Effect of cyclic, low dose pyrimethamine treatment in patients with Late Onset Tay Sachs: an open label, extended pilot study.

BACKGROUND: Late Onset Tay- Sachs disease (LOTS) is a rare neurodegenerative lysosomal storage disease which results from mutations in the gene encoding the α subunit (HEXA) of ß-hexosaminidase enzyme (HexA). At the present time, no effective treatment exists for LOTS and other neurodegenerative diseases involving the central nerve system (CNS). Pyrimethamine (PMT) was previously shown to act as a HexA chaperone in human fibroblasts in vitro carrying some (e.g., αG269S), but not all LOTS-related mutations. The present study assessed the effect of cyclic, low dose and long term pyrimethamine treatment on HexA in subjects with LOTS. METHODS: In an open label trial in 4 LOTS patients, PMT was initiated at an average daily dose of ~2.7 mg and administered cyclically guided by blood lymphocyte HexA activity for a mean duration of 82.8 (±22.5; SD) weeks (~1.5 year). RESULTS: HexA activity rose in all subjects, with a mean peak increase of 2.24 folds (±0.52; SD) over baseline activity (range 1.87-3). The mean treatment time required to attain this peak was of 15.7 (±4.8; SD) weeks. Following increase in activity, HexA gradually declined with the continued use of PMT, which was then stopped, resulting in the return of HexA activity to baseline. A second cycle of PMT treatment was then initiated, resulting again in an increase in HexA activity. Three of the patients experienced a measurable neuropsychiatric deterioration whereas one subject remained entirely stable. CONCLUSIONS: Cyclic low dose of PMT can increase HexA activity in LOTS patients. However, the observed increase is repeatedly transient and not associated with discernible beneficial neurological or psychiatric effects.

Pyrimethamine increases ß-hexosaminidase A activity in patients with Late Onset Tay Sachs.

OBJECTIVE: To assess whether or not pyrimethamine (PMT) can be used to enhance ß-hexosaminidase A activity (HexA) in subjects with Late Onset Tay Sachs (LOTS), we studied the effect of incremental doses of PMT in vivo in 9 LOTS patients carrying the αG269S/c.1278insTACT mutations. METHODS: PMT treatment was initiated at a dose of 6.25 mg, increasing gradually up to a maximal allowable dose of 75 mg daily at 4-6 weeks intervals for a total of up 10 months. Mean patients' age was 37.9±16.1 yrs (range 20-67 years). RESULTS: Lymphocyte HexA activity rose in all subjects, peaking at 78±30% over baseline activity (mean±SD; range 36-114%). The optimal PMT dose varied considerably, averaging at 30±24.1 mg (range-6.25-75 mg, daily). Further increase in PMT beyond the optimal dose was associated with gradual loss of effect on lymphocyte HexA. Improvement in speech was seen within several weeks in 4 out of 9 subjects, mostly paralleling the initial increment in HexA. Mood stabilization was also perceived in 3 subjects, but this was more difficult to assess due to the concomitant use of psychotropic/mood stabilizing agents. Reversible decline in motor activity manifesting predominantly in more frequent falls was seen in 3 subjects when the PMT dose was increased beyond the peak effect generating dose. CONCLUSIONS: PMT therapy can increase HexA activity in LOTS in vivo. Optimal doses should be tailored individually to avoid loss of biochemical effects. Clear cut neurological and psychiatric effects are difficult to discern at this time, mostly due to short term study follow up and large inter-individual variability.