Transplant Outcomes and Stabilization of Neurological Function in Young Children with MPS III (Sanfilippo Syndrome) after Unrelated Donor Umbilical Cord Blood Transplantation.

Between September 1998 and June 2004, 15 children, ages 10 – 55 months, 60% males, 14 Caucasian, 1 mixed racial background, underwent unrelated donor umbilical cord blood transplantation for treatment MPS III (Sanfilippo Syndrome, types A or B) Grafts were mismatched at 0 (n = 1), 1 (n = 10) or 2 (n = 4) HLA loci. All children were prepared for transplant with busulfan 40mg/m2/dose PO or 1mg/kg/dose IV targeting a Css of 600–900ng/ml), cyclophosphamide 50mg/kg/dose daily x 4, and equine ATG 30mg/kg/dose daily x 3. Cyclosporine and solumedrol were used for prophylaxis against GvHD. Engraftment with donor cells occurred in 10/15 patients, although one additional patient engrafted after a second transplant. Five patients, including the one transplanted a second time, died within 8 months of transplant of graft failure with respiratory failure and viral infections (Adenovirus, HSV). Six patients developed mild to moderate acute GvHD and 4 patients had limited (2) or extensive (2) chronic GvHD. All children were tested with baseline neurophysiologic, imaging and neurocognitive tests. These were then followed in surviving children every 6 months for 2 years and yearly thereafter. All children demonstrated deficits in hearing and mild to moderate developmental delays at the time of initial evaluation. MRIs showed varying degrees of volume loss generally increasing with the age of the patient at initial evaluation. EEGs were normal in the younger patients, but showed slowing and signs of generalized encephalopathy in the older patients. Two patients developed hydrocephalus requiring VP shunt placement within 1 year of transplant and one patient experienced subdural hematomas after minor head trauma. MRIs of all surviving patients stabilized for the first 4 years post transplant. One patient, now almost 5 years post transplant showed volume loss on the latest study. Patients transplanted at <3 years of age appear to have better neurocognitive outcomes than those over 3 since the younger patients continue to learn, albeit at a slower pace than typically developing children, while the older patients appear to have stabilized at their pretransplant level of functioning. All patients, however, show improvement in adaptive behaviors and general well being. Parents report less aggression, autistic like behaviors and improved sleep. We conclude that UCBT has a role in the therapy of children with MPS III. Effects of transplantation under the age of 2 years should be explored in a larger group of patients.