Lithium citrate reduces excessive intra-cerebral N-acetyl aspartate in Canavan disease.

Robert Wood Johnson Medical School, Neurology, 3 Cooper Plaza, Suite 320, Camden, NJ 08103, USA.
European journal of paediatric neurology: EJPN: official journal of the European Paediatric Neurology Society (Impact Factor: 1.93). 07/2010; 14(4):354-9. DOI: 10.1016/j.ejpn.2009.11.006
Source: PubMed

ABSTRACT Our group has previously reported the first clinical application of lithium in a child affected by Canavan disease. In this study, we aimed to assess the effects of lithium on N-acetyl aspartate (NAA) as well as other end points in a larger cohort. Six patients with clinical, laboratory and genetic confirmation of Canavan disease were recruited and underwent treatment with lithium. The battery of safety and efficacy testing performed before and after sixty days of treatment included Gross Motor Function Testing (GMFM), Magnetic Resonance Imaging (MRI) Proton Magnetic Spectroscopy (H-MRS) as well as blood work. The medication was safe without any clinical or laboratory evidence for toxicity. Parental reports indicated improvement in alertness and social interactions. GMFM did not show statistically significant improvement in motor development. H-MRS documented an overall drop in NAA which was statistically significant in the basal ganglia. T1 measurements recorded on MRI studies suggested a mild improvement in myelination in the frontal white matter after treatment. Diffusion Tensor Imaging was available in two patients and suggested micro-structural improvement in the corpus callosum. The results suggest that lithium administration may be beneficial in patients with Canavan disease.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Canavan disease (CD) is a genetic neurodegenerative leukodystrophy that results in the spongy degeneration of white matter in the brain. CD is characterized by mutations in the gene encoding aspartoacylase (ASPA), the substrate enzyme that hydrolyzes N-acetylaspartate (NAA) to acetate and aspartate. The elevated NAA levels and subsequent deficiency in acetate associated with this disease cause progressive neurological symptoms, such as macrocephaly, visuo-cognitive dysfunction, and psychomotor delay. The prevalence of CD is higher among Ashkenazi Jews, and several types of mutations have been reported in the gene coding ASPA. Highly elevated NAA is more specific to CD than other leukodystrophies, and an examination of urinary NAA concentrations is useful for diagnosing CD. Many researchers are now examining the mechanisms responsible for white matter degeneration or dysmyelination in CD using mouse models, and several persuasive hypotheses have been suggested for the pathophysiology of CD. One is that NAA serves as a water pump; consequently, a disorder in NAA catabolism leads to astrocytic edema. Another hypothesis is that the hydrolyzation of NAA in oligodendrocytes is essential for myelin synthesis through the supply of acetate. Although there is currently no curative therapy for CD, dietary supplements are candidates that may retard the progression of the symptoms associated with CD. Furthermore, gene therapies using viral vectors have been investigated using rat models. These therapies were found to be tolerable with no severe long-term adverse effects, reduced the elevated NAA levels in the brain, and may be applied to humans in the future.
    Pediatrics International 06/2014; 56(4). DOI:10.1111/ped.12422 · 0.73 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Diseases of the central nervous system (CNS) have traditionally been the most difficult to treat by traditional pharmacological methods, due mostly to the blood-brain barrier and the difficulties associated with repeated drug administration targeting the CNS. Viral vector gene transfer represents a way to permanently provide a therapeutic protein within the nervous system after a single administration, whether this be a gene replacement strategy for an inherited disorder or a disease-modifying protein for a disease such as Parkinson's. Gene therapy approaches for CNS disorders has evolved considerably over the last two decades. Although a breakthrough treatment has remained elusive, current strategies are now considerably safer and potentially much more effective. This chapter will explore the past, current, and future status of CNS gene therapy, focusing on clinical trials utilizing adeno-associated virus and lentiviral vectors.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Canavan disease is a spongiform leukodystrophy caused by an autosomal recessive mutation in the aspartoacylase gene. Deficiency of oligodendroglial aspartoacylase activity and a subsequent increase of its substrate N-acetylaspartate are the etiologic factors for the disease. N-acetylaspartate acts as a molecular water pump. Therefore, an osmotic-hydrostatic mechanism is thought to be involved in the development of the Canavan disease phenotype. Astrocytes express water transporters and are critically involved in regulating and maintaining water homeostasis in the brain. We used the ASPA(Nur7/Nur7) mouse model of Canavan disease to investigate whether a disturbance of water homeostasis might be involved in the disease's progression. Animals showed an age-dependent impairment of motor performance and spongy degeneration in various brain regions, among the basal ganglia, brain stem, and cerebellar white matter. Astrocyte activation was prominent in regions which displayed less tissue damage, such as the corpus callosum, cortex, mesencephalon, and stratum Purkinje of cerebellar lobe IV. Immunohistochemistry revealed alterations in the cellular distribution of the water channel aquaporin 4 in astrocytes of ASPA(Nur7/Nur7) mice. In control animals, aquaporin 4 was located exclusively in the astrocytic end feet. In contrast, in ASPA(Nur7/Nur7) mice, aquaporin 4 was located throughout the cytoplasm. These results indicate that astroglial regulation of water homeostasis might be involved in the partial prevention of spongy degeneration. These observations highlight aquaporin 4 as a potential therapeutic target for Canavan disease.
    Journal of Molecular Neuroscience 11/2013; 53(1). DOI:10.1007/s12031-013-0184-4 · 2.76 Impact Factor