with homozygous p.Leu490Pro mutation Haematopoietic stem cell transplantation in 3 Mucopolysaccharidosis I patients with homozygous p.Leu490Pro mutation Ghosh A1, Jones S1, Broomfield A1, Mercer J1, Wynn R2 1Willink Biochemical Genetics Unit, Manchester Centre for Genomic Medicine, 2Bone Marrow Transplantation Unit, Royal Manchester Children’s Hospital Introduction The p.Leu490Pro mutation is a missense mutation first described in an Indian patient and subsequently found in Pakistani patients. This genotype is associated with an attenuated MPS I phenotype. A previous report described a cohort of 14 UK patients with this mutation all of Pakistani/Kashmiri origin who were treated with ERT1. We describe three patients diagnosed shortly after birth who were treated with haematopoietic stem cell transplantation and their 5 siblings who were treated with ERT. Aims To describe the experience and outcomes of haematopoietic stem cell transplantation in 3 patients homozygous for the p.Leu490Pro mutation known to be associated with an attenuated phenotype. Methods Retrospective review of case notes, reporting on survival, transplant outcome, disease progression, neurological outcome and biomarker response Results 8 children from 3 families, all homozygous p.Leu490Pro genotype, all of Pakistani/Kashmiri origin living in the UK All ERT treated patients (5) had attenuated (Hurler-Scheie) phenotype, 2 started ERT at < 6 months as were siblings of known patients HSCT treated patients diagnosed early in life as siblings of known MPS I patients HSCT treated patients (3): All HSCT from related donors, 2/3 bone marrow, 1/3 peripheral blood stem cells All received ERT with laronidase (α-l-iduronidase) prior to HSCT at a dose of 0.58 U/kg weekly All received full intensity busulfan based conditioning with pharmacokinetic monitoring Table 1. HSCT treated patients Patient number Sex Signs at diagnosis Age at HSCT (months) ERT doses (pre-HSCT) (post-HSCT Age at last review (years) Survival & engraftment Clinical status Neurological outcome 1 F Trace corneal haze Vertebral beaking 5.8 22 3.0 Alive Stable chimerism (70-80% donor) Mild corneal clouding Spinal brace for gibbus Borderline overnight saturations (mean 94%) Normal development 2 M Borderline cardiac function No organomegaly or spinal deformity 3.9 10 1.9 Falling chimerism now stabilised (25%) donor Good cardiac function 2m post transplant 3 Mild hepatomegaly Normal spine 4.8 14 (92% donor) Small PFO on echo Table 2. ERT treated patients Patient number Sex Signs at diagnosis Age at starting ERT(years) Age at last review (years) Survival Clinical status Neurological outcome 4 M Hepatomegaly 0.6 12.2 Alive Asthma (FVC 81%, FEV1 72%) Thickened mitral valve Mild corneal opacification Full scale IQ 72 (borderline) 5 F Kyphosis Upper airway obstruction 2.4 10.6 Carpal tunnel syndrome Glaucoma (iridotomies age 8y) Moderate corneal clouding Dysplastic mitral/aortic valve Full scale IQ ‘extremely low’ range 6 Abnormal facial features Umbilical hernia Mild LVH, good function 2.8 12.1 Corneal clouding No LV dilatation, good function Snoring but sleep study good Mild restriction hips and shoulders FVC 59%, FEV1 67% Full scale IQ 92 ‘average’ range 7 Hepatosplenomegaly Corneal haze Frequent infections 6.1 15.4 Carpal tunnel release Adenoidectomy Restriction of hip movement 8-plate surgery for genu valgum Mild mitral/aortic regurgitation FVC 42%, FEV1 37% 8 Minimal No hepatosplenomegaly 0.4 8.6 Trivial mitral regurgitation Mild hearing impairment FVC 85%, FEV1 86% Language ability Working memory Figure 1. Total GAG reduction Conclusions Biochemical outcomes were equivalent for ERT and HSCT in this cohort though a previous report has shown better substrate reduction by HSCT than ERT2 Further follow up and experience is needed to fully assess clinical outcomes but age at therapy is likely to be an important determinant Neurological outcome has the potential to be better with HSCT References Arora, R. S., J. Mercer, M. Thornley, K. Tylee and J. E. Wraith (2007). "Enzyme replacement therapy in 12 patients with MPS I-H/S with homozygous p.Leu490Pro mutation." J Inherit Metab Dis 30(5): 821 Wynn, R. F., J. E. Wraith, J. Mercer, A. O'Meara, K. Tylee, M. Thornley, H. J. Church and B. W. Bigger (2009). "Improved metabolic correction in patients with lysosomal storage disease treated with hematopoietic stem cell transplant compared with enzyme replacement therapy." J Pediatr 154(4): 609-611. Total GAG not significantly different at 6m, 12m post treatment for HSCT vs ERT (Mann-Whitney U) GAG as % of ULN for age not significantly different at 6m, 12m, most recent for HSCT vs ERT (Mann-Whitney U) (data not shown) Urinary DS:CS ratio not significantly different for 6m, 12m, most recent for HSCT vs ERT (Mann-Whitney U) (data not shown)