title: Effect of cyclic, low dose pyrimethamine treatment in patients with Late Onset Tay Sachs: an open label, extended pilot study.
abstract: 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.
authors.affiliation: Institute of Endocrinology, Metabolism and Hypertension, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. esteros@tlvmc.gov.il.
authors.forename: Etty
authors.initials: E
authors.lastname: Osher
authors.affiliation: Pediatric Neurology Unit, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. vfatal@tlvmc.gov.il.
authors.forename: Aviva
authors.initials: A
authors.lastname: Fattal-Valevski
authors.affiliation: Pediatric Neurology Unit, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. lssagi@yahoo.com.
authors.forename: Liora
authors.initials: L
authors.lastname: Sagie
authors.affiliation: Institute of Endocrinology, Metabolism and Hypertension, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. naturshan@gmail.com.
authors.forename: Nataly
authors.initials: N
authors.lastname: Urshanski
authors.affiliation: Institute of Endocrinology, Metabolism and Hypertension, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. nadavos@yahoo.com.
authors.forename: Nadav
authors.initials: N
authors.lastname: Sagiv
authors.affiliation: Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. lpeleg@sheba.health.gov.il.|Department of Human Genetics, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. lpeleg@sheba.health.gov.il.
authors.forename: Leah
authors.initials: L
authors.lastname: Peleg
authors.affiliation: Pediatric Neurology Unit, Wolfson Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. asagie@post.tau.ac.il.
authors.forename: Tally
authors.initials: T
authors.lastname: Lerman-Sagie
authors.affiliation: Shaare Zedek Medical Center, Hadassa School of Medicine, Hebrew University, Jerusalem, Israel. gaucher@szmc.org.il.
authors.forename: Ari
authors.initials: A
authors.lastname: Zimran
authors.affiliation: Shaare Zedek Medical Center, Hadassa School of Medicine, Hebrew University, Jerusalem, Israel. debby.elstein@gmail.com.
authors.forename: Deborah
authors.initials: D
authors.lastname: Elstein
authors.affiliation: Department of Human Genetics, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. rnavon@post.tau.ac.il.
authors.forename: Ruth
authors.initials: R
authors.lastname: Navon
authors.affiliation: Tel Aviv-Sourasky Medical Center; Geha Mental Health Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. valevski@gmail.com.
authors.forename: Avi
authors.initials: A
authors.lastname: Valevski
authors.affiliation: Institute of Endocrinology, Metabolism and Hypertension, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. naftalis@tlvmc.gov.il.
authors.forename: Naftali
authors.initials: N
authors.lastname: Stern
mesh_terms: D000328:Adult; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D015971:Gene Expression Regulation, Enzymologic; D054818:Hexosaminidase A / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D010865:Pilot Projects; D011739:Pyrimethamine / Q000008:administration & dosage* / Q000627:therapeutic use*; D013661:Tay-Sachs Disease / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D054818:Hexosaminidase A; D011739:Pyrimethamine