Aspartoacylase Deficiency: The Enzyme Defect in Canavan Disease

Matalon, Reuben; Kaul, Rajinder; Casanova, J.; Michals, K.; Johnson, Anne B.; Rapin, Isabelle; Gashkoff, P.; Deanching, M.

doi:10.1007/978-94-009-1069-0_42

Cited by 30 publications

(21 citation statements)

References 6 publications

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“…Soon after, aspartoacylase (EC 3.5.1.15) deficiency was demonstrated in fibroblasts from a patient excreting large amounts of NAA in the urine [9] establishing the association of deficient aspartoacylase and CD [5,13]. This association has been confirmed in a series of 11 patients [14]. MRI has demonstrated profound leucodystrophy in CD [1,6,8,12,17] and proton magnetic resonance spectroscopy (1H-MRS) of the brain of Canavan patients has revealed a high ratio of NAA to choline (cho) containing compounds (NAA/ Cho) [1,8,12].…”

Section: Introductionmentioning

confidence: 75%

Magnetic resonance imaging in juvenile Canavan disease

et al. 1993

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We present a 2-year-old boy and a 6-year-old girl with mild Canavan disease (CD). Aspartoacylase activity in skin fibroblasts was deficient. Magnetic resonance imaging (MRI) of the brain did not show the prominent leucodystrophy previously reported in CD, but there was a hyperintense signal from the lentiform nuclei and the heads of the caudate nuclei on the T2-weighted MR images. This suggests a specific vulnerability of the corpus striatum in these patients. In the older patient, the white matter became affected at the age of 6 years. Proton magnetic resonance spectroscopy (1H-MRS) of white matter revealed a normal concentration of N-acetyl-L-aspartate (NAA) and a markedly decreased concentration of choline containing compounds (Cho) in the boy but a normal ratio of NAA to Cho in the girl. We conclude that deficient NAA catabolism affects myelin metabolism. This may present as changes in the striatum and/or as a low concentration of Cho before leucodystrophy appears on MRI.

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Section: Introductionmentioning

confidence: 75%

Magnetic resonance imaging in juvenile Canavan disease

et al. 1993

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“…It is also well known that the pediatric leukoencephalopathy, Canavan's disease, is associated with a large elevation of intracellular NAA, owing to deficiency of aspartoacylase, the enzyme that degrades NAA to acetate and aspartate. 16 Clearly, in these subjects, the high levels of NAA do not reflect an increase in neuronal density. There have also been several reports of reversible NAA deficits in a variety of pathologies, suggesting that the initial drop in NAA was not due to neuronal or axonal loss.…”

Section: N-acetyl Aspartate-a Neuronal Marker?mentioning

confidence: 99%

“…15 Although these forms of tau expression tend to covary with certain clinical phenotypes, they do not uniquely classify the disorders. 16 In addition, the presence or absence of insoluble tau may also help classify these disorders, yet, at this point, there does not appear to be unique correspondence between these characteristics of tau and the clinical syndromes. 17 Some investigators would contend that ultimately genetics will be able to characterize these disorders in an unambiguous fashion.…”

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confidence: 99%

N‐Acetyl Aspartate—A Neuronal Marker?

Barker

2001

Annals of Neurology

119

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“…ASPA deficiency results in the accumulation of NAA at high levels in the brain and its abnormal excretion in the urine of CD patients (Matalon et al, 1988). Since CD was linked to ASPA gene mutations (Matalon et al, 1989), a considerable effort has been made towards understanding the mechanism of disease pathology. Despite these efforts, there is not yet a clear link between deficient NAA hydrolysis and the myelin degeneration observed in CD (Matalon et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Nur7Is a Nonsense Mutation in the Mouse Aspartoacylase Gene That Causes Spongy Degeneration of the CNS

Τράκα¹,

Wollmann²,

Cerda³

et al. 2008

J. Neurosci.

108

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Aspartoacylase (ASPA) is an oligodendrocyte-restricted enzyme that catalyzes the hydrolysis of neuronally derived N-acetylaspartate (NAA) to acetate and aspartic acid. ASPA deficiency leads to the fatal childhood autosomal recessive leukodystrophy Canavan disease (CD). Here we demonstrate that the previously described ENU-induced nur7 mouse mutant is caused by a nonsense mutation, Q193X, in the Aspa gene (Aspa nur7 ). Homozygous Aspa nur7nur7 mice do not express detectable Aspa protein and display an early-onset spongy degeneration of CNS myelin with increased NAA levels similar to that observed in CD patients. In addition, CNS regions rich in neuronal cell bodies also display vacuolization. Interestingly, distinct myelin rich areas, such as the corpus callosum, optic nerve, and spinal cord white matter appear normal in Aspa nur7/nur7 mice. Reduced cerebroside synthesis has been demonstrated in CD patients and animal models. To determine the potential relevance of this observation in disease pathogenesis, we generated Aspa nur7/nur7 mice that were heterozygous for a null allele of the gene that encodes the enzyme UDP-galactose:ceramide galactosyltransferase (Cgt), which is responsible for catalyzing the synthesis of the abundant myelin galactolipids. Despite reduced amounts of cerebrosides, the Aspa nur7/nur7 ;Cgt ϩ/ Ϫ mice were not more severely affected than the Aspa nur7 mutants, suggesting that diminished cerebroside synthesis is not a major contributing factor in disease pathogenesis. Furthermore, we found that myelin degeneration leads to significant axonal loss in the cerebellum of older Aspa nur7 mutants. This finding suggests that axonal pathology caused by CNS myelin defects may underlie the neurological disabilities that CD patients develop at late stages of the disease.

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Aspartoacylase Deficiency: The Enzyme Defect in Canavan Disease

Cited by 30 publications

References 6 publications

Magnetic resonance imaging in juvenile Canavan disease

Magnetic resonance imaging in juvenile Canavan disease

N‐Acetyl Aspartate—A Neuronal Marker?

Nur7Is a Nonsense Mutation in the Mouse Aspartoacylase Gene That Causes Spongy Degeneration of the CNS

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