GM2 Gangliosidosis

10.1 Clinical Features and Laboratory Investigations

GM2 gangliosidoses are inherited disorders of GM2 ganglioside metabolism. Its inheritance is autosomal recessive. There are three major, biochemically distinct types: B, O, and AB. Among the B and O types, infantile, juvenile, and adult forms can be distinguished; the AB variant is known only as an infantile form. Infantile type B is the classic Tay-Sachs disease (TSD), and infantile type O is the same as Sandhoff disease (SD).

TSD is common in Ashkenazi Jews of eastern European origin. In the United States carrier the frequency is 1 in 30 among Ashkenazi Jews and only 1 in 380 among other groups. TSD infants seem normal at birth, and their early development apparently follows a normal pattern. The disease begins at the end of the first 6 months of life. An exaggerated startle response is often the earliest symptom, although it is frequently only recognized in retrospect. It is provoked by sudden noise and consists in extension, abduction, and elevation of the arms. Listlessness and irritability usually occur early in the course of disease. Gradually, psychomotor retardation and deterioration with loss of skills becomes evident. After 6 months of age the patient's vision noticeably deteriorates and hypotonic motor weakness becomes obvious. Affected infants may crawl, sit unaided, and pull themselves up to a standing position but do not usually manage to walk. By 1 year of age the deterioration of mental and motor capacities is obvious. The children no longer sit, hold, or transfer objects; they lose interest in their surroundings and usually lie placidly in bed. In the 2nd year hypotonic motor weakness progresses, and by the end of the 2nd year generalized flaccid paralysis has developed. The tendon reflexes are increased at all stages, and plantar responses may be extensor. In the later stages of the disease signs of spasticity, dystonia, rigidity, chorea and athetosis may be variably present. At the end of the 1st year of life most children are blind. Ophthalmoscopic examination reveals a cherry-red spot in one or both maculae in about 90% of the patients. Optic atrophy is also seen. Feeding becomes a problem in the 2nd year because of ineffective swallowing. Seizures are rare before the age of 1 year, but frequent thereafter. The epileptic manifestations may consist in tonic-clonic seizures, myoclonic epilepsy, and also gelastic epilepsy. A char acteristic sign in TSD is megalencephaly, which usually becomes prominent at about 2 years of age. By the age of 2 most patients are completely paralyzed, demented, blind, and deaf with frequent seizures. Decerebrate posturing may be present. Most patients die of bronchopneumonia and emaciation. Death usually occurs between 2 and 3 years of age, survival after the age of 4 being rare.

The clinical features of SD are similar to those of TSD, with the exception of hepatosplenomegaly, which does not occur in TSD. Occasionally there are bony deformities similar to those associated with infantile GM1 gangliosidosis. Infantile GM2 gangliosi-dosis type AB is also clinically similar to TSD. These disorders have no racial predilection.

In addition to the severe infantile forms of GM2 gangliosidosis, later onset forms are known. The so-called juvenile form usually has its onset between 2 and 6 years of age. The adult, or rather chronic, form, has its onset between the end of the 1st decade and the 3rd decade of life. Even later onset has been described. However, the age of onset is difficult to determine because of the very slow progression of the disease. While the juvenile form has no ethnic predilection, the adult B form is more frequent among Ashke-nazi Jews than in other ethnic groups. The main systems affected in the juvenile and adult variants are the cerebellum, the pyramidal cells, the lower motor neurons and, less frequently, the basal ganglia. Atypical spinocerebellar ataxia syndromes are common as modes of presentation of late-onset GM2 gangliosidosis. They are characterized by slowly progressive ataxia, spasticity, dysarthria, and muscle atrophy. Such cases have been diagnosed as atypical variants of Friedreich ataxia, however, usually without sensory involvement. In some patients additional abnormalities in the form of supranuclear or internuclear oph-thalmoplegia and sensory neuropathy have been described, but these are rare. Another relatively frequent presentation is as motor neuron disease. Clinical features include weakness, cramps, proximal muscle wasting, and fasciculations. This clinical picture closely resembles the Kugelberg-Welander pheno-type of spinal muscular atrophy or bulbospinal neu-ronopathy. Amyotrophic lateral sclerosis-like syndromes present with involvement of both lower and upper motor neurons. Apart from paresis, atrophy and fasciculations, high reflexes, and extensor plantar reflexes are found. Upper limb postural tremor may occur, as in other disorders of the lower motor neuron. Various extrapyramidal features have been described in late-onset GM2 gangliosidosis, either in isolation or in combination with the more common motor neuron and cerebellar syndromes. Dystonia, rigidity, choreiform movements, and athetoid posturing have been noted. Another clinical characteristic of late-onset GM2 gangliosidosis is the high incidence of recurrent psychosis. In addition, psychic changes include anxiety, depression, insomnia, aggressiveness, severe behavioral problems, and disintegration of the personality. The psychic changes may precede all other manifestations or may appear later. Neurovegetative disorders are common and take the form of sweating impairment, loss of libido, impaired esophagus motility, fixed cardiac frequency, and orthostat-ic hypotension. Intellectual deterioration is frequent. Epilepsy may occur, but is not obligatory. Blindness occurs late in the course of the disease. On ophthal-moscopic examination, optic atrophy and retinitis pigmentosa may be seen at that time,but a cherry-red spot is not a consistent finding and appears late if at all. In the juvenile variant death occurs between 5 and 15 years of age, often secondary to bronchopneumonia. Patients with the adult form usually live for some decades.

In the infantile variants, EEG is either normal or shows slight changes during the 1st year of life. In the 2nd year there are paroxysmal discharges of highvoltage, slow-wave activity with single and multiple spikes and sharp wave complexes. In the vegetative state of the disease there is a marked decrease in spike discharges. These findings are not specific for infantile GM2 gangliosidosis. In later onset variants the EEG shows variable, nonspecific findings. Nerve conduction velocities are usually normal in the first stage of the disease and then decline. EMG shows fascicula-tions, especially in the proximal muscles, and signs of loss of motor units with collateral reinnervation. Muscle biopsy shows signs of neurogenic atrophy with type grouping and increased connective tissue. Sural nerve biopsy demonstrates decreased fiber density. A histogram of counted nerve fibers shows a decrease in the number of large myelinated fibers and an increase in small myelinated fibers, indicating active regeneration. Rectal biopsy reveals swollen ganglion cells with vacuolated cytoplasm. Ultrastruc-turally, the ganglion cells contain membranous cyto-plasmic bodies, which are typically found in neurons in GM2 gangliosidosis.

A definitive diagnosis is established by assaying hexosaminidase A and B in serum, leukocytes, or cultured skin fibroblasts. In the case of variant B, hex-osaminidase A is deficient. In the case of variant O, both hexosaminidase A and hexosaminidase B are deficient. In the case of variant B1, the activities of hexosaminidase A and B are found to be normal when tested with the conventional, nonsulfated synthetic substrate, but a profound deficiency of hexosamini-dase A activity is found on testing with the natural substrate GM2 ganglioside or a sulfated synthetic substrate. Prenatal diagnosis of these variants of GM2 gangliosidosis is possible in the first trimester of pregnancy by enzyme analysis in cultured amniotic fluid cells or chorionic villi.

In the case of type AB, the activities of hex-osaminidase A and B are found to be normal, since in this type the defect is a deficiency of the GM2 activator protein. In type AB the diagnosis requires either the demonstration of accumulating GM2 ganglioside in the presence of normal hexosaminidase A and B activities or the demonstration of the GM2 activator protein deficiency. GM2 ganglioside accumulation can be demonstrated in brain biopsy tissue or alternative sources of nervous tissue (rectum, conjunctiva), and probably also in CSF, although the sensitivity and specificity of the latter test is not known. The deficiency of GM2 activator protein can be demonstrated by feeding radiolabeled GM2 ganglioside to cultured fibroblasts and correcting the disturbed degradation of this substance by the addition of purified GM2 activator protein to the culture medium. The expression level of GM2 activator protein can also be assessed in fibroblasts.

DNA analysis is possible for all variants of GM2 gangliosidosis. If the mutations responsible are found in a family, carrier testing and prenatal diagnosis become more reliable. Pseudodeficiency may occur, and DNA analysis helps to ensure the presence of a benign pseudodeficiency allele. Accurate and inexpensive screening tests are available for detection of GM2 gangliosidosis carriers. Enzymatic tests are used, which determine total serum hexosaminidase and hexosaminidase A activity; the leukocyte hex-osaminidase assay is used for confirmation. Nowadays screening for common mutations is preferred in populations with a high carrier frequency for certain mutations.

10.2 Pathology

In infantile GM2 gangliosidoses the gross changes in the brain vary with the length of the patient's life. The weight and volume of the brain increase massively during the 2nd year of life. The brain frequently weighs over 2000 g (normal weight 1000 g). Enlargement of the brain causes the gyri to become broadened. The cerebellum, however, is usually atrophic. On sectioning, the cut surface is abnormally firm. The hemispheric white matter may be gelatinous with local cavitation. The ventricles are variably enlarged.

Light microscopy shows ubiquitous involvement of the nerve cells throughout the brain, with a predilec tion for the neurons in the cerebral hemispheres over the ganglion cells of the motor cranial nerves or other brain stem nuclei. There is a diffuse disturbance of the cytoarchitecture of the gray matter with a reduction in the number of nerve cells, an unusual increase in size of the remaining neurons, and a concomitant augmentation in the number of glial elements. The neurons are large and distorted as a result of the deposition of lipid material. They have a distended, rounded outline; their nuclei are displaced to the circumference of the cell and are often shrunken and pyknotic. Cortical neuronal cells have swellings in the proximal axon segment or in the apical dendrite, resulting in so-called meganeurites. As the disease progresses, the neurons gradually disappear. There is a decrease in the number of axons seen within the white matter of the brain, which parallels the process of degeneration of the cerebral cortical nerve cells. With progression of the disease there are profound disturbances in myelination, with evidence of additional myelin loss. The myelin deficiency may be very extensive. In some patients the myelin deficiency is seen predominantly in the centrum semiovale with sparing of the subcortical U fibers, but in most patients it involves almost the entire white matter, including the U fibers. The internal capsule is usually well preserved. The preserved myelin sheaths frequently appear thinner than normal. Complete absence of myelin throughout the hemispheric white matter can occur if the patient survives for a long time. The white matter changes cannot be attributed to wallerian degeneration only. There is evidence for an additional role of both failure of myelination and active demyelination: the severity of myelin loss is often greater than the axonal loss, and the tendency to softening and cavitation in the most severely affected areas is consistent with active demyelination and not with wallerian degeneration only. As the disease progresses, the glial reaction increases and eventually large numbers of microglia can be observed as well as numerous proliferating astrocytes. The glial cells are swollen and filled with large globules. The contents of these glial cells show similar properties to those observed in neurons. The cerebellum shows extensive degenerative changes. Narrowing or reduction in size of the cerebellar folia is associated with decreased numbers of cells in the cerebellar cortex. The Purkin-je cells show extensive damage and those remaining are filled with the same material that is present in the neurons of the cerebral cortex. The neurons of the cerebellar nuclei also show the typical ballooning due to deposition of lipids. The spinal cord neurons undergo changes similar to those seen elsewhere in the CNS. The neurons of the anterior horns are more intensely affected than those of the posterior and lateral horns. The spinal cord white matter frequently shows rarefaction of the nerve fibers, particularly in the lateral columns and in the pyramidal tracts, but they are normally myelinated. Microscopic examination of the retina reveals extensive degeneration and loss of ganglion cells. The cytoplasm of the remaining cells is filled with lipid material similar to that seen in the neurons of the brain. These changes are particularly conspicuous in the area of the macula.

Electron-microscopic studies have shown that the cytoplasm of the distended neurons contains so-called membranous cytoplasmic bodies. These are membrane-bound structures, which contain closely packed lamellae, frequently arranged concentrically in a regular fashion. The lipid material, which is seen under light microscopy, is located in these membranous cytoplasmic bodies. They occupy a considerable proportion of the nerve cell cytoplasm. Their accretion within the neuronal cytoplasm causes the enormous ballooning of the cell and the displacement of the nucleus to the periphery. Accumulation of these storage bodies in proximal nerve processes leads to the formation of meganeurites and megadendrites. It has been shown that these storage bodies are lysosomal in origin. They are also found in axons and glial cells. In glial cells the deposits are more pleomorphic than in neurons.

Especially in SD, extraneuronal storage of lipids is found. Cells containing stored material are found in the spleen, in renal tubular cells, and in liver cells. The deposited material appears to be similar to that of the neurons.

In juvenile and adult GM2 gangliosidoses pathological changes predominantly affect the anterior horn cells of the spinal cord, the cerebellar cortical neurons,brain stem nuclei, and basal ganglia. In these areas prominent neuronal storage and degeneration are present. The cerebral cortex is less severely or minimally involved. This is the reverse of what occurs in infantile gangliosidoses. The cerebellum is atroph-ic. Slight diffuse myelin loss within the cerebral and cerebellar white matter may be observed.

10.3 Chemical Pathology

GM2 ganglioside is accumulated in abnormally large amounts in GM2 gangliosidoses. In the brain, the concentration of gangliosides is 100-300 times that in normal brain. The storage patterns of the ganglio-sides exhibit some characteristic differences in the three variants of GM2 gangliosidosis. In all cases the accumulation of the ganglioside GM2 is most pronounced. It is accompanied by minor storage of its sialic acid-free derivative, GA2. Variant 0 is characterized by the fact that the nervous tissue contains - in relative terms - the lowest amount of GM2 and the highest amount of GA2. Variant B and variant AB differ from each other in the extent to which GM2 and

GA2 are accumulated, the accumulation being higher in the AB variant. The gangliosides are mainly stored in the neuronal cells, but the ganglioside concentration of white matter is also increased. In late-onset forms of GM2 gangliosidosis, cerebral levels of GM2 and GA2 are markedly increased above normal, but not to the extent seen in infantile forms. A regional variation in ganglioside accumulation in the brain can be seen, depending on the variation of neuronal storage in the different types of GM2 gangliosidosis.

Some 30-40% of the lysosomal inclusion bodies consist of GM2 ganglioside. Other components are proteolipid protein, cholesterol, phospholipids, and glycolipids.

Except for a high concentration of GM2 ganglioside, the change in chemical composition of the white matter is nonspecific and reflects the extent of myelin deficit. The main findings are decreases in proteolipid protein, total lipids, glycolipids, and phospholipids and the presence of significant amounts of cholesterol esters as a sign of active myelin breakdown.

In the B variant and the AB variant, GM2 ganglio-side is not stored in large amounts outside the nervous system. In the O variant there is an extensive storage of globoside in the visceral organs, besides storage of GM2 and GA2 ganglioside. The level of glo-boside is approximately normal in the visceral organs in the B variant and the AB variant.

10.4 Pathogenetic Considerations

Gangliosides are glycosphingolipids, which contain sialic acid in their oligosaccharide chain. GM2 gan-gliosidosis is caused by a deficient activity of the lysosomal enzyme p-hexosaminidase, also called GM2 gangliosidase or p-N-acetylgalactosaminidase. This enzyme hydrolyzes the terminal N-acetylgalac-tosamine from the ganglioside GM2. Hexosaminidase is composed of two subunits. The a- and the p-chain can associate in different combinations to produce isoenzymes of different structure and catalytic activity. Isoenzyme ap is called hexosaminidase A, isoenzyme pp hexosaminidase B, isoenzyme aa hexosaminidase S. Hexosaminidase A cleaves the substrates ganglioside GM2, the asialo derivative GA2, globoside, neutral oligosaccharides, and negatively charged substrates, such as terminal p-linked N-acetylglucosamine-6-sulfate contained in keratan sulfate, chondroitin sulfate, and dermatan sulfate. Hex-osaminidase B has an overlapping substrate specificity and cleaves GA2, globoside, and neutral oligosac-charides. Hexosaminidase B does not possess any significant ganglioside GM2-cleaving activity. Hex-osaminidase S has only negligible catalytic activity. Apart from the a- and p-chains of hexosaminidase, a third protein is necessary for in vivo catabolism of

GM2 ganglioside: an activator protein. This activator protein is termed GM2 activator protein (GM2AP) or sphingolipid activator protein 3 (SAP-3). The GM2 activator protein has an isoenzyme specificity for hexosaminidase A, and not for hexosaminidase B or S. Interaction of the activator protein with GM2 ganglioside or related compounds results in the formation of a water-soluble dimer. The activator-lipid complex binds to a specific recognition site of hexosaminidase A in such a way that the glycosidic bond is positioned at the active site in the a-subunit. Thus, the GM2 activator functions as a transport protein rather than as an activator of the enzyme.

The different types of GM2 gangliosidosis are characterized by the isoenzyme, which is missing. In type B, there is a deficiency of hexosaminidase A (isoenzyme aß) resulting from mutations in the gene encoding the a-chain, HEXA, located on chromosome 15q23-24. In type O, both hexosaminidase A (aß) and hexosaminidase B (ßß) are deficient. This is the result of mutations in the gene encoding the ß-chain on chromosome 5q13, HEXB. Type AB is caused by a deficiency of the GM2 activator protein, encoded by a gene located on chromosome 5q31.3-33.1, GM2A. A special variant of GM2 gangliosidosis has been described, the B1 variant, which is allelic to the B variant. In the B1 variant, a mutation affects a specific a-chain site to which the activator-substrate complex binds. The mutant enzyme has an almost normal activity towards substrates that are split at the active site located on the ß-subunit (including non-sulfated synthetic substrates). It is virtually inactive towards the substrates that are exclusively or preferentially cleaved at the active site of the a-subunit (GM2 ganglioside and also synthetic substrates containing a sulfate group). The B1 mutation appears to be rare in the homozygous form, but may be more commonly encountered in the B/Bj compound heterozygous form.

The time of onset and clinical severity of the disease are related to the rate of ganglioside accumulation, which is inversely related to the residual activity of hexosaminidase in the patient's tissues. The variable residual enzyme activities among infantile, juvenile, and adult-onset GM2 gangliosidosis patients are related to different mutations present either in the homozygous or the compound heterozygous state. In its homozygous state the most common mutation in the a-subunit gene causes a total absence of hex-osaminidase A and leads to the severe infantile form of the disease, TSD. In contrast, adult a-subunit mutations cause a severe, but not complete, deficiency of hexosaminidase A. Both the infantile and adult a-subunit mutations occur with enhanced frequency among Ashkenazi Jews. Compound heterozygotes carrying an infantile and an adult a-subunit mutation on homologous chromosomes have adult-onset GM2

gangliosidosis. The patients who are homozygous for the Bi mutation generally belong to the juvenile category. The clinical severity in compound heterozygotes depends on the other allele. When the other allele is totally inactive a late-infantile phenotype results. Compound heterozygosity in which the other allele carries an adult GM2 gangliosidosis mutation is responsible for the patients with a chronic form of Bi variant with survival into the third decade of life. For the p-subunit gene too, different mutations have been identified and variations in residual enzyme activity appear to explain the different clinical phenotypes.

Gangliosides are typical components of the outer leaflet of plasma membranes and are particularly abundant in the neuronal plasma membranes. An accumulation of these lipids will therefore occur predominantly in neurons. The accumulation of lipids occurs primarily inside the lysosomes,where they fail to be broken down in the absence of adequate hex-osaminidase activity. The accumulating amphipathic lipids will precipitate and form lamellar structures. Although the stored compounds are normal, non-toxic, components of the cell, their excessive storage will interfere with normal cell function. In cells with extreme storage mechanical destruction of the neurons may occur. Undegraded storage material is not completely confined to the lysosomes, but can to some extent be recycled and reach other compartments, such as the Golgi apparatus and plasma membrane via normal membrane flow. This may lead to changes in the content and pattern of gangliosides in the neuronal plasma membrane. Gangliosides are implicated in cell-cell communication and recognition phenomena including dendrotogenesis and synapto-genesis. Presence of abnormalities in gangliosides in neuronal plasma membranes interferes with the establishment of proper connections and leads to aberrant synaptogenesis. Inappropriate proliferation of secondary neurites, a tremendous increase in synap-tic spines on neurons, and formation of meganeurites and megadendrites occurs. Increased ganglioside content in plasma membranes results in markedly reduced membrane fluidity. Evaluation of neurotrans-mitter metabolism has shown reduced high-affinity uptake of glutamate, GABA, and norepinephrine by synaptosomes. Other studies have suggested abnormal calcium homeostasis and interference with second messenger systems.

In the infantile form, mechanical storage is responsible for the megalencephaly and may be a major cause of neuronal dysfunction and death. In the late-onset forms the lipid accumulation is much less pronounced and the other mechanisms mentioned may be more important in explaining the neuronal dysfunction. It is difficult to explain why neurons from different locations are preferentially involved in different variants of the disease. It may have something to do with the relative contribution of pathogenetic mechanisms mentioned in each particular variant. In addition,the regulation of substrate and enzyme synthesis and turnover may not be identical in different types of cells and may not be the same over the years, altering the distribution of cells in which saturation of the residual enzyme occurs most prominently. Impairment of cellular functions can occur at different threshold values of accumulated gangliosides in different types of cells at different times.

The white matter disease in infantile forms of GM2 gangliosidosis can be explained by a combination of hypomyelination, myelin loss secondary to wallerian degeneration, and primary demyelination. The hy-pomyelination may be secondary to neuronal dysfunction, as a normal neuron-myelin interaction is necessary for normal myelin deposition. The de-myelination might be explained by altered myelin composition, structure, and stability. The myelin membrane fluidity is decreased by the increased content of GM2 ganglioside. GM2 gangliosides contain long, saturated fatty acid moieties, which increase the packing density of the lipid matrix, resulting in reduced fluidity.

10.5 Therapy

Treatment in GM2 gangliosidosis is largely restricted to supportive care and management of intercurrent problems. Attempts at enzyme replacement have been made by intravenous, intrathecal, and intraventricu-lar injection of hexosaminidase preparations; these attempts have been unsuccessful. It has been suggested that hematopoietic stem cell transplantation might be successful in halting the disease, but the results so far have been disappointing. This form of treatment would have a better chance in the later onset and slower variants of the disease. Substrate deprivation is another option. This method uses a specific inhibitor of glycolipid biosynthesis to partially reduce the synthesis of the unwanted products. The feasibility of this approach is presently being tested with N-butyldeoxynojirimycin. Oral administration of the compound has been shown to result in the reduced storage of glycolipid in multiple organs, including the brain, and an improved clinical course in mice with GM2 gangliosidosis. The combination of hematopoi-etic stem cell transplantation and substrate deprivation worked even better. The efficacy of the approach in humans has to be verified. Gene therapy is still in the experimental stage.

10.6 Magnetic Resonance Imaging

A characteristic abnormality in infantile GM2 gan-gliosidosis is a homogeneously and symmetrically increased density within the thalami on CT scan (Fig. 10.1). Sometimes, the caudate nucleus,putamen, and globus pallidus are also hyperdense (Fig. 10.1). Thalami have a low or mixed low and high signal intensity on T2-weighted MR images. They have a high signal on Trweighted images. In addition,MRI shows high signal intensity abnormalities on T2-weighted images in the caudate nucleus, globus pallidus, and putamen on both sides (Fig. 10.2). These nuclei have a low or mixed low and high signal intensity on T1-weighted images. The appearance of the cerebral white matter is at first suggestive of delayed myelina-tion,but over time the signal intensity becomes more markedly abnormal,suggesting a combination of disturbed and abnormal myelination and myelin loss. The corpus callosum is well myelinated and intact. The cerebellar white matter may also be insufficiently myelinated and become more deeply abnormal in the course of the disease. In later stages cerebral and cerebellar atrophy ensues.

The finding of a high density of the thalamus on CT scans and low signal intensity of the thalamus on T2-weighted MR images is also seen in globoid cell leukodystrophy (Krabbe disease). However, in the latter disease many more brain structures may show a similarly high density on CT, the T2 hyperintense signal abnormalities in the thalami and basal ganglia are lacking, and the white matter disease does not spare the corpus callosum. The images in GM2 gangliosido-sis are indistinguishable from those seen in GM1 gan-gliosidosis.

In late-onset GM2 gangliosidosis, CT and MRI show cerebral and cerebellar atrophy, generally in combination with slight white matter signal changes (Figs. 10.3,10.4). These abnormalities are consistent with primary neuronal degeneration. Considering the histopathological findings, one might expect abnormalities in signal intensity on MR images of basal ganglia (Fig. 10.3.).

A highly unusual patient has been reported by Nassogne et al. (2003): this child presented with progressive cerebellar ataxia and Babinski signs at the age of 3 years. MRI revealed asymmetrical lesions in the brain stem and middle cerebellar peduncles with some mass effect. The lesions had a high signal on T2-weighted images and a low signal on Trweighted images, and did not enhance after contrast. The slight mass effect suggested a tumoral or inflammatory process. A stereotactic biopsy was performed, and microscopy revealed evidence of lipid storage in neurons and glial cells. Enzymatic analysis revealed a deficiency of hexosaminidase A, indicative of variant B of GM2 gangliosidosis.

Gangliosidosis Mri

Fig. 10.1. The CT scan of a 12-month-old girl with SD (left) shows the hyper-density of the thalamus on both sides. From Brismar et al.(1990), with per-mission.The CT scan of a 5-year-old child with TSD (right) shows hyperden-sity of thalamus, globus pallidus, putamen, and caudate nucleus, together with some diffuse white matter hypo-density and cerebral atrophy. From Fukumizu et al.(1992), with permis-

Fig. 10.1. The CT scan of a 12-month-old girl with SD (left) shows the hyper-density of the thalamus on both sides. From Brismar et al.(1990), with per-mission.The CT scan of a 5-year-old child with TSD (right) shows hyperden-sity of thalamus, globus pallidus, putamen, and caudate nucleus, together with some diffuse white matter hypo-density and cerebral atrophy. From Fukumizu et al.(1992), with permis-

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