Gangliosidoses

As a group, the gangliosidoses (..IĀ§ble30:2. ) are characterized by central ganglioside accumulation, autosomal recessive inheritance, psychomotor retardation, often organomegaly, and they may show cherry-red spots.

Pathogenesis and Pathophysiology. All the gangliosidoses are characterized by storage of abnormal gangliosides in neurons and other parts of the nervous system (see Table 30:2) . The storage of the ganglioside material results from the absence or inaction of a cleaving enzyme that normally promotes lipid breakdown. y The enzyme itself may be absent, or the enzyme may be present but the protein necessary to activate it is deficient. In all of the gangliosidoses, there is a dramatic accumulation of lipid that distends the neuronal cell body; the resulting mechanical factors interfere with metabolic function and ultimately destroy the cell. Different neuronal populations are involved and produce different symptoms. The storage is primarily neuronal and tends to occur mainly in the polioencephalon in large neurons. The weight and volume of the affected brain increase markedly during the second year of life; it can often weigh well over twice the normal amount for age and sex. Thereafter, cystic degeneration of the remaining cortex and subcortex occurs. The neuropathological process is not limited to the brain, and motor neurons of the anterior horn cells of the spinal cord are also affected. Pathological examination of these disorders reveals distorted and ballooned neurons. Fusiform swelling of the axons, termed torpedoes, occurs, and astrocytic proliferation is seen. White matter degeneration occurs secondary to the neuronal dysfunction and cell death. Electron microscopic studies show the gangliosides usually tightly packed within the individual cells. In most gangliosidoses, these cytosomes, or membranous cytoplasmic bodies, are osmophilic and often take on a loosely "whorled" form.

Epidemiology and Risk Factors. These exclusively autosomal recessive genetic disorders are globally distributed. Because intermarriage among relatives increases gene frequency, there are often pockets of these diseases in certain sequestered populations. Thus, type I GM 2 -gangliosidosis, or Tay-Sachs disease, has a high frequency among Ashkenazi Jews. Although this disease was once considered rare in black populations, it has been recently noted to occur in the southern United States in areas with a history of consanguinity. [io] In Saudi Arabia, which has high consanguinity and reproduction rates, there is also a high gene

564

TABLE 30-2

-- GANGLIOSIDO

SES

Type

Name

Enzyme Defect

Storage Product

Genetics

Age at Onset

Primary Clinical Features

GM1 -gangliosidosis type I

Infantile form

Beta-galactosidase

GMl

Autosomal recessive

Birth

Cherry-red spot in 50 percent, edematous face, hepatosplenomegaly, seizures mental and motor retardation

GM1 ,-gangliosidosis type II

Juvenile form

Beta-galactosidase

GM!

Autosomal recessive

5-15 yr

As above, but slower in evelution

GM1 ,-gangliosidosis type III

Adult form

Beta-galactosidase

GM!

Autosomal recessive

Adult

Prominent extrapyramidal signs without hepatosplenomegaly

GM2 -gangliosidosis type I

Tay-Sachs disease; infantile form

Hexosaminidase A

gm2

Autosomal recessive

Infants

Hyperexcitability, blindness, cherry-red spot

GM2 -gangliosidosis type II

Juvenile form

Hexosaminidase A

gm2

Autosomal recessive

5 yr

Seizures, dementia, pyramidal and extrapyramidal motor signs

GM2 gangliosidosis type III

Adult form

Hexosaminidase A

gm2

Autosomal recessive

Adult or adolescence

Variable pictures, including myelopathic, motor neuron, or extrapyramidal signs

GM2 -gangliosidosis: activator factor abnormality

Hexosaminidase A deficiency due to activator factor dysfunction

gm2

Autosomal recessive

Childhood

Similar presentation to Tay-Sachs disease

GM2 -gangliosidosis

Sandhoff's disease

Hexosaminidase A and B

Globoside and GM2 ganglioside

Autosomal recessive

Infants

Clinically similar to Tay-Sachs with hepatosplenomegaly

GM3 -gangliosidosis

Hematoside sphingolipodystrophy

Not known

(hematoside)

Autosomal recessive

Infants

Respiratory difficulties, seizures, with delayed motor and mental retardation

frequency of the GM2 -gangliosidosis known as Sandhoff's disease. y None of the gangliosidoses result from other types of genetic transmission.

Clinical Features and Associated Disorders. Generalized gangliosidosis, first reported by Norman and colleagues in 1959, y affects the brain and organs outside the central nervous system.y There are clinical similarities between children with these diseases and those with both Hurler's disease and Tay-Sachs disease. In type I GM1 - gangliosidosis, affected subjects appear abnormal from birth. Nonpitting edema of the face and extremities produces a dull, heavy-appearing facies with frontal bossing, depressed nasal ridge, low-set ears, and large maxilla. The gums and tongue may be large. Ocular signs include a cherry-red spot in about 50 percent of such patients, but corneal clouding is unusual. Hepatomegaly and splenomegaly occur often. Intellectual and motor development are retarded from birth, and children eat poorly, gain weight slowly, and are generally weak and incoordinated. Joints tend to be enlarged, and the long bones are wide in the center and tapered at the ends; kyphoscoliosis and breaking of vertebrae are usual. Myotactic hyperreflexia, hypertonus, and flexion contractures occur. Seizures usually occur late in the disease, and affected children, blind and in respiratory failure associated with infection, die by the age of 2 years.

Type II GM1 -gangliosidosis (juvenile form) follows a more prolonged course and shows a less precipitous decline in activity. Onset of symptoms occurs between 5 and 15 years of age, and the affected patient may appear normal through the first years of life.

Type III GM1 -gangliosidosis (adult type) is characterized by a slowly progressive course with predominant extrapyramidal signs of dystonia and postural reflex impairment. Rigidity is common, and speech disturbances and increased muscle tone are frequent additional features. Neuronal ganglioside storage occurs in the basal ganglion, y and, in contrast to the infantile and juvenile forms, no visceral or skeletal changes occur. Magnetic resonance imaging (MRI) demonstrates symmetrical high-intensity lesions in the putamen on T2-weighted images. It has been suggested that the putaminal lesions may be primarily responsible for the dystonia.y In adult-type GM1 -gangliosidosis there is a structural mutation of the gene for beta-galactosidase that is alalic with the mutations seen in type I GM 1 -gangliosidosis.

The symptoms in type I GM2 -gangliosidosis (infantile form, or Tay-Sachs disease) are uniform in type and timing of development. The first clinical manifestations occur within 6 months of birth, yet the infant appears normal for the first 3 months. Initially, excessive hyperexcitability and irritability develop, and infants have a heightened startle reflex to noises and tactile stimuli. Hypotonia and a delay in motor and mental development are characteristic. During the first 6 months of life the child's visual acuity is usually deficient and continues to deteriorate to the point of blindness by 1 year of age. The early blindness is thought to be retinal in origin, since the GM2 -ganglioside storage lesion is within the ganglion cells of the macula, and normal pupillary responses persist. The macular cherry-red spot, appearing in all cases within the first 3 months of life, is highly characteristic, although it tends to disappear late in the disease owing to total retinal atrophy. The color of the macula has little pathophysiological significance compared to the milky, whitish halo found around the macular region. This finding is a result of the buildup of opaque gangliosides. Because of this macular lesion, the baby has fixation defects and searching conjugate eye movements. At times, the extreme hyperexcitability and reactivity suggest frank seizure activity. If seizures occur, they are of a myoclonic character that closely resembles infantile spasms (see Chapter..52 ). The progression of symptoms continues through the second and sometimes third year of life, and most children die before the age of 4. Megalocephaly is predominant even in the terminal stages.

A juvenile variant of type II GM2 -gangliosidosis follows a much different course. These children first become ill after 5 years of age, and death occurs within 10 years following a course of seizures, progressive dementia, and cerebellar, pyramidal, extrapyramidal, and spinal dysfunction as well as optic atrophy. [8 Such patients have a partial deficiency of hexosaminidase-A in spleen, liver, and brain in assays performed with the natural substrate for the ganglioside. This form of the disease may present as a progressive pure form of dystonia and dementia that begins before 5 years of age. These cases differ from the classic form of GM 2 -gangliosidosis in the regional preferences of the storage process. y

Adult-onset type III GM2 -gangliosidosis has been reported with a number of phenotypic patterns, and the clinical picture may vary within families. Adults between 16 and 28 years of age, who have had very mild symptoms in childhood, develop pronounced motor symptomatology. The adult form may be associated with a partial deficiency of hexosaminidase-A, and in such cases, spinal and cerebral degeneration is usually predominant. y These individuals do not have seizures, funduscopic abnormalities, or dementia. Other adult patients may show predominant extrapyramidal abnormalities with dystonia and choreoathetosis, y motor neuron,y or pure neuropsychiatric signs.y

Sandhoff's disease results in the storage of GM2 -ganglioside, globoside, and asialo-GM 2 -ganglioside in visceral tissues. These storage materials are biochemically distinguishable from those of Tay-Sachs disease. The disease is a result of a deficiency of both hexosaminidase-A and hexosaminidase-B activity. [9] Patients with Sandhoff's disease have clinical symptoms that are similar to those characteristic of Tay-Sachs disease, with hyperacusis, decreased vision, a cherry-red macular spot, decerebrate rigidity, and megalencephaly. In contrast to Tay-Sachs disease, hepatosplenomegaly is seen, and the tubular epithelial cells of the kidneys are filled with sphingolipids. Cardiomyopathy and mitral insufficiency may be present, and death usually occurs between 2 and 4 years of age. y There are some variants of Sandhoff's disease, including a juvenile form in which patients are normal until 5 years of age, when they develop ataxia, slurred speech, intellectual deterioration, and progressive hyperreflexia and hypertonia. Funduscopic examination may be normal.

A few cases have been reported of infants with severe neurological and systemic problems that have been traced to excessive accumulation of GM3 -ganglioside (hematoside) in tissues[8] without GM! or GM2 . In these cases, there is a decrease in the enzyme W-acetylgalactososaminyl transferase, which is important in the synthesis of GM! and GM2 from GM3 . These infants have pronounced respiratory difficulties in the first weeks of life, when generalized

seizures become prominent. Poor motor and mental development is typical, and dysplastic features such as an enlarged tongue, high-arched palate, inguinal hernia, and loose skin are found. The hands and feet are broad, and there is marked hirsutism. Generalized muscle hypotonia, poor responses, and diminished reflexes develop, but the optic fundi are normal, and the liver and spleen are minimally enlarged. Because of dysphagia and difficulty in feeding, death usually occurs within the first few months of life. On autopsy, spongy degeneration in the brain stem and diencephalon is evident, and intracytoplasmic bodies are seen in astrocytes.

Differential Diagnosis. The other group of degenerative disorders that should be considered in the differential diagnosis is the cerebroretinal syndromes. In patients with some variant forms, such as the neuronal ceroid-lipofuscinoses, primary movement disorders and spinocerebellar degeneration must be considered.

Evaluation. The full workup for these disorders includes a detailed clinical evaluation, neuroimaging, electroencephalography, cerebrospinal fluid analysis, and tissue histology. EEG studies show hypsarhythmoid patterns. Neuroimaging demonstrates a deep cortical zone associated with decreased white matter volume and ventricular dilatation. The gray matter may be disproportionally large. In some cases, a small cerebellum and brain stem are seen. Specific diagnosis rests with evaluation of the accumulated stored material or specific enzymatic deficiency assays. Electromicroscopic studies reveal cytosomal lipid bodies in a variety of tissues depending on the type of disease.

Special testing is warranted for populations at particular risk. Since approximately 80 percent of patients with Tay- Sachs disease are of Jewish ancestry, massive population screening studies of white blood cell enzymes to detect the carrier state have been successful. Amniotic fluid removed early in pregnancy and chorionic villi may also be studied to determine whether the Tay-Sachs disorder is present. Several pitfalls should be avoided in diagnosing patients with gangliosidosis. For example, there is often confusion between Sandhoff's disease and Tay-Sachs disease because of similar clinical and biochemical results. DNA testing, coupled with enzyme analysis, provides a good level of sensitivity and specificity. Pseudodeficiency has been reported in a non-Jewish patient; the diagnosis can be confirmed by DNA testing.y

Management, Prognosis, and Future Perspectives. Definitive treatment is not available for patients with most of the gangliosidoses, but some experimental approaches may be effective. Enzyme replacement therapy with multiple laminar lyposomes coated with human IgG has not been effective. [8] Bone marrow transplantation is being used, but the attendant risks of radiation to the brain and chronic immunosuppressive therapy are worrisome. Palliative therapies are helpful. The prognosis remains dismal. Future research with enzyme replacement, inhibitors, and activators, identification of new enzyme activators, and genetic counseling are all indicated.

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