TY - JOUR
T1 - Effect of cyclic, low dose pyrimethamine treatment in patients with Late Onset Tay Sachs
T2 - An open label, extended pilot study
AU - Osher, Etty
AU - Fattal-Valevski, Aviva
AU - Sagie, Liora
AU - Urshanski, Nataly
AU - Sagiv, Nadav
AU - Peleg, Leah
AU - Lerman-Sagie, Tally
AU - Zimran, Ari
AU - Elstein, Deborah
AU - Navon, Ruth
AU - Valevski, Aviva Fattal
AU - Stern, Naftali
N1 - Publisher Copyright:
© 2015 Osher et al.; licensee BioMed Central.
PY - 2015/4/17
Y1 - 2015/4/17
N2 - 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 β-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.
AB - 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 β-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.
KW - Late Onset Tay Sachs
KW - Pyrimethamine
KW - β hexosaminidase A
UR - http://www.scopus.com/inward/record.url?scp=84928005199&partnerID=8YFLogxK
U2 - 10.1186/s13023-015-0260-7
DO - 10.1186/s13023-015-0260-7
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AN - SCOPUS:84928005199
SN - 1750-1172
VL - 10
JO - Orphanet Journal of Rare Diseases
JF - Orphanet Journal of Rare Diseases
IS - 1
M1 - 45
ER -