Jane E Potter1, Gemma Petts2, Arunabha Ghosh3, Fiona J White3,4, Jane L Kinsella5, Stephen Hughes6, Jane Roberts3, Adam Hodgkinson2, Kathryn Brammeier3, Heather Church3, Christine Merrigan7, Joanne Hughes7, Pamela Evans8, Helen Campbell5, Denise Bonney5, William G Newman3,9, Brian W Bigger10, Alexander Broomfield3, Simon A Jones3, Robert F Wynn5. 1. Department of Blood and Marrow Transplantation, Royal Manchester Children's Hospital, Oxford Road, Manchester, UK. janeelizabeth.potter@mft.nhs.uk. 2. Department of Paediatric Histopathology, Royal Manchester Children's Hospital, Oxford Road, Manchester, UK. 3. Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Oxford Road, Manchester, UK. 4. Department of Therapy and Dietetics, Manchester University NHS Foundation Trust, Oxford Road, Manchester, UK. 5. Department of Blood and Marrow Transplantation, Royal Manchester Children's Hospital, Oxford Road, Manchester, UK. 6. Paediatric Allergy and Immunology Department, Royal Manchester Children's Hospital, Oxford Road, Manchester, UK. 7. National Centre for Inherited Metabolic Disorders, Children's Health Ireland at Temple Street, Dublin, Ireland. 8. Department of Haematology and Oncology, Children's Health Ireland at Crumlin, Dublin, Ireland. 9. Evolution and Genomic Science, School of Biological Sciences, University of Manchester, Manchester, UK. 10. Stem Cell and Neurotherapies Laboratory, Division of Cell Matrix Biology and Regenerative Medicine, University of Manchester, Manchester, UK.
Abstract
BACKGROUND: Wolman disease is a rare, lysosomal storage disorder in which biallelic variants in the LIPA gene result in reduced or complete lack of lysosomal acid lipase. The accumulation of the substrates; cholesterol esters and triglycerides, significantly impacts cellular function. Untreated patients die within the first 12 months of life. Clinically, patients present severely malnourished, with diarrhoea and hepatosplenomegaly, many have an inflammatory phenotype, including with hemophagocytic lymphohistiocytosis (HLH). Hematopoietic stem cell transplant (HCT) had been historically the only treatment available but has a high procedure-related mortality because of disease progression and disease-associated morbidities. More recently, enzyme replacement therapy (ERT) with dietary substrate reduction (DSR) has significantly improved patient survival. However, ERT is life long, expensive and its utility is limited by anti-drug antibodies (ADA) and the need for central venous access. RESULTS: We describe five Wolman disease patients diagnosed in infancy that were treated at Royal Manchester Children's Hospital receiving ERT with DSR then HCT-multimodal therapy. In 3/5 an initial response to ERT was attenuated by ADA with associated clinical and laboratory features of deterioration. 1/5 developed anaphylaxis to ERT and the other patient died post HCT with ongoing HLH. All patients received allogeneic HCT. 4/5 patients are alive, and both disease phenotype and laboratory parameters are improved compared to when they were on ERT alone. The gastrointestinal symptoms are particularly improved after HCT, with reduced diarrhoea and vomiting. This allows gradual structured normalisation of diet with improved tolerance of dietary fat. Histologically there are reduced cholesterol clefts, fewer foamy macrophages and an improved villous structure. Disease biomarkers also show improvement with ERT, immunotherapy and HCT. Three patients have mixed chimerism after HCT, indicating a likely engraftment-defect in this condition. CONCLUSION: We describe combined ERT, DSR and HCT, multimodal treatment for Wolman disease. ERT and DSR stabilises the sick infant and reduces the formerly described prohibitively high, transplant-associated mortality in this condition. HCT abrogates the problems of ERT, namely attenuating ADA, the need for continuing venous access, and continuing high cost drug treatment. HCT also brings improved efficacy, particularly evident in improved gastrointestinal function and histology. Multimodal therapy should be considered a new paradigm of treatment for Wolman disease patients where there is an attenuated response to ERT, and for all patients where there is a well-matched transplant donor, in order to improve long term gut function, tolerance of a normal diet and quality of life.
BACKGROUND: Wolman disease is a rare, lysosomal storage disorder in which biallelic variants in the LIPA gene result in reduced or complete lack of lysosomal acid lipase. The accumulation of the substrates; cholesterol esters and triglycerides, significantly impacts cellular function. Untreated patients die within the first 12 months of life. Clinically, patients present severely malnourished, with diarrhoea and hepatosplenomegaly, many have an inflammatory phenotype, including with hemophagocytic lymphohistiocytosis (HLH). Hematopoietic stem cell transplant (HCT) had been historically the only treatment available but has a high procedure-related mortality because of disease progression and disease-associated morbidities. More recently, enzyme replacement therapy (ERT) with dietary substrate reduction (DSR) has significantly improved patient survival. However, ERT is life long, expensive and its utility is limited by anti-drug antibodies (ADA) and the need for central venous access. RESULTS: We describe five Wolman disease patients diagnosed in infancy that were treated at Royal Manchester Children's Hospital receiving ERT with DSR then HCT-multimodal therapy. In 3/5 an initial response to ERT was attenuated by ADA with associated clinical and laboratory features of deterioration. 1/5 developed anaphylaxis to ERT and the other patient died post HCT with ongoing HLH. All patients received allogeneic HCT. 4/5 patients are alive, and both disease phenotype and laboratory parameters are improved compared to when they were on ERT alone. The gastrointestinal symptoms are particularly improved after HCT, with reduced diarrhoea and vomiting. This allows gradual structured normalisation of diet with improved tolerance of dietary fat. Histologically there are reduced cholesterol clefts, fewer foamy macrophages and an improved villous structure. Disease biomarkers also show improvement with ERT, immunotherapy and HCT. Three patients have mixed chimerism after HCT, indicating a likely engraftment-defect in this condition. CONCLUSION: We describe combined ERT, DSR and HCT, multimodal treatment for Wolman disease. ERT and DSR stabilises the sick infant and reduces the formerly described prohibitively high, transplant-associated mortality in this condition. HCT abrogates the problems of ERT, namely attenuating ADA, the need for continuing venous access, and continuing high cost drug treatment. HCT also brings improved efficacy, particularly evident in improved gastrointestinal function and histology. Multimodal therapy should be considered a new paradigm of treatment for Wolman disease patients where there is an attenuated response to ERT, and for all patients where there is a well-matched transplant donor, in order to improve long term gut function, tolerance of a normal diet and quality of life.
Authors: Xuntian Jiang; Rohini Sidhu; Forbes D Porter; Nicole M Yanjanin; Anneliese O Speak; Danielle Taylor te Vruchte; Frances M Platt; Hideji Fujiwara; David E Scherrer; Jessie Zhang; Dennis J Dietzen; Jean E Schaffer; Daniel S Ory Journal: J Lipid Res Date: 2011-04-24 Impact factor: 5.922
Authors: S H Lum; W P Miller; S Jones; K Poulton; W Ogden; H Lee; A Logan; D Bonney; T C Lund; P J Orchard; R F Wynn Journal: Bone Marrow Transplant Date: 2017-02-20 Impact factor: 5.483
Authors: Simon A Jones; Vassili Valayannopoulos; Eugene Schneider; Stephen Eckert; Maryam Banikazemi; Martin Bialer; Stephen Cederbaum; Alicia Chan; Anil Dhawan; Maja Di Rocco; Jennifer Domm; Gregory M Enns; David Finegold; J Jay Gargus; Ornella Guardamagna; Christian Hendriksz; Iman G Mahmoud; Julian Raiman; Laila A Selim; Chester B Whitley; Osama Zaki; Anthony G Quinn Journal: Genet Med Date: 2015-08-27 Impact factor: 8.822