Canavan disease

A monogenic trait with complex genomic interaction

Sankar Surendran, Kimberlee Michals-Matalon, Michael J. Quast, Stephen K. Tyring, Jingna Wei, Ed L. Ezell, Reuben Matalon

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Canavan disease (CD) is an inherited leukodystrophy, caused by aspartoacylase (ASPA) deficiency, and accumulation of N-acetylaspartic acid (NAA) in the brain. The gene for ASPA has been cloned and more than 40 mutations have been described, with two founder mutations among Ashkenazi Jewish patients. Screening of Ashkenazi Jews for these two common mutations revealed a high carrier frequency, approximately 1/40, so that programs for carrier testing are currently in practice. The enzyme deficiency in CD interferes with the normal hydrolysis of NAA, which results in disruption of myelin and spongy degeneration of the white matter of the brain. The clinical features of the disease are macrocephaly, head lag, progressive severe mental retardation, and hypotonia in early life, which later changes to spasticity. A knockout mouse for CD has been generated, and used to study the pathophysiological basis for CD. Findings from the knockout mouse indicate that this monogenic trait leads to a series of genomic interaction in the brain. Changes include low levels of glutamate and GABA. Microarray expression analysis showed low level of expression of GABA-A receptor (GABRA6) and glutamate transporter (EAAT4). The gene Spi2, a gene involved in apoptosis and cell death, showed high level of expression. Such complexity of gene interaction results in the phenotype, the proteome, with spongy degeneration of the brain and neurological impairment of the mouse, similar to the human counterpart. Aspartoacylase gene transfer trial in the mouse brain using adenoassociated virus (AAV) as a vector are encouraging showing improved myelination and decrease in spongy degeneration in the area of the injection and also beyond that site.

Original languageEnglish (US)
Pages (from-to)74-80
Number of pages7
JournalMolecular Genetics and Metabolism
Volume80
Issue number1-2
DOIs
StatePublished - Sep 2003

Fingerprint

Canavan Disease
Brain
Genes
Knockout Mice
Mutation
Gene transfer
Amino Acid Transport System X-AG
Megalencephaly
Jews
Cell death
GABA-A Receptors
Proteome
Microarrays
Muscle Hypotonia
Viruses
gamma-Aminobutyric Acid
Microarray Analysis
Myelin Sheath
Glutamic Acid
Hydrolysis

Keywords

  • AAV
  • Canavan disease
  • EAAT4
  • GABA
  • Glutamate
  • Spi2

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Endocrinology, Diabetes and Metabolism

Cite this

Surendran, S., Michals-Matalon, K., Quast, M. J., Tyring, S. K., Wei, J., Ezell, E. L., & Matalon, R. (2003). Canavan disease: A monogenic trait with complex genomic interaction. Molecular Genetics and Metabolism, 80(1-2), 74-80. https://doi.org/10.1016/j.ymgme.2003.08.015

Canavan disease : A monogenic trait with complex genomic interaction. / Surendran, Sankar; Michals-Matalon, Kimberlee; Quast, Michael J.; Tyring, Stephen K.; Wei, Jingna; Ezell, Ed L.; Matalon, Reuben.

In: Molecular Genetics and Metabolism, Vol. 80, No. 1-2, 09.2003, p. 74-80.

Research output: Contribution to journalArticle

Surendran, S, Michals-Matalon, K, Quast, MJ, Tyring, SK, Wei, J, Ezell, EL & Matalon, R 2003, 'Canavan disease: A monogenic trait with complex genomic interaction', Molecular Genetics and Metabolism, vol. 80, no. 1-2, pp. 74-80. https://doi.org/10.1016/j.ymgme.2003.08.015
Surendran S, Michals-Matalon K, Quast MJ, Tyring SK, Wei J, Ezell EL et al. Canavan disease: A monogenic trait with complex genomic interaction. Molecular Genetics and Metabolism. 2003 Sep;80(1-2):74-80. https://doi.org/10.1016/j.ymgme.2003.08.015
Surendran, Sankar ; Michals-Matalon, Kimberlee ; Quast, Michael J. ; Tyring, Stephen K. ; Wei, Jingna ; Ezell, Ed L. ; Matalon, Reuben. / Canavan disease : A monogenic trait with complex genomic interaction. In: Molecular Genetics and Metabolism. 2003 ; Vol. 80, No. 1-2. pp. 74-80.
@article{e55b5db73e744dbb89174890854944eb,
title = "Canavan disease: A monogenic trait with complex genomic interaction",
abstract = "Canavan disease (CD) is an inherited leukodystrophy, caused by aspartoacylase (ASPA) deficiency, and accumulation of N-acetylaspartic acid (NAA) in the brain. The gene for ASPA has been cloned and more than 40 mutations have been described, with two founder mutations among Ashkenazi Jewish patients. Screening of Ashkenazi Jews for these two common mutations revealed a high carrier frequency, approximately 1/40, so that programs for carrier testing are currently in practice. The enzyme deficiency in CD interferes with the normal hydrolysis of NAA, which results in disruption of myelin and spongy degeneration of the white matter of the brain. The clinical features of the disease are macrocephaly, head lag, progressive severe mental retardation, and hypotonia in early life, which later changes to spasticity. A knockout mouse for CD has been generated, and used to study the pathophysiological basis for CD. Findings from the knockout mouse indicate that this monogenic trait leads to a series of genomic interaction in the brain. Changes include low levels of glutamate and GABA. Microarray expression analysis showed low level of expression of GABA-A receptor (GABRA6) and glutamate transporter (EAAT4). The gene Spi2, a gene involved in apoptosis and cell death, showed high level of expression. Such complexity of gene interaction results in the phenotype, the proteome, with spongy degeneration of the brain and neurological impairment of the mouse, similar to the human counterpart. Aspartoacylase gene transfer trial in the mouse brain using adenoassociated virus (AAV) as a vector are encouraging showing improved myelination and decrease in spongy degeneration in the area of the injection and also beyond that site.",
keywords = "AAV, Canavan disease, EAAT4, GABA, Glutamate, Spi2",
author = "Sankar Surendran and Kimberlee Michals-Matalon and Quast, {Michael J.} and Tyring, {Stephen K.} and Jingna Wei and Ezell, {Ed L.} and Reuben Matalon",
year = "2003",
month = "9",
doi = "10.1016/j.ymgme.2003.08.015",
language = "English (US)",
volume = "80",
pages = "74--80",
journal = "Molecular Genetics and Metabolism",
issn = "1096-7192",
publisher = "Academic Press Inc.",
number = "1-2",

}

TY - JOUR

T1 - Canavan disease

T2 - A monogenic trait with complex genomic interaction

AU - Surendran, Sankar

AU - Michals-Matalon, Kimberlee

AU - Quast, Michael J.

AU - Tyring, Stephen K.

AU - Wei, Jingna

AU - Ezell, Ed L.

AU - Matalon, Reuben

PY - 2003/9

Y1 - 2003/9

N2 - Canavan disease (CD) is an inherited leukodystrophy, caused by aspartoacylase (ASPA) deficiency, and accumulation of N-acetylaspartic acid (NAA) in the brain. The gene for ASPA has been cloned and more than 40 mutations have been described, with two founder mutations among Ashkenazi Jewish patients. Screening of Ashkenazi Jews for these two common mutations revealed a high carrier frequency, approximately 1/40, so that programs for carrier testing are currently in practice. The enzyme deficiency in CD interferes with the normal hydrolysis of NAA, which results in disruption of myelin and spongy degeneration of the white matter of the brain. The clinical features of the disease are macrocephaly, head lag, progressive severe mental retardation, and hypotonia in early life, which later changes to spasticity. A knockout mouse for CD has been generated, and used to study the pathophysiological basis for CD. Findings from the knockout mouse indicate that this monogenic trait leads to a series of genomic interaction in the brain. Changes include low levels of glutamate and GABA. Microarray expression analysis showed low level of expression of GABA-A receptor (GABRA6) and glutamate transporter (EAAT4). The gene Spi2, a gene involved in apoptosis and cell death, showed high level of expression. Such complexity of gene interaction results in the phenotype, the proteome, with spongy degeneration of the brain and neurological impairment of the mouse, similar to the human counterpart. Aspartoacylase gene transfer trial in the mouse brain using adenoassociated virus (AAV) as a vector are encouraging showing improved myelination and decrease in spongy degeneration in the area of the injection and also beyond that site.

AB - Canavan disease (CD) is an inherited leukodystrophy, caused by aspartoacylase (ASPA) deficiency, and accumulation of N-acetylaspartic acid (NAA) in the brain. The gene for ASPA has been cloned and more than 40 mutations have been described, with two founder mutations among Ashkenazi Jewish patients. Screening of Ashkenazi Jews for these two common mutations revealed a high carrier frequency, approximately 1/40, so that programs for carrier testing are currently in practice. The enzyme deficiency in CD interferes with the normal hydrolysis of NAA, which results in disruption of myelin and spongy degeneration of the white matter of the brain. The clinical features of the disease are macrocephaly, head lag, progressive severe mental retardation, and hypotonia in early life, which later changes to spasticity. A knockout mouse for CD has been generated, and used to study the pathophysiological basis for CD. Findings from the knockout mouse indicate that this monogenic trait leads to a series of genomic interaction in the brain. Changes include low levels of glutamate and GABA. Microarray expression analysis showed low level of expression of GABA-A receptor (GABRA6) and glutamate transporter (EAAT4). The gene Spi2, a gene involved in apoptosis and cell death, showed high level of expression. Such complexity of gene interaction results in the phenotype, the proteome, with spongy degeneration of the brain and neurological impairment of the mouse, similar to the human counterpart. Aspartoacylase gene transfer trial in the mouse brain using adenoassociated virus (AAV) as a vector are encouraging showing improved myelination and decrease in spongy degeneration in the area of the injection and also beyond that site.

KW - AAV

KW - Canavan disease

KW - EAAT4

KW - GABA

KW - Glutamate

KW - Spi2

UR - http://www.scopus.com/inward/record.url?scp=0142026108&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0142026108&partnerID=8YFLogxK

U2 - 10.1016/j.ymgme.2003.08.015

DO - 10.1016/j.ymgme.2003.08.015

M3 - Article

VL - 80

SP - 74

EP - 80

JO - Molecular Genetics and Metabolism

JF - Molecular Genetics and Metabolism

SN - 1096-7192

IS - 1-2

ER -