GM Gangliosidosis Chapter 10

10.1 Clinical Features

and Laboratory Investigations GM

gangliosidoses are inherited disorders of GM

ganglioside metabolism. Its inheritance is autosomal recessive. There are three major, biochemically dis- tinct types: B, O, and AB. Among the B and O types, infantile, juvenile, and adult forms can be distin- guished; 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 Euro- pean origin. In the United States carrier the frequen- cy 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 frequent- ly 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. Gradual- ly, psychomotor retardation and deterioration with loss of skills becomes evident. After 6 months of age the patient’s vision noticeably deteriorates and hypo- tonic motor weakness becomes obvious. Affected in- fants 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 paraly- sis 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 vari- ably present. At the end of the 1st year of life most children are blind. Ophthalmoscopic examination re- veals 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 usu- ally 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 in- fantile GM

gangliosidosis. Infantile GM

gangliosi- dosis type AB is also clinically similar to TSD. These disorders have no racial predilection.

In addition to the severe infantile forms of GM

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 de- scribed. However, the age of onset is difficult to deter- mine because of the very slow progression of the dis- ease. While the juvenile form has no ethnic predilec- tion, 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. Atypi- cal spinocerebellar ataxia syndromes are common as modes of presentation of late-onset GM

gangliosido- sis. They are characterized by slowly progressive atax- ia, 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 abnormali- ties in the form of supranuclear or internuclear oph- thalmoplegia and sensory neuropathy have been de- scribed, but these are rare.Another relatively frequent presentation is as motor neuron disease. Clinical fea- tures 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 syn- dromes 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

GM ₂ Gangliosidosis

occur, as in other disorders of the lower motor neu- ron. Various extrapyramidal features have been de- scribed in late-onset GM

gangliosidosis, either in isolation or in combination with the more common motor neuron and cerebellar syndromes. Dystonia, rigidity, choreiform movements, and athetoid postur- ing have been noted.Another clinical characteristic of late-onset GM

gangliosidosis is the high incidence of recurrent psychosis. In addition, psychic changes in- clude anxiety, depression, insomnia, aggressiveness, severe behavioral problems, and disintegration of the personality. The psychic changes may precede all other manifestations or may appear later. Neurovege- tative disorders are common and take the form of sweating impairment, loss of libido, impaired esoph- agus 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 bronchopneumo- nia. 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 high- voltage, 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 infan- tile GM

gangliosidosis. In later onset variants the EEG shows variable, nonspecific findings. Nerve con- duction 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 den- sity. 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 GM

gangliosidosis.

A definitive diagnosis is established by assaying hexosaminidase A and B in serum, leukocytes, or cul- tured 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 B

, 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 GM

ganglioside or a sulfated synthetic sub- strate. Prenatal diagnosis of these variants of GM

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 GM

activa- tor protein. In type AB the diagnosis requires either the demonstration of accumulating GM

ganglioside in the presence of normal hexosaminidase A and B activities or the demonstration of the GM

activator protein deficiency. GM

ganglioside accumulation can be demonstrated in brain biopsy tissue or alter- native sources of nervous tissue (rectum, conjuncti- va), and probably also in CSF, although the sensitivity and specificity of the latter test is not known. The de- ficiency of GM

activator protein can be demonstrat- ed by feeding radiolabeled GM

ganglioside to cul- tured fibroblasts and correcting the disturbed degra- dation of this substance by the addition of purified GM

activator protein to the culture medium. The expression level of GM

activator protein can also be assessed in fibroblasts.

DNA analysis is possible for all variants of GM

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 inex- pensive screening tests are available for detection of GM

gangliosidosis carriers. Enzymatic tests are used, which determine total serum hexosaminidase and hexosaminidase A activity; the leukocyte hex- osaminidase assay is used for confirmation. Nowa- days screening for common mutations is preferred in populations with a high carrier frequency for certain mutations.

10.2 Pathology

In infantile GM

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). Enlarge- ment of the brain causes the gyri to become broad- ened. 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-

Chapter 10 GM2Gangliosidosis 104

tion for the neurons in the cerebral hemispheres over the ganglion cells of the motor cranial nerves or oth- er brain stem nuclei. There is a diffuse disturbance of the cytoarchitecture of the gray matter with a reduc- tion 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 de- position 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, re- sulting in so-called meganeurites. As the disease pro- gresses, 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 addi- tional 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 fre- quently appear thinner than normal. Complete ab- sence 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 of- ten 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 pro- gresses, 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 ob- served 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 un- dergo changes similar to those seen elsewhere in the CNS. The neurons of the anterior horns are more in- tensely affected than those of the posterior and later- al 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 examina- tion 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 particu- larly 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 membra- nous cytoplasmic bodies. They occupy a considerable proportion of the nerve cell cytoplasm. Their accre- tion within the neuronal cytoplasm causes the enor- mous 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 lysoso- mal 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 GM

gangliosidoses patho- logical 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

GM

ganglioside is accumulated in abnormally large

amounts in GM

gangliosidoses. In the brain, the con-

centration 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 GM

gangliosidosis. In all cases the

accumulation of the ganglioside GM

is most pro-

nounced. It is accompanied by minor storage of its

sialic acid-free derivative, GA

. Variant 0 is character-

ized by the fact that the nervous tissue contains – in

relative terms – the lowest amount of GM

and the

highest amount of GA

. Variant B and variant AB dif-

fer from each other in the extent to which GM

and

GA

are accumulated, the accumulation being higher in the AB variant. The gangliosides are mainly stored in the neuronal cells, but the ganglioside concentra- tion of white matter is also increased. In late-onset forms of GM

gangliosidosis, cerebral levels of GM

and GA

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 GM

gangliosidosis.

Some 30–40% of the lysosomal inclusion bodies consist of GM

ganglioside. Other components are proteolipid protein, cholesterol, phospholipids, and glycolipids.

Except for a high concentration of GM

ganglio- side, 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 choles- terol esters as a sign of active myelin breakdown.

In the B variant and the AB variant, GM

ganglio- side is not stored in large amounts outside the ner- vous system. In the O variant there is an extensive storage of globoside in the visceral organs, besides storage of GM

and GA

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. GM

gan- gliosidosis is caused by a deficient activity of the lysosomal enzyme β-hexosaminidase, also called GM

gangliosidase or β-N-acetylgalactosaminidase.

This enzyme hydrolyzes the terminal N-acetylgalac- tosamine from the ganglioside GM

. Hexosaminidase is composed of two subunits. The α- and the β-chain can associate in different combinations to produce isoenzymes of different structure and catalytic activ- ity. Isoenzyme αβ is called hexosaminidase A, isoen- zyme ββ hexosaminidase B, isoenzyme αα hex- osaminidase S. Hexosaminidase A cleaves the sub- strates ganglioside GM

, the asialo derivative GA

, globoside, neutral oligosaccharides, and negatively charged substrates, such as terminal β-linked N- acetylglucosamine-6-sulfate contained in keratan sul- fate, chondroitin sulfate, and dermatan sulfate. Hex- osaminidase B has an overlapping substrate specifici- ty and cleaves GA

, globoside, and neutral oligosac- charides. Hexosaminidase B does not possess any significant ganglioside GM

-cleaving activity. Hex- osaminidase S has only negligible catalytic activity.

Apart from the α- and β-chains of hexosaminidase, a third protein is necessary for in vivo catabolism of

GM

ganglioside: an activator protein. This activator protein is termed GM

activator protein (GM2AP) or sphingolipid activator protein 3 (SAP-3). The GM

activator protein has an isoenzyme specificity for hexosaminidase A, and not for hexosaminidase B or S. Interaction of the activator protein with GM

gan- glioside or related compounds results in the forma- tion of a water-soluble dimer. The activator–lipid complex binds to a specific recognition site of hex- osaminidase A in such a way that the glycosidic bond is positioned at the active site in the α-subunit. Thus, the GM

activator functions as a transport protein rather than as an activator of the enzyme.

The different types of GM

gangliosidosis are char- acterized by the isoenzyme, which is missing. In type B, there is a deficiency of hexosaminidase A (iso- enzyme αβ) resulting from mutations in the gene encoding the α-chain, HEXA, located on chromo- some 15q23–24. In type O, both hexosaminidase A (αβ) and hexosaminidase B (ββ) are deficient. This is the result of mutations in the gene encoding the β-chain on chromosome 5q13, HEXB. Type AB is caused by a deficiency of the GM

activator protein, encoded by a gene located on chromosome 5q31.3–

33.1, GM2A. A special variant of GM

gangliosidosis has been described, the B

variant, which is allelic to the B variant. In the B

variant, a mutation affects a specific α-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 β-subunit (including non- sulfated synthetic substrates). It is virtually inactive towards the substrates that are exclusively or prefer- entially cleaved at the active site of the α-subunit (GM

ganglioside and also synthetic substrates con- taining a sulfate group). The B

mutation appears to be rare in the homozygous form, but may be more commonly encountered in the B/B

compound het- erozygous form.

The time of onset and clinical severity of the dis- ease are related to the rate of ganglioside accumula- tion, which is inversely related to the residual activity of hexosaminidase in the patient’s tissues. The vari- able residual enzyme activities among infantile, juve- nile, and adult-onset GM

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 α-subunit gene causes a total absence of hex- osaminidase A and leads to the severe infantile form of the disease, TSD. In contrast, adult α-subunit muta- tions cause a severe, but not complete, deficiency of hexosaminidase A. Both the infantile and adult α-subunit mutations occur with enhanced frequency among Ashkenazi Jews. Compound heterozygotes carrying an infantile and an adult α-subunit mutation on homologous chromosomes have adult-onset GM

Chapter 10 GM2Gangliosidosis 106

gangliosidosis. The patients who are homozygous for the B

mutation generally belong to the juvenile cate- gory. 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 GM

gangliosidosis mutation is re- sponsible for the patients with a chronic form of B

variant with survival into the third decade of life. For the β-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 pre- dominantly 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 neu- rons may occur. Undegraded storage material is not completely confined to the lysosomes, but can to some extent be recycled and reach other compart- ments, such as the Golgi apparatus and plasma mem- brane via normal membrane flow. This may lead to changes in the content and pattern of gangliosides in the neuronal plasma membrane. Gangliosides are im- plicated in cell–cell communication and recognition phenomena including dendrotogenesis and synapto- genesis. Presence of abnormalities in gangliosides in neuronal plasma membranes interferes with the es- tablishment of proper connections and leads to aber- rant 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 re- duced membrane fluidity. Evaluation of neurotrans- mitter metabolism has shown reduced high-affinity uptake of glutamate, GABA, and norepinephrine by synaptosomes. Other studies have suggested abnor- mal calcium homeostasis and interference with sec- ond messenger systems.

In the infantile form, mechanical storage is respon- sible 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 pro- nounced and the other mechanisms mentioned may be more important in explaining the neuronal dys- function. It is difficult to explain why neurons from

different locations are preferentially involved in dif- ferent 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 syn- thesis 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. Im- pairment of cellular functions can occur at different threshold values of accumulated gangliosides in dif- ferent types of cells at different times.

The white matter disease in infantile forms of GM

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 dys- function, 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 con- tent of GM

ganglioside. GM

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 GM

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 suggest-

ed 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 syn-

thesis 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

GM

gangliosidosis. The combination of hematopoi-

etic stem cell transplantation and substrate depriva-

tion 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 GM

gan- gliosidosis is a homogeneously and symmetrically in- creased 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 in- tensity on T

-weighted MR images. They have a high signal on T

-weighted images. In addition, MRI shows high signal intensity abnormalities on T

-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 T

- 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 dis- turbed and abnormal myelination and myelin loss.

The corpus callosum is well myelinated and intact.

The cerebellar white matter may also be insufficient- ly 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 T

-weighted MR images is also seen in globoid cell leukodystrophy (Krabbe disease). However, in the lat- ter disease many more brain structures may show a

similarly high density on CT, the T

hyperintense sig- nal abnormalities in the thalami and basal ganglia are lacking, and the white matter disease does not spare the corpus callosum. The images in GM

gangliosido- sis are indistinguishable from those seen in GM

gan- gliosidosis.

In late-onset GM

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 ab- normalities 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 pro- gressive 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 T

- weighted images and a low signal on T

-weighted im- ages, and did not enhance after contrast. The slight mass effect suggested a tumoral or inflammatory process.A stereotactic biopsy was performed, and mi- croscopy revealed evidence of lipid storage in neu- rons and glial cells. Enzymatic analysis revealed a de- ficiency of hexosaminidase A, indicative of variant B of GM

gangliosidosis.

Chapter 10 GM2Gangliosidosis 108

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, puta- men, and caudate nucleus, together with some diffuse white matter hypo- density and cerebral atrophy. From Fukumizu et al. (1992), with permis- sion

Fig. 10.2. The T2-weighted images of an 18-month-old girl with TSD show abnormal thalami, the signal intensity being too low. The caudate nucleus, globus pallidus, and putamen have a high signal intensity.The caudate nucleus has a slightly swollen aspect. The signal intensity of the cerebral white mat- ter is diffusely abnormally high, except for the corpus callosum and internal capsule.The cerebellar white matter is also abnor-

mal.The T1-weighted images show that the basal ganglia have an abnormally low signal intensity, whereas the thalamus has an abnormally high signal. The signal intensity of the cerebral white matter is inhomogeneous on the T1-weighted images, high in some parts and low in others, suggestive of a combina- tion of hypomyelination and myelin loss

Chapter 10 GM2Gangliosidosis 110

Fig. 10.3. T2-weighted images in a 5-year-old boy with juve- nile GM2gangliosidosis show that the cerebral white matter is slightly abnormal, suggestive of underlying axonal degenera-

tion. The basal ganglia also have a slightly abnormal signal.

Courtesy of Dr. P.G. Barth, Department of Child Neurology, Academic Medical Center, Amsterdam, The Netherlands

Fig. 10.4. T2-weighted images in a 9-year-old girl with juve- nile GM2gangliosidosis show a picture of advanced cerebral atrophy. There are mild signal abnormalities in the cerebral

white matter, as seen in neuronal degenerative disorders.

Courtesy of Dr. S. Blaser, Department of Diagnostic Imaging, Hospital for Sick Children, Toronto