title: Pyrimethamine increases β-hexosaminidase A activity in patients with Late Onset Tay Sachs.
abstract: OBJECTIVE
  To assess whether or not pyrimethamine (PMT) can be used to enhance β-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.
authors.affiliation: Institute of Endocrinology, Metabolism and Hypertension, Tel Aviv-Sourasky Medical Center, Israel.
authors.forename: Etty
authors.initials: E
authors.lastname: Osher
authors.forename: Aviva
authors.initials: A
authors.lastname: Fattal-Valevski
authors.forename: Liora
authors.initials: L
authors.lastname: Sagie
authors.forename: Nataly
authors.initials: N
authors.lastname: Urshanski
authors.forename: Yifat
authors.initials: Y
authors.lastname: Amir-Levi
authors.forename: Sara
authors.initials: S
authors.lastname: Katzburg
authors.forename: Leah
authors.initials: L
authors.lastname: Peleg
authors.forename: Tally
authors.initials: T
authors.lastname: Lerman-Sagie
authors.forename: Ari
authors.initials: A
authors.lastname: Zimran
authors.forename: Deborah
authors.initials: D
authors.lastname: Elstein
authors.forename: Ruth
authors.initials: R
authors.lastname: Navon
authors.forename: Naftali
authors.initials: N
authors.lastname: Stern
authors.forename: Avi
authors.initials: A
authors.lastname: Valevski
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects*; D005260:Female; D005493:Folic Acid Antagonists / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D054818:Hexosaminidase A / Q000378:metabolism*; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D011739:Pyrimethamine / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D013661:Tay-Sachs Disease / Q000188:drug therapy* / Q000378:metabolism*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D005493:Folic Acid Antagonists; D054818:Hexosaminidase A; D011739:Pyrimethamine