Gangliosidosis is a lysosomal storage disease which affects primarily the nervous system. This disease is the result of an autosomal recessive mutation which causes a lack or deficiency of an enzyme important in the metabolism of gangliosides. This deficient enzyme can vary depending on the type of mutation present causing either GM1 or GM2 gangliosidosis. Each of these will be discussed later, although the overall effects are similar. Increased amounts of gangliosides inside neurons leads to, often lethal, neurodegenerative disorders.

TAY- SACHS

One of the more common of these disorders is known as Tay--Sachs. Bernard Sachs was the first to describe the cellular morphological features of this disease, "distended cytoplasm of the neurons and ballooning of their dendrites". Later, in the 1930’s, the term ganglioside was used to describe the accumulating material in the neurons which was characteristic of the disease. Tay-Sachs is an infantile form of GM2 gangliosidosis most often found in Ashkenazi Jews. The rate of this disease is almost ten times higher in this population than in most others.

Genetically, Tay-Sachs disease (TSD) is caused by a mutation at the alpha subunit locus. In Ashkenazi Jews the mutation is primarily found in two forms. The first is a 4 base pair insertion into exon 11, the other is a G-to-C transversion mutation in the intron 12 splice site. A separate mutation has been found in the Moroccan Jews, the deletion of a phenylalanine codon in the alpha subunit sequence. Recently, other mutations have been identified in these and other populations. In all cases, these mutations impair the alpha subunit of beta hexosaminidase A resulting in the absence of enzyme activity. Hexosaminidase enzyme is involved in the cleaving the terminal N-acetylgalactoamine or N- acetylglucosamine from glycoconjugates. Hexosaminidase A has the capacity to transport GM2 ganglioside to the lysosome of a cell and cleave it’s glycosidic bond. A deficit of this enzyme results in the dangerous accumulation of GM2 ganglioside in the lysosomes of neurons leading to progressive neuronal degeneration.

The clinical progression of Tay-Sachs disease extends over a period of a few years. At birth, affected infants appear normal. The earliest symptoms of the disease begin at 3- 5 months of age. These symptoms include mild motor weakness and exaggerated response to auditory stimuli, or hyperacusis. The most characteristic feature of TSD is a cherry- red spot on the macula of the eye. The spot is the result of ganglioside accumulation in the retinal ganglion cells and is present as early as age 3 months. Although these red spots are round in other cases, such as retinal ischemia and Niemann- Picks disease, it’s presence in a Jewish infant is highly suggestive of Tay-Sachs.

During the age of 6-10 months there is progressive loss of motor control, hypotonia, weakness, seizures, and decreased visual acuity. At this point parents usually recognize the abnormalities and consult a physician. After one year, the central nervous system progressively degenerates, seizures are more prominent, reflexes are hyperactive, blindness and deafness follow. Death occurs between the ages of 2 and 4.

The clinical progression of Tay-Sachs disease extends over a period of a few years. At birth, affected infants appear normal. The earliest symptoms of the disease begin at 3- 5 months of age. These symptoms include mild motor weakness and exaggerated response to auditory stimuli, or hyperacusis. The most characteristic feature of TSD is a cherry- red spot on the macula of the eye. The spot is the result of ganglioside accumulation in the retinal ganglion cells and is present as early as age 3 months. Although these red spots are round in other cases, such as retinal ischemia and Neimann- Picks disease, it’s presence in a Jewish infant is highly suggestive of Tay-Sachs.

Neuroradiological studies of TSD patients using MRI’s and PET scans indicate 3 phases of the diseases clinical course. Phase I (0- 14 months) is characterized by neuronal cytoplasmic distention, mild gliosis, and the loss of few neuron cells. Lesions of the caudate nucleus and cerebral white matter are more developed than those in the cerebral cortex and putamen during this phase. Phase II (15- 24 months) is characterized by gliosis and demyelination primarily around the anterior and posterior horns of the lateral ventricles. The caudate nucleus and cerebral cortex are characterized by increased size due to edema which causes protrusion into the lateral ventricles. Phase III ( > 24 months) is indicated by extensive edema, neuronal and cerebral degeneration, and significant atrophy of the brain. Although the radiological features of TSD have not been fully clarified or understood, these findings suggest that TSD lesions begin in the caudate nucleus and white matter (Fukumizu, 1992).

Diagnosis of TSD is based on the demonstration of Hexosaminidase A deficiencies in the patients serum, plasma, or fibroblasts. Newer methods include the use of DNA analysis and PCR amplification to identify the mutant gene. Prenatal diagnosis is accomplished by measuring the Hex A enzyme in the amniotic fluid or by chorionic villi sampling. There is also DNA carrier testing available for those groups, such as Ashkenazi Jews, who have high carrier rates of TSD.

OTHER GM2 GANGLIOSIDOSES

Juvenile GM2 Gangiosidosis. Juvenile forms of GM2 gangliosidosis have been described by a group of physicians in Portugal. As reported by Maria Maia et. al., patients with a later onset such as this suffer from a less severe mental retardation, and the other symptoms follow a slower course of development compared to those of the infantile disease. These patients are also biochemically different. Hexosaminidase A activity is present but the enzyme functions at much lower levels than normal. The actual level is still controversial, reports showing a wide range of varying levels between 16-70%.

Onset of juvenile GM2 gangliosidosis is at approximately 3 years of age or older. Initial symptoms include speech and gait disturbances, and a decrease in mental skills. There seems to be no motor deficits present nor any abnormal tendon reflexes. Later stages of this disorder are characterized by dystonic movements, hypotonia, hyperreflexia, and seizures. Neuroradiological examination of patients show generalized or cortical atrophy. At no point during the disease process are there changes in the macula or visual deterioration.

Diagnosis of the juvenile form of the disease is similar to that of the infantile form. Leukocytes were used to determine the amount and activity of hexosaminidase A present. Nerve and skin biopsies were used to determine the degree of lysosomal storage in the neurons. After reviewing of several cases presented by M. Maia (1992) I found that neither of these tests appear to be very sensitive to early stages of the disease, although CT scans seem to show the characteristic generalized atrophy present early in the disease.

Chronic GM2 Gangliosidosis. Several cases have been reported in which clinical signs of a hexosaminidase A deficiency are present in older children or adult patients. Similar to the juvenile forms, this disease is less severe than the infantile form and progresses at a much slower rate. Onset can vary but usually occurs between the end of the first and third decades of life.

Because GM2 gangliosidosis primarily effects lysosomal storage of neurons, neuronal systems are one of the primary areas affected by the disease. Several different phenotypes have been observed among patients, the following are the most common. It is important to realize that this disease involves multi-system degeneration, therefore, these characteristic symptoms occur in several combinations.

Cerebellar symptoms are common to those affected individuals. Cerebellar ataxia causing falling and clumsiness, dysarthria, muscle atrophy, and tremors are the clinical symptoms. These reports are supported by the significant cerebellar neuron loss seen in gross examination of a diseased brain.

A second clinical feature is motor neuron disease. Patients present with weakness, fasciculations, and hyperreflexia. The symptoms suggest involvement of both the upper and lower motor neurons. Dystonia and psychosis are also often seen in this form of GM2 gangliosidosis. High incidences of psychosis is not only found in fully affected patients but also in carriers of the mutation. This psychosis can cause significant problems since many psychoactive drugs act by inhibiting lysosomal activity which thereby worsening the initial disease.

The final clinical symptom to be discussed is known as Neurovegetative Systems Alterations. This condition is characterized by decreased sweating, libido, and alterations in cardioregulatory activity.

Gross examination and neuroradiological evaluation of an affected brain demonstrates cerebellar atrophy along with some cerebral atrophy. This noted cerebellar atrophy has been found to be due to the degeneration of Purkinje and granular cells. A moderate degree of neuronal storage of gangliosides is also detected. This storage is more significant in the deep nuclear structures than in the cortical regions. While all of these clinical manifestations are highly variable, most chronic forms of GM2 gangliosidosis survive well into adulthood without suffering from total disability.

GM1 GANGLIOSIDOSIS

GM1 gangliosidosis is an autosomal recessive disorder which results in a deficiency of beta- galactosidase. The results of this deficiency are very similar to those of hexosaminidase A. In fact, the infantile form is neuropathologically identical to that of Tay-Sachs disease. Clinically, there is one primary difference between the two genetic disorders, visceral involvement.

Visceral involvement associated with GM1 gangliosidosis is due to histiocytes of the visceral organs which store significant amounts of gangliosides. Cellular storage has been noted in the reticulo-endothelial system, and Kupffer cells of the liver, as well as cells of other visceral organs. Clinically, these storage histiocytes are associated with visceromegaly and bony abnormalities.

Both infantile and chronic forms of GM1 gangliosidosis also involve neuronal storage defects. Infantile states of the disease are associated with significant brain atrophy, in particular researchers have found atrophy of the cerebral cortex and cerebellar folia. Microscopic study of the brain demonstrates the Purkinje cells of the cerebellum causing their ‘balloon-like’ appearance and stages are associated with the death of these cells.

Chronic forms of GM’ gangliosidosis are variable and there have been a limited number of cases to study (Suzuki, 1992). Onset occurs during late infantile or juvenile periods and patients often survive to adulthood. Clinical symptoms are characterized by pyramidal and extrapyramidal disturbances which include dystonia and an ataxic gait. Gross study of the brain indicates a unique pattern of lysosomal storage (Suzuki,1992), ganglioside storage occurs primarily in the basal ganglia. Cortical atrophy is found in insignificant amounts while those nuclei of the basal ganglia (caudate, putamen, and globus pallidus) show a notable decrease in size.

A comparison of gross morphological features of GM1 and GM2 gangliosidotic brains indicates a significant difference in storage patterns between the two diseases. GM1 gangliosidosis results in storage defects of primarily the basal ganglia with some involvement of visceral cells. GM2 gangliosidosis results in the same type of storage defect but is more widely dispersed throughout the brainstem nuclei and cerebellum (Suzuki, 1992). Despite these differences the clinical characteristics of the two disorders are unduly similar.

Although these genetic disorders are relatively rare among the general public, it will be important as a physician to understand the severity of the disease. I believe patients from ethnic groups which have a high carrier rate must receive proper counseling and genetic testing before trying to conceive children. As physicians it will be our responsibility to ensure this aspect of the disease is not forgotten.

BIBLIOGRAPY

Arisoy, S. E. "Picture of the Month. Tay-Sachs Disease." Am.J.- Dis.Child., 1992 June; 767-8.

Drucker, L."Identification and Rapid Detection of Three Tay--Sachs Mutations in the Moroccan Jew Population." Am. J. Human Genetics. 1992; 51: 371-77.

Fredrico, A. "The Clinical Aspect of Adult Hexosaminidase Deficiencies." Developmental Neuroscience. 1991; 13: 280-287

Fukumizu, M. "Tay-Sachs Disease: Progression of Changes on Neuroimaging in Four Cases." Neuroradiology. 1992; 34: 483-486.

Gravel, R.A. "Biochemistry and Genetics of Tay-Sachs Disease." The Canadian Journal of Neurological Sciences. 1991; 18: 419-423.

Maia, Maria. "Juvenile GM2 Variant B1: Clinical and Biochemical Study in Seven Patients." Neuropediatrics. 1990; 21: 18-23.

Specola, N. "The Juvenile and Chronic Forms of GM2 Gangliosidosis." Neurology. 1990; 40: 145-150.

Suzuki, K. "Neuropathology of Late Onset Gangliosidosis." Developmental Neuroscience. 1991;13: 205-10.