PMID- 16807907
OWN - NLM
STAT- MEDLINE
DCOM- 20061114
LR  - 20220311
IS  - 1080-4013 (Print)
IS  - 1080-4013 (Linking)
VI  - 12
IP  - 2
DP  - 2006
TI  - Canavan disease: a white matter disorder.
PG  - 157-65
AB  - Breakdown of oligodendrocyte-neuron interactions in white matter (WM), such as 
      the loss of myelin, results in axonal dysfunction and hence a disruption of 
      information processing between brain regions. The major feature of 
      leukodystrophies is the lack of proper myelin formation during early development 
      or the onset of myelin loss late in life. These early childhood WM diseases are 
      described as hypomyelination or dysmyelination arising from a primary block in 
      normal myelin synthesis because of a genetic mutation expressed in 
      oligodendrocytes, or failure in myelination secondary to neuronal or astroglial 
      dysfunctions (van der Knaap 2001 Dev. Med. Child Neurol. 43:705-712). Here, we 
      describe the pathophysiological parameters of Canavan disease (CD), caused by 
      genetic mutations of the aspartoacylase (ASPA) gene, a metabolic enzyme 
      restricted in the central nervous system (CNS) to oligodendrocytes. CD presents 
      pathophysiological dysfunctions similar to diseases caused by myelin gene 
      mutations, such as Pelizaeus-Merzbacher disease (PMD) and several animal models, 
      such as myelin deficient rat (md), jimpy (jp), shiverer (sh), and quaking (qk 
      viable) mutant mice. These single gene mutations have pleiotropic effects, 
      whereby the alteration of one myelin gene expression disrupts functional 
      expression of other oligodendrocyte genes with an outcome of 
      hypomyelination/dysmyelination. Among all of the known leukodystrophies, CD is 
      the first disorder, which was approved and tested for the adeno-associated virus 
      vector (AAV)-ASPA gene therapy (Leone et al. 2000 Ann. Neurol. 48:27-38; Janson 
      et al. 2001 Trends Neurosci. 24:706-712) without much success following the first 
      two attempts. ASPA gene delivery attempts in animal models have shown a lowering 
      of N-acetyl L-aspartate and a change in motor functions, while sponginess of the 
      WM, a characteristic of CD remained unchanged (Matalon et al. 2003 Mol. Ther. 7 
      (5, Part 1):580-587; McPhee et al. 2005 Brain Res. Mol. Brain Res. 135:112-121) 
      even with better viral serotype and delivery of the gene during early phase of 
      development (Klugmann et al. 2005 Mol. Ther. 11:745-753). While different 
      approaches are being sought for the success of gene therapy, there are pivotal 
      developmental questions to address regarding the specific regions of the CNS and 
      cell lineages that become the target for the onset and progression of CD symptoms 
      from early to late stages of development.
FAU - Kumar, Shalini
AU  - Kumar S
AD  - Department of Neurobiology, Mental Retardation Research Center, Semel Institute 
      for Neuroscience and Human Behavior, University of California, Los Angeles, 
      California 90095-7332, USA.
FAU - Mattan, Natalia S
AU  - Mattan NS
FAU - de Vellis, Jean
AU  - de Vellis J
LA  - eng
PT  - Journal Article
PT  - Review
PL  - United States
TA  - Ment Retard Dev Disabil Res Rev
JT  - Mental retardation and developmental disabilities research reviews
JID - 9517974
RN  - 0 (Biomarkers)
RN  - 30KYC7MIAI (Aspartic Acid)
RN  - 3KX376GY7L (Glutamic Acid)
SB  - IM
MH  - Aspartic Acid/metabolism
MH  - Biomarkers
MH  - Brain/*anatomy & histology/metabolism/*pathology
MH  - Canavan Disease/metabolism/*pathology
MH  - Diagnosis, Differential
MH  - Genetic Counseling
MH  - Glutamic Acid/metabolism
MH  - Homeostasis/physiology
MH  - Humans
MH  - Infant
MH  - Magnetic Resonance Imaging
MH  - Myelin Sheath/metabolism/pathology
MH  - Neuroglia/metabolism/pathology
MH  - Neurons/pathology
MH  - Oligodendroglia/pathology
RF  - 176
EDAT- 2006/06/30 09:00
MHDA- 2006/11/15 09:00
CRDT- 2006/06/30 09:00
PHST- 2006/06/30 09:00 [pubmed]
PHST- 2006/11/15 09:00 [medline]
PHST- 2006/06/30 09:00 [entrez]
AID - 10.1002/mrdd.20108 [doi]
PST - ppublish
SO  - Ment Retard Dev Disabil Res Rev. 2006;12(2):157-65. doi: 10.1002/mrdd.20108.