Introduction

Pelizaeus-Merzbacher disease (PMD) is a rare X-linked leukodystrophy caused by mutations in the proteolipid protein 1 gene (PLP1). Neuropathological and MRI studies show diffuse and symmetrical hypomyelination in brain (see for review Nave and Boespflug-Tanguy,1 Hudson and colleagues2). PLP1 maps to the long arm of the chromosome at the Xq22 region and encodes the two major myelin proteins, PLP and its isoform DM20. All types of mutation are encountered, but duplications are the most frequent causative mutations.2 Clinical features of PMD include impairment of psychomotor development, nystagmus, ataxia, dystonia, and spasticity.2

Despite of the tremendous progress in understanding the molecular basis of PMD, knowledge about the neurochemical mechanisms underlying the dysmyelination process remains incomplete. Evidence for neuronal dysfunction, a significant and widespread decreased of brain N-acetylaspartate (NAA), has been reported in patients with known PLP gene mutations.3 Recently, Takanashi et al. (2002)4 reported increased concentrations of total NAA in the brain of five patients with PLP duplications using

Alessandro P. Burlina, Mario Ermani, Department of Neuroscience, Neurological Clinic, University Hospital, Via Giustiniani 5, I-35128, Padova, E-mail: [email protected], Vanni Ferrari, Department of Veterinary Medicine, University of Padova, ITALY; Alberto B. Burlina, Department of Pediatrics, Metabolic Unit, University Hospital, University of Padova, ITALY; Odile Boespflug-Tanguy, INSERM U 384, University of Clermont-Ferrand, Clermont-Ferrand, FRANCE; Enrico Bertini, Unit of Molecular Medicine, Department of Laboratory Medicine, Bambino Gesu Hospital, Rome, ITALY; Clinical ENBDD (European Network on Brain Dysmyelinating Disease): M. Baethmann, J. Gärtner, F. Hanefeld, A. Kohlschutter, J.-M. Lopez-Terradas, S. Peudenier, J.M. Prats-Vinas, D. Rodriguez, R. Surtees, G. Uziel, L.Vallee, and T. Voit.

proton magnetic resonance spectroscopy (MRS).4 Therefore, in vivo MRS data suggest an involvement of the NAA biochemical pathway in the pathophysiology of PMD.

N-acetylaspartylglutamate (NAAG) is one of the most abundant dipeptide in the brain and has a neuronal localization.5 However, in vivo proton MRS demonstrated that NAAG concentrations in human brain are higher in white matter (1.5-2.7 mM) than those found in gray matter (0.6-1.5 mM).6 Rat cell cultures have shown that NAAG can be synthesized from NAA and glutamate in astrocytes,7 and is catabolized to NAA and glutamate by two NAAG peptidases, also known as glutamate carboxypeptidase II and III (GCPII and GCPIII).8,9 Our study shows that N-acetylaspartylglutamate is increased in the CSF of PMD patients.

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