Saturday, December 4, 2010

Canavan Spongiform Leukodystrophy: Aspartoacylase Deficiency

Kvittingen et al. first described patients with cerebral atrophy and leukodystrophy with N-acetylaspartic aciduria. It was the merit of Matalon et al and divry et al. to link this disorder with Canavan disease.

Clinical Presentation Canavan Spongiform Leukodystrophy: Aspartoacylase Deficiency

The diagnosis of Canavan disease can be suggested by clinical features including leukodystrophy, megaloencephaly, mental retardation, and optic atrophy. Death usually occurs in the first decade of life. Computed Tomography (CT) scan or magnetic resonance imaging (MRI) show white matter attenuation. Brain histopathology shows spongy degeneration of the myelin, astrocytic swelling, and elongated mitochondria; neurons are normal. Three clinical variants of the disease have been described:
• A congenital form in which the disease is apparent from birth
• An infantile form, which is the most common and which becomes manifest after the first 6 months of life (this form is frequently seen among Jewish patients)
• A juvenile form in which symptoms appear after the first 5 years of life.

Metabolic Derangement Canavan Spongiform Leukodystrophy: Aspartoacylase Deficiency

The key feature is accumulation of N-acetylaspartic acid in the body fluids, levels in the CSF being much higher than in the serum. The enzymatic defect can be confirmed by assay of aspartoacylase in fibroblasts. Aspartoacylase is also deficient in Brain, liver, and kidney.
N-acetylaspartic acid is abundant in Brain, where its concentration is second only to glutamic acid in the free amino acid pool and is higher than that of GABA Brain is the only organ where biosynthesis of N-acetylaspartic acid has been demonstrated. Its normal function is not well understood. It has been reffered to as an essential component in a series of reactions required for the conversion of lignoceric acid to cerebronic acid, a component of myelin, and the formation of glutamic acid and has been assigned a possible role in neurotransmission and in the production of N-acetylaspartylglutamate. It may also serve as a chemical compartment so that aspartate is released only by the action of aspartoacylase and the released aspartate may be channeled to form arginine.

Diagnostic Tests Canavan Spongiform Leukodystrophy: Aspartoacylase Deficiency



The diagnosis is based on gas chromatography mass spectrometry (GCMS) of urine or other body fluids showing increased N-acetylaspartic acid levels and is confirmed by aspartoacylase assay on cultured fibroblasts and/or by restriction fragment length polymorphism (RFLP) or mutation analysis of DNA. For prenatal diagnosis the measurement of aspartoacylase in fresh chorionic villi samples or the quantitation of N-acetylaspartic acid in amniotic fluid supernatant are the methods of choice. Obviously, molecular diagnosis using RFLP or mutation analysis within given families will provide prenatal diagnostic facilities and carrier detection in at risk populations in the near future.

Treatment and Prognosis Canavan Spongiform Leukodystrophy: Aspartoacylase Deficiency



It has been proposed that N-acetylaspartic acid serves as a transporter of acetyl groups from mitochondria to the cytosol for lipogenesis. Therefore, in an attempt to supply alternative substrate for lipogenesis in the brain, a ketogenic diet was given to one patient for 5 months. No improvement was seen. No other treatment is available. Progressive deterioration leads to a decorticate condition and death within a few years.

Genetics Canavan Spongiform Leukodystrophy:Aspartoacylase Deficiency

Genetic transmission is autosomal recessive. The human aspartoacylase gene is localized on chromosome 17 p13-ter. A full-length human cDNA for aspartoacylase has been isolated and a predominant point mutation 856 A>C was identified in Jewish patients.

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