ORIGINALARTICLE Long-termmetabolic,endocrine,andneuropsychologicaloutcome ofhematopoieticcelltransplantationforWolmandisease J Tolar 1 , A Petryk 2 , K Khan 3 , KJ Bjoraker 4 , J Jessurun 5 , M Dolan 5 , T Kivisto 1 , L Charnas 4 , EG Shapiro 4 and PJ Orchard 1 1 Division of Pediatric Hematology-Oncology, Department of Pediatrics, Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN, USA; 2 Division of Endocrinology, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA; 3 Division of Gastroenterology, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA; 4 Division of Pediatric Clinical Neuroscience, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA and 5 Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA Wolman disease is the infantile form of autosomal recessive acid lipase deficiency, typically presenting in earlyinfancywithdiarrhea,massivehepatosplenomegaly, failure to thrive, and calcification of adrenal glands. Hematopoietic cell transplantation (HCT) is the only therapy reported to prevent hepatic failure and death, which without treatment occurs within the first year of life.Wereportasingleinstitution’sexperiencewithHCT treatmentoffourWolmanpatients,twoofwhomarelong- term survivors (the longest survival reported to date, (4 and 11 years). Survivors showed resolution of diarrhea within weeks after engraftment, normalized hepatic function, improved hepatosplenomegaly, and in one patient normal adrenal function. The older patient has normal adaptive functions but mild to moderate neuro- cognitivedeficienciesthoughttobesecondarytotreatment andothermedicalproblems.Theyoungerpatienthasage- appropriate neurodevelopmental and adaptive abilities. We conclude that Wolman disease can be successfully treatedwithHCT,andthathepaticandcognitivefunction canbepreservedwithearlydiagnosisandtimelyreferral toatransplantcenter. Bone Marrow Transplantation (2009) 43, 21–27; doi:10.1038/bmt.2008.273;publishedonline8September2008 Keywords: Wolman disease; acid lipase; adrenal insuffi- ciency; hematopoietic cell transplantation; hyperthyroidism; growth hormone deficiency Introduction Wolman disease, initially described by Abramov et al. in 1956, 1 is an autosomal recessive disorder of infancy caused by deficiency of the soluble mannose-6-phosphate-targeted lysosomal enzyme acid lipase (AL). 2 Deficiency of this enzyme leads to massive storage of cholesterol and cholesteryl esters. Triglycerides and cholesteryl esters are internalized by the cell through receptor-mediated endocy- tosis of lipoproteins and metabolized, in part, by AL. 3,4 The clinical manifestations of this disorder are caused by both accumulation of cholesteryl esters and triglycerides, and toxicity from lipoprotein oxidation. 5 Children affected with Wolman disease appear healthy at birth but shortly thereafter develop hepatosplenomegaly, jaundice, diarrhea, severe vomiting, failure to thrive, and pathognomonic pattern of calcification of the adrenal glands. 1,2 Wolman disease is uniformly lethal in early infancy unless treated with hematopoietic cell transplant- ation (HCT). 6–8 Donor cells supply AL to lysosomes of host cells, and restore sufficient enzymatic activity for normal hydrolysis of triglycerides and cholesteryl esters. 2,4,9,10 Graft failure and the high mortality rate associated with disease-related pretransplant liver injury and post-transplant liver sinusoidal obstruction syndrome (veno-occlusive disease) 6,7 are, however, major barriers to optimal outcomes. Wolman disease is rare (with fewer than 80 cases identified by a PubMed search) and available long-term follow-up data are limited. We report a single institution experienceofHCTtreatmentoffourWolmanpatients,two of whom are long-term survivors, for 4 and 11 years after HCT. Patients Table 1 summarizes the specifics of the transplant procedure and graft characteristics. The University of Minnesota Institutional Review Board approved all transplantation protocols, and informed consent was Received 1 July 2008; accepted 25 July 2008; published online 8 September 2008 Correspondence: Dr J Tolar, Division of Pediatric Hematology- Oncology, Department of Pediatrics, Blood and Marrow Transplantation, University of Minnesota, MMC 366, 420 Delaware Street SE, Minnea- polis, MN 55455, USA. E-mail: tolar003@umn.edu Bone Marrow Transplantation (2009) 43, 21–27 & 2009 Macmillan Publishers Limited All rights reserved 0268-3369/09 $32.00 www.nature.com/bmt