Allogeneic BMT Followed by Substrate Deprivation Therapy with N-butyldeoxynojirimycin in a Child with Tay-Sachs Disease.

Introduction: Tay-Sachs Disease (G_M2 gangliosidosis) is a lysosomal storage disorder caused by beta-hexosaminidase A (Hex-A) deficiency, which leads to severe and progressive neurological damage. BMT has been used successfully as treatment strategy in some storage disorders. G_M2 gangliosidosis mouse models demonstrate that after BMT donor-derived metabolically competent cells infiltrate the CNS leading to delayed onset of symptoms and prolonged survival. Further enhancement of survival has been reported in mice receiving a combination of substrate deprivation therapy and BMT. To our knowledge data on the effects of BMT in children with Tay-Sachs disease are lacking.

Patient: A three-year-old girl was diagnosed with Tay-Sachs disease with minimal clinical symptoms, after the same diagnosis was made in her symptomatic older sister. Pre-BMT conditioning consisted of busulfan, cyclophosphamide and ATG. She received T-cell depleted marrow from an HLA identical unrelated donor. Ciclosporin-A (CsA) was given as GvHD prophylaxis. Follow-up is 2.5 years.

Results: Hex-A levels in leukocytes increased initially to donor levels and decreased to a steady level of 30% of controls for the last 1.5 years, indicating stable mixed chimerism. Also the enzyme levels in serum increased to 10% of controls, indicating release of enzyme into serum. Shortly after BMT, rapid progression of neurological symptoms occurred (MRI, EEG and neuro-psychological tests). Some neurological symptoms partially improved, others stabilized after CsA was stopped, suggesting that CsA had contributed to the neurological deterioration. Experimental substrate deprivation therapy with N-butyldeoxynojirimycin was started 1.5 years after BMT. No adverse effects of this drug were observed.

Conclusion: BMT followed by substrate deprivation therapy in our patient with early stage of Tay-Sachs disease resulted in Hex-A enzyme levels in leukocytes and serum of 30% and 10% of normal levels respectively. Neurological deterioration occurred shortly after BMT and seemed to stabilize thereafter, but follow-up is too short to draw firm conclusions yet.