A rare disease a day: Tay-Sachs

Continuing the rare disease a day theme started with Hunter Syndrome, and Gaucher’s disease, today the topic is Tay-Sachs which is a  also known as GM2 gangliosidosis or hexosaminidase A deficiency. Tay Sachs is a rare autosomal recessive genetic disorder and extensive information can be found online. Tay–Sachs disease is classified into several forms, differentiated based on the onset age of neurological symptoms.

Infantile Tay–Sachs disease. As neurons become distended with gangliosides, a relentless deterioration of mental and physical abilities begins at 6 months resulting in blindness, deafness, unable to swallow and paralytic the children die usually before age 4. Juvenile Tay–Sachs disease. Usually seen in children between two and ten years old and they develop cognitive and motor skill deterioration, dysarthria, dysphagia, ataxia, and spasticity with death occuring between ages 5-15 years.Adult/Late-Onset Tay–Sachs disease. Usually has its first symptoms in a patient in their 30s or 40s and is usually not fatal . It is characterized by unsteadiness of gait and progressive neurological deterioration with symptoms such as speech and swallowing difficulties.

Hexosaminidase A is a lysomal enzyme  that breaks down  fatty acid derivatives called gangliosides. The hydrolysis of GM2-ganglioside requires two subunits of hexosaminidase A and a small glycolipid transport protein (the GM2 activator protein, GM2A). Deficiency in any one of these 3 proteins leads to ganglioside storage. It is thought most Tay–Sachs mutations probably do not directly affect the protein active site but cause incorrect folding or disable intracellular transport.

There is currently no FDA approved drug for this disease. Research has focused on enzyme replacement therapy. Most recently one group described a the computer-aided design of a modified HexB with GM2-degrading activity and binding ability as to GM2AP. This protein was active in patient fibroblasts and in the mouse model, retaining enzyme activity.

As with Gaucher and other lysosomal storage diseases, there has been exploration of potential chaperones such as the L-iminosugar LABNAc and its derivatives ,the D-iminosugar DABNAc and its derivatives and early screens of FDA approved drugs which lead to pyrimethamine . Two clinical studies used pyrimethamine as a chaperone in Late onset Tay-Sachs and in one lymphocyte HexA activity rose in all subjects and effects on speach and mood were noted. A second trial reported a 4-fold enhancement of Hex A activity at doses of 50 mg per day.

It would appear that we are far from a treatment for Tay-Sachs but one could imagine exploring analogs of the animalarial pyrimethamine as this has shown in vivo activity. For instance Lamotrigine and trimethoprim which have some degree of structural similarity may be worth testing as FDA approved drugs (anticonvulsant and antibacterial, respectively). The figure shows a similarity search based on pyrimethamine in the Approved drugs mobile appsimilarity search on Pyrimethamine. One could also imagine these compounds docked into homology models of Hex A .


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  1. Tim Hayes says:

    While it’s not fully proven, miglustat is being investigated as a treatment for Tay-Sachs, as well as GM1.

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