ASPA gene aspartoacylase Normal Function The ASPA gene provides instructions for making an enzyme called aspartoacylase. In the brain, this enzyme breaks down a compound called N-acetyl-L-aspartic acid (NAA) into aspartic acid (an amino acid that is a building block of many proteins) and another molecule called acetic acid. The production and breakdown of NAA appears to be critical for maintaining the brain's white matter, which consists of nerve fibers surrounded by a myelin sheath. The myelin sheath is the covering that protects nerve fibers and promotes the efficient transmission of nerve impulses. The precise function of NAA is unclear. Researchers had suspected that it played a role in the production of the myelin sheath, but recent studies suggest that NAA does not have this function. The enzyme may instead be involved in the transport of water molecules out of nerve cells (neurons). Health Conditions Related to Genetic Changes Canavan disease More than 80 mutations in the ASPA gene are known to cause Canavan disease, which is a rare inherited disorder that affects brain development. Researchers have described two major forms of this condition: neonatal/infantile Canavan disease, which is the most common and most severe form, and mild/juvenile Canavan disease. The ASPA gene mutations that cause the neonatal/infantile form severely impair the activity of aspartoacylase, preventing the breakdown of NAA and allowing this substance to build up to high levels in the brain. The mutations that cause the mild/juvenile form have milder effects on the enzyme's activity, leading to less accumulation of NAA. An excess of NAA in the brain is associated with the signs and symptoms of Canavan disease. Studies suggest that if NAA is not broken down properly, the resulting chemical imbalance interferes with the formation of the myelin sheath as the nervous system develops. A buildup of NAA also leads to the progressive destruction of existing myelin sheaths. Nerves without this protective covering malfunction, which disrupts normal brain development. While Canavan disease occurs in people of all ethnic backgrounds, it is most common Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 1 in people of Ashkenazi (eastern and central European) Jewish heritage. Two specific ASPA gene mutations cause almost all cases of the disease in people of Ashkenazi Jewish descent. One of these mutations replaces the amino acid glutamic acid with the amino acid alanine at position 285 of the enzyme (written as Glu285Ala or E285A). This genetic change greatly reduces the amount of functional aspartoacylase. The other mutation, which is written as Tyr231Ter or Y231X, prematurely stops protein production and leads to an abnormally small, nonfunctional version of the enzyme. A different ASPA gene mutation is most common in people who are not of Ashkenazi Jewish descent. This mutation substitutes the amino acid glutamic acid for the amino acid alanine at position 305 of aspartoacylase (written as Ala305Glu or A305E). This mutation also leads to the production of a nonfunctional version of the enzyme. Other Names for This Gene • ACY2 • ACY2_HUMAN • aminoacylase 2 • aminoacylase II • ASP • N-acyl-L-aspartate amidohydrolase Additional Information & Resources Tests Listed in the Genetic Testing Registry • Tests of ASPA (https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=443[geneid]) Scientific Articles on PubMed • PubMed (https://pubmed.ncbi.nlm.nih.gov/?term=%28aspartoacylase%5BTIAB%5D %29+AND+english%5Bla%5D+AND+human%5Bmh%5D+AND+%22last+3600+day s%22%5Bdp%5D) Catalog of Genes and Diseases from OMIM • ASPARTOACYLASE (https://omim.org/entry/608034) Research Resources • ClinVar (https://www.ncbi.nlm.nih.gov/clinvar?term=ASPA[gene]) • NCBI Gene (https://www.ncbi.nlm.nih.gov/gene/443) Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 2 R eferences • Baslow MH. Brain N-acetylaspartate as a molecular water pump and its role inthe etiology of Canavan disease: a mechanistic explanation. J Mol Neurosci.2003;21(3): 185-90. Review. Citation on PubMed (https://pubmed.ncbi.nlm.nih.gov/14645985) • Bitto E, Bingman CA, Wesenberg GE, McCoy JG, Phillips GN Jr. Structure ofaspartoacylase, the brain enzyme impaired in Canavan disease. Proc Natl Acad Sci U S A. 2007 Jan 9;104(2):456-61. Epub 2006 Dec 28. Citation on PubMed (https ://pubmed.ncbi.nlm.nih.gov/17194761) or Free article on PubMed Central (https://ww w.ncbi.nlm.nih.gov/pmc/articles/PMC1766406/) • Guo F, Bannerman P, Mills Ko E, Miers L, Xu J, Burns T, Li S, Freeman E, McDonough JA, Pleasure D. Ablating N-acetylaspartate prevents leukodystrophy in aCanavan disease model. Ann Neurol. 2015 May;77(5):884-8. doi: 10.1002/ana. 24392. Epub 2015 Mar 27. Citation on PubMed (https://pubmed.ncbi.nlm.nih.gov/25 712859) • Hershfield JR, Pattabiraman N, Madhavarao CN, Namboodiri MA. Mutationalanalysis of aspartoacylase: implications for Canavan disease. Brain Res. 2007 May7;1148:1-14. Epub 2007 Mar 3. Citation on PubMed (https://pubmed.ncbi.n lm.nih.gov/17391648) or Free article on PubMed Central (https://www.ncbi.nlm.nih.g ov/pmc/articles/PMC1933483/) • Madhavarao CN, Arun P, Moffett JR, Szucs S, Surendran S, Matalon R, Garbern J, Hristova D, Johnson A, Jiang W, Namboodiri MA. Defective N- acetylaspartatecatabolism reduces brain acetate levels and myelin lipid synthesis in Canavan'sdisease. Proc Natl Acad Sci U S A. 2005 Apr 5;102(14):5221-6. Epub 2005 Mar 22. Citation on PubMed (https://pubmed.ncbi.nlm.nih.gov/15784740) or Free article on PubMed Central (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5 55036/) • Namboodiri AM, Peethambaran A, Mathew R, Sambhu PA, Hershfield J, Moffett JR, Madhavarao CN. Canavan disease and the role of N-acetylaspartate in myelinsynthesis. Mol Cell Endocrinol. 2006 Jun 27;252(1-2):216-23. Epub 2006 May 2.Review. Citation on PubMed (https://pubmed.ncbi.nlm.nih.gov/16647192) • Sommer A, Sass JO. Expression of aspartoacylase (ASPA) and Canavan disease. Gene. 2012 Sep 1;505(2):206-10. doi: 10.1016/j.gene.2012.06.036. Epub 2012 Jun28. Citation on PubMed (https://pubmed.ncbi.nlm.nih.gov/22750302) • Tacke U, Olbrich H, Sass JO, Fekete A, Horvath J, Ziyeh S, Kleijer WJ, RollandMO, Fisher S, Payne S, Vargiami E, Zafeiriou DI, Omran H. Possiblegenotype-phenotype correlations in children with mild clinical course of Canavan disease. Neuropediatrics. 2005 Aug;36(4):252-5. Citation on PubMed (https://pubmed.ncbi.nlm.nih.gov/16138 249) • Zano S, Wijayasinghe YS, Malik R, Smith J, Viola RE. Relationship betweenenzyme properties and disease progression in Canavan disease. J Inherit MetabDis. 2013 Jan;36(1):1-6. doi: 10.1007/s10545-012-9520-z. Epub 2012 Aug 1. Erratumin: J Inherit Metab Dis. 2013 Jan;36(1):159-60. Citation on PubMed (https://p ubmed.ncbi.nlm.nih.gov/22850825) • Zeng BJ, Pastores GM, Leone P, Raghavan S, Wang ZH, Ribeiro LA, Torres P, Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 3 Ong E, Kolodny EH. Mutation analysis of the aspartoacylase gene in non-Jewishpatients with Canavan disease. Adv Exp Med Biol. 2006;576:165-73; discussion361-3. Citation on PubMed (https://pubmed.ncbi.nlm.nih.gov/16802711) • Zeng BJ, Wang ZH, Torres PA, Pastores GM, Leone P, Raghavan SS, Kolodny EH. Rapid detection of three large novel deletions of the aspartoacylase gene innon- Jewish patients with Canavan disease. Mol Genet Metab. 2006Sep-Oct;89(1-2):156- 63. Epub 2006 Jul 18. Citation on PubMed (https://pubmed.ncbi.nlm.nih.gov/168546 07) Genomic Location The ASPA gene is found on chromosome 17 (https://medlineplus.gov/genetics/chromos ome/17/). Page last updated on 18 August 2020 Page last reviewed: 1 April 2015 Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 4.