ed .

ited by Aronson, S . M . and Volk, B . W . New York, 1962 . Academic Press, Inc . 147 . ILAIRMANN, W . Genetic aspects of lipidoses. In : Lipids and Lipidoses, p . 490. Edited by Schettler, G . New York, 1967 . Springer-Verlag . 148 . MYRIANTHOPOULOS, N . C . and ARONSON, S. M . Reproductive fitness and selection in Tay-Sachs disease. In : Inborn Disorders of Sphingolipid Metabolism, p . 431 . Edited by Aronson, S . M . and Volk, B. \V . New York, 1967 . Pergamon Press, Inc . 149 . VoLK, B . W. Pathologic anatomy . In : Tay-Sachs Disease, p . 36 . Edited by Volk, B . W. New York, 1964 . Grune & Stratton, Inc . 150 . WFNDEROWIc, E., SOKOLANSKY, C . and KLOSSOWSKY, R . Beitrage zur Hisopathologic der Tay-Sachsschen Krankheit nit besonderer Berucksichtigung der dabei statttindenden Faserveranderungen and ihrer Charakteristik. Monatsschr. Psychiat. u . Neural ., 78 : 305, 1931 . 151 . ScHOB, F . Die amaurotische Idiotic . In : Handbuch der Geisteskrankheiten, vol. 11, pt . 7 . Berlin, 1930 . Springer-Verlag. 152 . ARONSON, S. M . and VOLK, B . W . Pathogenesis of white matter changes in Tay-Sachs disease . In : Cerebral Sphingolipidoses : A Symposium on Tay-Sachs Disease and Allied Disorders, p . 15 . Edited by Aronson, S, M . and Volk, B . W. New York, 1962 . Academic Press, Inc. 153 . NAKAI, H . and LANDING, B . H . Suggested use of rectal biopsy in the diagnosis of neural lipidoses . Pediatrics, 26 : 225, 1960 . 154 . RolziN, L ., SLADE, W„ HERSIIDA, H . and Asso, H, Comparative histologic, histochemical and electron microscopic studies of rectal biopsies in a case of adult hereditary cerebromacular degeneration . In : Cerebral Sphingolipidoscs. A Symposium on Tay-Sachs Disease and Allied Disorders, p . 57 . Edited by Aronson, S . M . and Volk, B . W . New York, 1962 . Academic Press, Inc . 155 . BODIAN, M . and LAKE, B . D . The rectal approach to neuropathology. Brit . J . Surg ., 50 : 702, 1963 . 156 . TERRY, R, D ., KOREV, S . R . and WEISS, M . Electron microscopy of the cerebrum in Tay-Sachs disease. In : Cerebral Sphingolipidoses. A Symposium on Tay-Sachs Disease and Allied Disorders, p . 49 . Edited by Aronson, S . M, and Volk, B . W . New York, 1962 . Academic Press, Inc . 157 . TERRY, R . D. and WEISS, M. Studies on Tay-Sachs disease . n . Ultrnstructure of the cerebrum . J . Neuropath . & Exper. Neural ., 22 : 18, 1963 . 158 . VOLK, B . W . and WALLACE, B . J. The liver in lipidosis. An electron microscopic and histochemical study . Am . J . Path ., 49 : 203, 1966 . 159 . WALLACE, B . J., LAZARUS, S. S . and VOLK, B . W . Electron microscopic and histochemical studies of viscera in lipidoses . In : Inborn Disorders of Sphingolipid Metabolism, p . 114 . Edited by Aronson, S . M . and Volk, B. W. New York, 1967. Pergamon Press, Inc. 160. SHANKLIN, W . M ., Iss1DORIDES, M . and SALAM, M. Histochemistry of the cerebral cortex from a case of amaurotic family idiocy . J. Neuropath . L- Ex per. Neural ., 21 : 284, 1962 . AMERICAN JOURNAL OF MEDICINE

The Gangliosidoses-Schneck et al . 161 . WOLMAN, M . Lipids. Second Part . Histochemistry of lipids in pathology . In : Handbuch der Histochemie, vol . 5, p . 208 . Stuttgart, 1964 . Gustav Fischer Verlag. 162 . DiEZEL, P . B . Die Stoffwechselstorungen der Sphingolipoide. Berlin, 1957 . Springer-Verlag . 163 . WOLMAN, M . A histochemical study of various forms of cerebral lipidoses . J. Clin . Path . . 15 ; 324,1962 . 164 . SVENNERHOLM, L. Determination of gangliosides in nervous tissue. In : Cerebral Lipidosis, p . 122, Edited by van Bogaert, L ., Cumings, J . N . and Lowenthal, A . Oxford, 1957 . Blackwell Scientific Publications. 165 . FRANCESCHETTI, A., WILT, E . and KLEIN, D . Ex . amen anatomoclinique d'un cas d'idiotie amaurotique infantile (Tay-Sachs) . Acta genEt . e t stat . med ., 5 : 343, 1955 . 166 . LAZARUS, S . S ., WALLACE, B . J . and VOLK, B, W . Neuronal enzyme alterations in Tay-Sachs disease . Am . J. Path ., 41 : 579, 1962 . 167 . DIEZEL, P . B. Histochemical study of primary lipidosis . In : Cerebral Lipidosis, p. 11 . Edited by van Bogaert, L., Comings, J . N . and Lowenthal, A . Oxford, 1957 . Blackwell Scientific Pub . lications . 168 . WALLACE, B . J ., VOLK, B . W., ScHNECK, L . and KAPLAN, H . Fine structural localization of two hydrolytic enzymes in the cerebellum of children with lipidoses. J . Neuropath . & Exper. Neurol ., 25 : 76, 1966 . 169 . KLENK, E . Die Chcmie der Lipoidosen and der Entmarkungskrankheiten . Wien . Ztschr . Nervenh ., 13 : 309, 1957 . 170 . RosENDERC, A . and CHARGAFF, E. Some observations on the mucolipids of normal and Tay-Sacbs disease brain tissue. Am . J, Dis . Child ., 97 : 739 . 1959 .

VOL . 46, FEBRUARY 1969

263

171 . SVENNERBOLM, L . The chemical structure of normal brain and Tay-Sachs gangliosides. Biochem . & Biophys. Res. Commun ., 9 : 436, 1962 . 172- LrnEEN, R ., SALSMAN, K. and CABRERA, M . Structural studies of the Tay-Sachs ganglioside and its normal brain counterpart. In : Inborn Disorden of Sphingolipid Metabolism, p . 231 . Edited by Aronson, S. M . and Volk, B . W . New York, 1967 . Pergamon Press, Inc . 173. GArn, S . and BERMAN, E . R, Studies on brain lipids in Tay-Sachs disease. I. Isolation of two sialic-acid free glycolipids . J . Neurochem ., 10 : 43, 1963. 174 . SAcprz, R ., JUIF, M ., GIGONNET, M . and GRUNNER, J. E . La maladie Landing on idiotic amaurotique infantile prdcoce avec gangliodose generalisee de type G R, . Pediatric, 22 : 143, 1967 . 175. ArrAL, C ., FARKAS-BARUETON, E ., EDGAR, C . W, F ., TRONC, P . H ., GIARO, F . and MozztcoNACet, P . Idiotic amaurotique infantile familiale avec surcharge viscerale. Ann . Pediat ., 43 : 1725, 1967. 176. Scorn, R . C ., LACUNOFF, D . and TRUMP, P . F. Familial neurovisceral lipidosis . J . Pediat, 71 : 357, 1967 . 177 . SCNNECK, L ., KLEINBERc, W. and VOLK, B . W . Cardiac gangliosides in sphingolipidoses . Proc . Soc. Exper . Biol. & Med ., in press . 178 . VOTE, B . W ., ADACHn, M ., SCHNECK, L., SAWER, A. and KLEINBFRG, W . G;-ganglioside variant of systemic late infantile lipidosis (generalized gangliosidosis) . Arch . Path ., in press . 179 . DERRY, D . M ., F.AWCETT, J . S ., ANDERMANN, F . and Woers, L. S . Late infantile systemic lipidosis . Major monosialogangliosidosis. Delineation of two types . Neurology, 18 : 340, 1968. 180 . SuzuRu, K . Cerebral GH,-gangliosidosis. Chemical pathology of the visceral organs . Science, 159 : 1471, 1968.

J.

J.