Molecular Genetics and Metabolism 86 (2005) 150–159 www.elsevier.com/locate/ymgme 1096-7192/$ - see front matter  2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2005.06.023 Biochemical and pathological evaluation of long-lived mice with globoid cell leukodystrophy after bone marrow transplantation Paola Luzi a , Mohammad A. RaW a , Mariam Zaka a , Han Zhi Rao a , Mark Curtis b , Marie T. Vanier c , David A. Wenger a,¤ a Department of Neurology, JeVerson Medical College, 1020 Locust Street, Room 394, Philadelphia, PA, USA b Department of Pathology, JeVerson Medical College, Philadelphia, PA, USA c INSERM U 189, Lyon-Sud Medical School and Foundation Gillet-Merieux, Lyon-Sud Hospital, Pierre Benite, France Received 25 May 2005; received in revised form 16 June 2005; accepted 21 June 2005 Abstract Globoid cell leukodystrophy (GLD) is a disorder of the central and peripheral nervous systems caused by the deWciency of the lysosomal enzyme galactocerebrosidase (GALC). The pathological changes associated with the disease include accumulation of glo- boid cells and loss of myelin due to production of psychosine, a toxic metabolite responsible for the apoptosis of oligodendrocytes. While most patients present with symptoms before 6 months of age, older patients are also diagnosed. Treatment at this time is lim- ited to hematopoietic stem cell transplantation in asymptomatic and late-onset patients. GLD occurs naturally in several animal spe- cies including mice, dogs, and monkeys. In addition, a transgenic (trs) mouse model of GLD was generated in our laboratory. Trs mice develop symptoms slower than twitcher mice and survive an average of 10 days longer. In this study, we evaluated the therapeu- tic eVects of bone marrow transplantation (BMT) using trs mice. BMT prolonged the life of some treated animals to over one year. After BMT, GALC activity reached 15–20% of normal in brain and near normal values in liver and sciatic nerve. In long-lived trans- planted animals psychosine levels were normalized in the brain and greatly reduced in the sciatic nerve. Staining of brain sections showed more abundant and better quality myelin and near absence of globoid cells. Electron micrographs of sciatic nerves showed reduced endoneurial edema, increased axon density, and abundant onion bulb structures associated with remyelinating axons. There- fore, BMT can ameliorate many of the biochemical and pathological features of GLD. However, additional therapies may be required to completely correct the features of this disease.  2005 Elsevier Inc. All rights reserved. Keywords: Krabbe disease; Globoid cell leukodystrophy; Bone marrow transplantation; Myelin; Galactocerebrosidase; Lysosomal storage disease; Twitcher mouse; Psychosine Introduction Globoid cell leukodystrophy (GLD) is an autosomal recessive disease caused by the deWciency of galacto- cerebrosidase (GALC) activity, a lysosomal enzyme involved in the metabolism of important galactolipids found in myelin including galactosylceramide and psy- chosine [1,2]. Psychosine is a toxic metabolite that accu- mulates in GLD and results in the apoptotic death of oligodendrocytes and demyelination [3]. The disease is characterized by progressive loss of central nervous sys- tem (CNS) and peripheral nervous system (PNS) myelin with formation of characteristic macrophages (globoid cells) containing indigested lipids and proteins [4,5]. The most patients have the infantile form which presents by * Corresponding author. Fax: +1 215 955 9554. E-mail address: david.wenger@jeVerson.edu (D.A. Wenger).