Abstract
BackgroundLate 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.MethodsIn 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).ResultsHexA 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.ConclusionsCyclic 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.
Highlights
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)
Late Onset Tay Sachs disease (LOTS) is a rare variant of Tay Sachs disease (TSD), that results from mutations in the gene encoding the α subunit of β-hexosaminidase A (HexA)
Osher et al Orphanet Journal of Rare Diseases (2015) 10:45 and the clinical phenotype in subjects carrying TSD mutations, it has been suggested that 10% of the normal HexA activity could be sufficient to avoid the development of a clinical disorder [3]
Summary
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). No clinically effective treatment for LOTS and other lysosomal diseases involving the central nerve system presently exists Since any such putative mode of therapy requires access to the central nervous system (CNS), the use of small molecules functioning as pharmacological chaperones, which can potentially stabilize the native folding of the protein despite its anomalous conformation, preventing aggregation and restoring enzyme activity, appears attractive. We have previously reported that PMT administered in a dose escalating protocol was able to enhance HexA activity in 9 patients LOTS patients who were compound heterozygotes carrying the αG269S/ c.1278insTACT mutations. This may have been associated with some subtle clinical benefits. We tested the effect of cyclic low dose PMT on HexA activity in 4 out of the 9 LOTS patients included our previous study
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
