Aspa, which encodes aspartoacylase, is a crucial gene. Aspartoacylase hydrolyses N-acetylaspartate (NAA) to acetate and aspartate [1]. Mutations in Aspa are associated with Canavan disease, an autosomal recessive leukodystrophy, highlighting its significance in normal neurological function [1,2,3].

A study on 4 affected cats with a mutation (c.859G>C) in exon 6 of the Aspa gene reported a feline neurodegenerative disease similar to human Canavan disease. These cats showed gait disturbance, head tremors, dysstasia, and seizures, along with abnormal MRI findings, increased NAA excretion, and specific histopathological changes, suggesting that feline Aspa deficiency leads to spongy degeneration of the central nervous system [1].

In another study, introducing the wild-type Aspa gene into patient iPSCs, differentiating them into NPCs, and transplanting these NPCs into CD mice reconstituted Aspa activity, reduced elevated NAA levels, and rescued pathological phenotypes of Canavan disease, demonstrating a potential cell therapy approach [2].

A one-year-old female patient with Canavan disease was found to have a homozygous likely pathogenic variant NM_000049.4(ASPA):c.857C > A p.(Ala286Asp), with a loss of maternal heterozygosity in the 17p13.3-p13.2 region of the Aspa gene [3].

In conclusion, Aspa is essential for the normal metabolism of NAA and its deficiency is associated with Canavan disease. Studies on animal models and patient-derived cells with Aspa mutations have provided insights into the disease mechanism and potential therapeutic strategies for Canavan disease.

References:

1. Takaichi, Yuta, Chambers, James K, Shiroma-Kohyama, Moeko, Nakayama, Hiroyuki, Uchida, Kazuyuki. 2021. Feline Spongy Encephalopathy With a Mutation in the ASPA Gene. In Veterinary pathology, 58, 705-712. doi:10.1177/03009858211002176. https://pubmed.ncbi.nlm.nih.gov/33779415/

2. Chao, Jianfei, Feng, Lizhao, Ye, Peng, Matalon, Reuben, Shi, Yanhong. 2022. Therapeutic development for Canavan disease using patient iPSCs introduced with the wild-type ASPA gene. In iScience, 25, 104391. doi:10.1016/j.isci.2022.104391. https://pubmed.ncbi.nlm.nih.gov/35637731/

3. Yalcintepe, Sinem, Maras, Tuba, Kizilyar, Ilke, Ozen, Yasemin, Gurkan, Hakan. 2024. Homozygous Paternally Inherited ASPA Variant in a Patient with Canavan Disease. In Molecular syndromology, 15, 284-288. doi:10.1159/000536386. https://pubmed.ncbi.nlm.nih.gov/39119446/