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  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
Warren Tay in 1881 observed cherry-red macular degeneration in a twelve month old child with marked weakness of the trunk and limbs  . Subsequently he reported two additional cases in the same family  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  . Several years later he had collected additional cases, all occurring in Jewish children  . 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 .
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  . Peterson , Hirsch  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  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  in 1905 and Spielmeyer  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  . Optic atrophy and retinitis pigmentosa are the typical retinal lesions [261 . Vacuolated lymphocytes have been reported to be present in the heterozygote  as well as the homozygote [28,29] . The neurologic changes are essentially similar to but less marked than those seen in TSD  . Jansky [41 and Bielschowsky  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 , Seitelherger  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  in 1917 described a congenital form of "TSD" in which the clinical picture became evident within the second week of lifeNorman and Wood  and Hagberg et al .  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  in 1925 published his observations on an adult with "amaurotic idiocy ." The clinical manifestations  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  . 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" , "TSD with visceral involvement" , "pseudo-Hurler's disease" , "neurovisceral lipidosis" , "biochemically special form of infantile amaurotic idiocy" , "systemic late infantile lipidosis"  and "generalized gangliosidosis"  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  . 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  reported that the neurons in TSD exhibit intracytoplasmic membranous bodies . These bodies were shown to contain gangliosides  . 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  which in normal brains comprises a minor percentage of the total monosialoganglioside fraction  . The ganglioside stored in excess in the systemic late infantile form is G MI , the ganglioside which is the major monosialoganglioside in the normal brain . Suzuki and Chen  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 .
et al .
diseases [34,60-65] . Jatzkewitz and colleagues  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  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  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  . 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  . 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 .
TABLE I STRUCTURES, NOTATIONS AND DISTRIBUTION
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
Klenk et al .
Kuhn et al .
% of Total Penick, GangliMcCluer oside
Gr, aot GO, GNTrII
NANA Gal(1-3)GaINAc(1-4)Gal (1-4)Gluc (1-1)Ccr
G DI .
NANA NANA Gal(1-3)GaINAc(1-4)Gal(1-4)Gluc(1-1)Cer
NANA NANA Gal(1-3)Ga1NAc(1-4)GaI(1-4)Gluc(1-1)Cer
* Based upon tables by Schettler, G . and Kahlke, W. (p . 215 ) 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  . An elegant quantitative micromethod has been developed by Suzuki [911 . He utilized the descending system of Korey and Gonatas  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  . 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  (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  . 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
The Gangliosidoses-Schneck et al . from patients with disorders of ganglioside metabolism  . 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  . Gatt  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  and Burton  . The chemistry of sialic acid has been described by Gottschalk  and Warren  . 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  and Kaufman, Basu and Roseman  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  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  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 .
TABLE 11 HISTOCHEMICAL REACTIONS OF GANGLIOSIDES
Method Sudan Black Periodic acid-Schiff
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  . Bogoch  and van Heyningen and Miller  described the protective action of gangliosides against certain viruses and bacterial toxins, and Gottschalk  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  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  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
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
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  . 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  . Blindness, which becomes noticeable between the twelfth to eighteenth months of life, is of central rather than peripheral origin  . 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  . Optic atrophy is evident by two years of age . It may precede or follow the blindness -
TABLE III DISEASES WITH SECONDARY DISTURBANCES IN GANGLIOSIDE METABOLISM
Disease Gargoylisrn and variants Niemann-Pick disease Infantile metachromatic leucodystrophy Subacute sclerosing leucoencephalitis Infantile Gaucher's disease
Total Ganglioside Content
GM, GM, GM,
Gml GM2 Gma Ga, * G, : GM, Gms C,, Gxa Gma Gma Gma Gma
Increased Increased (white matter) Normal
* 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
The Gangliosidoses-Schneck et al . Jampel  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  . 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  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  . Wallace et al .  presented electron microscopic evidence and Svennerholm  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  . No specific roentgenographic abnormalities have been noted in TSD . Early and marked elevation of serum glutamic oxaloacetic transaminase (SCOT) and
lactic dehydrogenase (LDH) activity , and decrease in serum fructose- l-phosphate aldolase (F-1-PA) activity is characteristic of this disorder  . A decrease in serum F-I-PA activity is found in the heterozygote also  . Clinical signs of fructose intolerance nevertheless are absent  . Recent studies of serum LDH isoenzymes suggest an elevation in the ratio of the third to fifth fraction  . 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  . A perinatal elevation of SGOT and LDH can reflect nonspecific brain damage or liver immaturity  . 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  . 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  . 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,
The Gangliosidoses-Schneck et al . "There is marked proliferation of protoplasmic
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  . 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  . 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  . 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  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
The Gangliosidoses-Schneck et al .
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  . Some of the liver cells contain membrane-filled structures near the bile canaliculi  . 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  . 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 .
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  . Diezel  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  but, as Svennerholm has pointed out, the free translation of staining reactions into biochemical structural data is of questionable validity  . In 1955 Franceschetti, Wildi and Klein (165] observed large amounts of acid phosphatase in neurons of patients with TSD . Lazarus et al .  confirmed these observations and found this enzyme activity also in glial cells . The distribution of acid phosphatase in
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 .  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  . Svennerholm  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  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  . 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
The Gangliosidoses-Schneck et al .
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  and the abnormally high water content in white matter  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 .  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  . Nacetyl galactosaminidase is the third enzyme system that has been implicated in the pathogenesis of TSD  . 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 .
Girt GANGLIOSIDO5IS (LANDING'S DISEASt) (SYSTEMIC LATE INFANTILE LIPMOSIS)
A number of cases reported in the literature as "familial neurovisceral lipidosis" , "variant of Hurler's syndrome" , "Tay-Sachs disease with visceral involvement" [38,41], "pseudo-Hurler's disease" , "Landing's disease" , "systemic late infantile gangliosidosis" , "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 .
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  . 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.  . 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  . 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  ; 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  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 , 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  . AMERICAN JOURNAL OF MEDICINE
The Gangliosidoses-Schneck et al .
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 , as is a ceramide tetrahexoside chemically related to the asialo derivative of G Mr  . Brain cerebroside sulfate and sphingomyelin were found to be equivalent to control values, and white matter cholesterol concentrations were slightly diminished  . 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 .
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  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
The Gangliosidoses-Schneck et al .
TSD  . A
of systemic G m, gangliosidosis was de-
scribed with electron microscopic and clinical features similar to late infantile amaurotic idiocy  . It has been suggested that Gut gangliosidosis be divided into type I and type
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  . Finally, Suzuki  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 .
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