14800-DvRappard

20 Chapter 1 in these patients is too fast. Presymptomatic juvenile and adult patients are good candidates for HCT. In ambiguous cases, patients with mild symptoms at neurological examination or mild cognitive decline, the decision whether or not to transplant is often difficult. We assessed the efficacy of HCT in our patient cohort in order to formulate decision guidelines for the treatment of HCT, which is described in chapter 5. Hematopoietic Stem Cell-Gene Therapy It is evident that effective treatment for all clinical subtypes of MLD is needed. Recently, HCT and gene therapy have been combined into lentiviral vector-mediated hematopoietic stem cell gene therapy (HSC-GT). 40 Bone marrow-derived CD34+ HSCs are transduced with a clinical grade lentiviral vector, which introduces a functional ARSA gene into the HSCs. This results in supraphysiological expression of the ARSA gene throughout the HSCs. After myeloablative conditioning, the HSCs are infused and thought to mediate cross correction of CNS and PNS resident cells. 40 The corrected cells secrete ARSA protein which is endocytosed by neighboring cells for therapeutic correction. 3 It is therefore not necessary to transfer the normal ARSA cDNA to all of the cells in the CNS. 3 There were concerns for an oncogenic potential of lentiviral vectors and possible negative effects of supraphysiological expression of ARSA , but animal and clinical studies so far report no increased incidence of neoplasms. 3 Longer follow up studies are needed to gain insight on long-term effects of supraphysiological levels of ASA enzyme on the other sulfatases and sulfatide levels. SCOPE OF THIS THESIS This thesis provides a broad overview of MLD, by studying both its natural course and its course after treatment. In chapter 2 , the disease and its current treatment options are reviewed. Chapter 3 presents late juvenile and adult cases, initially diagnosed with a psychiatric disorder. In chapter 4 , we describe the effect of intrathecal baclofen treatment for spasticity in MLD. The efficacy of HCT compared to the natural course of the disease is analyzed in chapter 5 . In chapter 6 , the inflammatory response and oligodendrocyte numbers in brain tissue between transplanted and non-transplanted patients is compared. In chapter 7 we focus on the possible value of MRS parameters at diagnosis in predicting eventual clinical outcome. In chapter 8 , we use DTI parameters to gain more insight into brain microstructure abnormalities in MLD. The association between gallbladder polyps and carcinoma and MLD is presented in chapter 9 . A summary of these findings, their possible implications and future perspectives are discussed in chapter 10.