MIXED DONOR CHIMERISM AND LOW LEVEL IDURONIDASE EXPRESSION MAY BE ADEQUATE FOR NEURODEVELOPMENTAL PROTECTION IN HURLER SYNDROME JENNIFER CONWAY, MD, SARAH DYACK, MD, FRCPC, FCCMG, BRUCE N. A. CROOKS, MB, CHB, BSC, MRCP, AND CONRAD V. FERNANDEZ, MD, FRCPC Hurler syndrome is a lysosomal storage disease resulting in fatal cardiac or neurologic sequelae unless alpha-iduronidase production is reconstituted with hematopoietic stem cell transplantation. We report on a 4-year, 6-month-old boy with mixed donor chimerism and low enzyme levels but a normal neurodevelopmental trajectory. (J Pediatr 2005;147:106-8) C hildren with Hurler syndrome lack the lysosomal enzyme alpha-L-iduronidase. This results in glycosaminoglycan (GAG) accumulation with progressive mental retardation and death. 1,2 Recombinant alpha-L-iduronidase appears to ameliorate some of the systemic effects in Hurler syndrome, but hematopoietic stem cell transplantation remains the only means of preventing the neurologic deterioration. 3 Children with Hurler syndrome have normal intelligence at birth, but on average their IQ declines by 2 standard deviations within the first 2 years of life (30-point decrease in IQ). 4 The negative correlation between age and IQ has been found to be significant (r = 20.82, P # .0003). 2 Good neuropsychological outcomes after bone marrow transplantation (BMT) are dependent on multiple factors including age at transplantation (<24 months), mental developmental indexes >70 before transplantation, adequate engraftment (as measured by full donor chimerism), and posttransplantation iduronidase activity. 4-6 We report the case of a patient with Hurler syndrome in whom a good neurologic outcome was achieved in spite of poor sustained engraftment and very low serum alpha-L-iduronidase activity after BMT. CASE REPORT At 9 months of age, the patient presented with coarse facies and a lumbar gibbus. He had dysostosis multiplex and a positive mucopolysaccharide (MPS) screen result. Hurler syndrome was confirmed by the absence of alpha-L-iduronidase activity in peripheral blood leukocytes. He had a homozygous mutation of his IDUA gene, W402X, common to those with a severe Hurler phenotype. At 15 months of age, the patients underwent BMT from a male matched related donor. Conditioning regimen included cyclophosphamide (50 mg/kg 3 4 doses), busulfan (based on targeted AUC 18mg/kg divided every 6 hours over 4 days), and low-dose total body irradiation (300 cGy). The patient was transplanted with 5.6 3 10 8 nucleated cells/ kg. He had no unexpected transplant-related toxicity and specifically no central nervous system complications. After BMT, his musculoskeletal abnormalities persisted but were stable, his facial features softened, and airway obstruction resolved. An echocardiogram obtained 2 years after transplantation showed resolution of both his atrial septal defect and mild valvular regurgitation. Initially he fully engrafted. He was followed by chimerisms on whole blood and alpha-L-iduronidase levels on unfractionated peripheral leukocytes. He expressed normal levels of alpha-L-iduronidase after transplantation but failed to sustain these beyond 4 months after BMT. The patient has remained at very low levels of activity (Table). BMT Bone marrow transplantation CNS Central nervous system 106 From the Department of Pediatrics, the Division of Genetics, the Division of Pediatric Hematology/Oncology, at the IWK Health Centre and Dalhousie University, Halifax, Nova Scotia. Submitted for publication Oct 23, 2004; last revision received Jan 12, 2005; accepted Mar 3, 2005. Reprint requests: Conrad Fernandez MD, FRCPC, IWK Health Centre 5850 University Avenue, PO Box 9700, Halifax, Nova Scotia B3K 6R8 Canada. E-mail: conrad.fernandez@ iwk.nshealth.ca. 0022-3476/$ - see front matter Copyright ª 2005 Elsevier Inc. All rights reserved. 10.1016/j.jpeds.2005.03.005