Canavan disease was first reported by Myrtelle Canavan in 1931 and was recognized as a distinct disease by Van Bogaert and Bertrand in 1949.1 The clinical symptoms of CD include poor head control, macrocephaly, marked developmental delay, optic atrophy, seizures, hypotonia and death in early childhood.2-4 Three clinical variants of CD are recognized: 1) the neonatal form in which the disease is more severe and is recognizable in the first few weeks of life, 2) the infantile form, the most common form in which the disease is apparent by 6 months of age and 3) the juvenile form in which the disease manifests only by age 4 or 5.4-6

The pathologies associated with Canavan disease include cortical and subcortical spongy degeneration, a lack of myelination, accumulation of water in the brain, and hypertrophy and hyperplasia of astrocytes.1,7-9 Ultrastructural studies have demonstrated intramyelinic vacuolation, intense astrocyte swelling and unusually elongated mitochondria within those astrocytes, and most of these changes are detectable in the recent mouse model.4,10-13

Earlier, diagnosis of CD was established by brain biopsy demonstrating spongy degeneration of the white matter with vacuoles within myelin sheaths, astrocyte swelling and deformed mitochondria. Biochemical analyses have shown that hypomyelination is a characteristic feature of Canavan disease.14 Patients with CD are found to excrete 10-100 fold higher amounts of NAA in their urine, and deficiency of the NAA degradative enzyme ASPA was demonstrated in their cultured skin fibroblasts.15 NAA levels are also elevated in the blood and cerebrospinal fluid of CD patients. Proton nuclear magnetic resonance

Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd, Bethesda MD, 20814 USA,

1 Laboratory of Clinical Science, NIMH, NIH, Bethesda MD 20892, USA.

spectroscopy (MRS) of CD patients has revealed increased NAA levels in the brain.16,17 However, increased urinary NAA remains the most reliable marker for CD, especially to distinguish it from other leukodystrophies.

Cloning of the human ASPA gene has enabled molecular genetic studies of CD.18 Two mutations were found to be prevalent among Ashkenazi Jewish patients with CD.9,19,20 A missense mutation in codon 285 causing substitution of glutamic acid to alanine accounts for 83.6 % of the mutations identified in 104 alleles from 52 unrelated Ashkenazi Jewish patients. A nonsense mutation on codon 231, which converts tyrosine to a stop codon, was found in 13.4% of the alleles from the Jewish patients. Among non-Jewish patients, the mutations are different and more diverse (see Zeng et al. this volume).6 The most common is in codon 305, a missense mutation substituting alanine for glutamic acid. This mutation was observed in 35.7% of the 70 alleles from 35 unrelated non-Jewish patients. Fifteen other mutations were detected in 24 other CD patients. More recently, additional mutations, some with the children dying immediately after birth, have been reported6. The diverse mutations limit the use of DNA analysis for prenatal diagnosis to couples who are both carriers and their mutations are known.

The precise pathogenesis of CD is not known, primarily due to our lack of understanding the role of NAA in the nervous system. NAA is synthesized in neuronal mitochondria by acetylation of aspartate by acetyl CoA. Aspartate W-acetyl transferase (Asp-NAT), the enzyme that catalyzes this reaction, is highly specific to aspartate, and is found only in the nervous system.21 In contrast, ASPA, which degrades NAA to aspartate and acetate with high specificity, has a ubiquitous distribution in the body22. In the brain, ASPA is distributed predominantly in oligodendrocytes, the myelin synthesizing cells of the CNS. However, immunohistochemical localization studies have shown that NAA is distributed primarily in neurons.23-25

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