Mixed Donor Chimerism and Low level alpha-L-iduronidase Expression May Be Adequate for Neurodevelopmental Protection in Hurler’s Syndrome.
Authors: Conway Jennifer , Dyack Sarah , Crooks Bruce N.A. , Schmidt Matthias , Fernandez Conrad V. 
Published: October 2019

Abstract
Background. Hurler’s syndrome is a lysosomal storage disease with devastating neurological sequelae if left untreated. The negative correlation between age and IQ is significant (r = −0.82, p< 0.0003). These children have a normal intelligence at birth but on average decline by 2 standard deviations within the first 2 years of life (represents 30 point decrease in IQ). The underlying abnormality is an absence of the enzyme alpha-L-iduronidase, which is available as a recombinant enzyme but does not cross the blood-brain barrier. Currently, bone marrow transplant (BMT) is the only way to prevent the expected neurological deterioration. It is believed that higher levels of enzyme activity are associated with better neurological outcomes.
Case report: We report on a 4 year 6 month old boy who was diagnosed with Hurler’s syndrome at 9 months of age. At 15 months of age, he received a matched related transplant with a preparative regimen of cyclophosphamide, busulfan and low dose total body irradiation (300 cGy). In the post transplant period, he had some minor complications but no neurological insults. He received Cyclosporin A for GVHD prophylaxis, which was discontinued after 5 months. Initially there was complete engraftment and normal enzyme activity but this was temporary (See Table 1).
Table 1 Alpha-L-iduronidase Chimerism % * believed to be secondary to assay problems Pretransplant 0 Post transplant Normal 14–41 nmol/h/mg protein Ideal > 90% 1 month 28 90 4 months 0 45 6 months 14 30 1 year 3 15 1 year 5 months 2 15 1 year 8 months 3 10 2 year 1 month 73* 15 2 year 6 months 4 10 3 year 2 months 3 10
He had an excellent clinical response to BMT with softening of the characteristic facial features and resolution of airway obstruction. Prior to BMT he was report to be developing normally. He sat at 61/2 months, stood at 7 month, had single words at 10 months, and walked at 13 months. Despite mixed chimerism and sub-optimal enzyme activity, his development since BMT has been impressive. 2 years post-BMT (age 3 yr 3 mo), he underwent a formal neuropsychological evaluation. Full Scale intelligence testing revealed he had average intelligence (45th percentile), with a discrepancy between his verbal and performance intelligence. His language skills were within normal limits. He was reported to have some difficulties with visual spatial testing (in block design). Clinical assessment, at this time, revealed that he was doing well in school and had been fully toilet trained. At his last assessment at age 4 yr 5 mo (3 yr 2 mo post BMT), he had made dramatic improvements on the Peabody Developmental Motor Skills, with an age equivalent of 41 months. This was likely hampered somewhat by flexion contractures of his fingers. He continued to do well in school and was speaking both English and French. He had clinically normal development for age. Formal neuropsychological tests will be presented in poster format.
Conclusions : This case is the first in the literature with halting of the characteristic neurological decline in Hurler’s syndrome despite poor engraftment and low enzyme activity following BMT. Full donor chimerism and normal alpha-L-iduronidase expression may not be needed to ameliorate the devastating consequences of Hurler’s syndrome.