Abstract
The neuropsychiatric adult onset Tay-Sachs disease is relatively unknown. Although clinical features and mode of presentation are variable, there are common symptoms and signs of, for example, spinocerebellar atrophy, motor neuron disease, psychiatric disorder, and neuroimaging features of cerebellar atrophy. This chapter reviews the neuropsychiatric features of Late Onset Tay-Sachs disease, discussing possible interconnections between psychosis and the cerebellum in this disease. Understanding this interlink offers some important insights into the rarity of the disease that together with the diverse clinical onset and manifestations are responsible for a marked delay in diagnosis and even misdiagnosis. Genetic testing for the activity of Hexosaminidase A, prompted by the presence of cerebellar atrophy will establish the diagnosis. In all, the combination of cerebellar degeneration together with atypical psychiatric features is in line with the ongoing assumption that the cerebellum and its thalamo-cortical outflow are responsible for psychosis, and in particular, schizophrenia.
TopTowards The Rare Neuronopathy Gm2 Glangliosidosis
GM2 gangliosidosis is a rare neurometabolic lysosomal storage disease. The lysosomes are cytoplasmic membrane bound organelles that contain a variety of enzymes (hydrolases) necessary for breaking down complex macromolecules. A deficiency of a single lysosomal enzyme will cause storage of a macromolecule which, is the substrate for this enzyme within the lysosome. GM2 together with three other gangliosides are major components of the brain, accounting for more than 90% of its total ganglioside fraction. G refers to ‘ganglioside’, the M to monosialic (i.e., it has one sialic acid), and 2 is due to the fact that it was the second monosialic ganglioside discovered.
Although the functions of gangliosides are not fully understood, they are involved in ion transport, binding of neurotransmitters and cell adhesion. Hexosaminidase, a lysosomal enzyme necessary for degradation (breakdown) of GM2, is presented in the form of the isoenzymes Hexosaminidase A (Hex-A) and Hexosaminidase B (Hex-B). While both isoenzymes can hydrolyze a wide spectrum of macromolecules, only HEX-A is able to hydrolyze GM2 (Ferreira &, Gah, 2017). Deficient activity of HEX-A results in storage of GM2 within neurons, a condition known as neuronopathy, in contrast to neuropathy which is a disorder of peripheral nerves. It was found that the content of GM2 within the gray matter of the brain where the neurons are located is 100-300 times greater than the normal levels. The affected neurons take a ballooned appearance due the accumulation of the storage lipid material (GM2) (Figure 1). GM2 storage is caused by total deficiency of Hex-A, partial deficiency of Hex-A, a combined deficiency of Hex A and B, known as Sandhoff disease and a deficiency of the non-catalytic GM2 activator which manifest similarly to infantile TSD.
All the above-mentioned enzymes are responsible for degradation of GM2 (Lemieux et al., 2006; Navon, & Proia, 1989; Sandhoff, Harzer, Wässle, & Jatzkewitz, 1971; Zaroff et al., 2004).
Key Terms in this Chapter
GM2 Gangliosidosis: A very rare neuronopathy, in which intraliposomal storage of GM2 ganglioside is caused by a total or relative deficiency of the lysosomal enzyme ß- hexosaminidase A (Hex-A). This enzyme catalyzes the biodegradation of the gangliosides. The GM2 gangliosidoses consist of three related genetic disorders: Tay–Sachs disease, AB variant, and Sandhoff disease.
Ganglioside: The name ganglioside was first used in 1942 to lipids newly isolated from ganglion cells of the brain. A ganglioside is a molecule composed of a glycosphingolipid (ceramide and oligosaccharide) with one or more sialic acids (e.g. n-acetylneuraminic acid, NANA) linked on the sugar chain. GM2 is a type of ganglioside. G refers to ganglioside, the M is for monosialic (it has one sialic acid), and 2 refers to the fact that it was the second monosialic ganglioside discovered. It is associated with GM2 gangliosidoses.
Hexosaminidase A (HEX-A): Alpha-polypeptide enzyme encoded in Human gene HEXA, chromosome 15. Hexosaminidase A deficiency caused by mutations in the HEXA gene, is an inherited disease that causes brain and other nerve cells to die.
Adult Onset Tay-Sachs Disease: A very rare, with a progressive complex and variable clinical course due to aging and the presence of heterogeneous mutations which are responsible for different degrees of enzyme deficiency.