Pyrimethamine as a Treatment for Late-Onset GM2-gangliosidosis (Tay-Sachs and Sandhoff Disease)

Inclusion Criteria: * biochemically and genetically confirmed diagnosis of GM2-gangliosidosis caused by β-hexosaminidase deficiency resulting from mutations in the HEXA or HEXB genes; * having HEXA or HEXB mutations shown to be responsive to pyrimethamine in vitro; * over 17 years of age at the time of study initiation; * able to understand and cooperate with the requirements of the study protocol; * mentally competent, have the ability to understand and willingness to sign the informed consent form; * able to travel to one of the three participating study sites; * women of child-bearing potential must use accepted contraceptive methods and must have a negative serum or urine pregnancy test within one week prior to treatment initiation; * fertile men must practice effective contraceptive methods during the study period, unless documentation of infertility exists; * laboratory values ≤2 weeks prior to randomization must show adequate hematologic, hepatic, renal, and coagulation function; and body weight \>40 kg. Exclusion Criteria: * serious medical illness, significant cardiac disease or severe debilitating pulmonary disease; * any hematologic abnormality, especially megaloblastic anemia, leukopenia, thrombocytopenia, pancytopenia; * any active uncontrolled bleeding or any bleeding diathesis (e.g., active peptic ulcer disease); * possible folate deficiency, and those receiving therapy (such as phenytoin) affecting folate levels; * any complex disease that may confound treatment assessment; * pregnant women or women of child-bearing potential not using reliable means of contraception; * lactating females; * fertile men unwilling to practice contraceptive methods during the study period; * unwilling or unable to follow protocol requirements; * known hypersensitivity reactions, intolerance or adverse reactions to pyrimethamine; * evidence of active infection, or serious infection within the past month; * HIV infection; * a history of cancer of any type; * receiving any other standard or investigational treatment for any indication within the past 4 weeks prior to initiation of pyrimethamine treatment; * receiving immunotherapy of any type within the past 4 weeks prior to initiation of pyrimethamine treatment; or any condition or abnormality, which may, in the opinion of the investigator, compromise the safety of patients.