Two patients with Canavan disease and structural modeling of a novel mutation

Metab Brain Dis. 2017 Feb;32(1):171-177. doi: 10.1007/s11011-016-9896-9. Epub 2016 Aug 17.

Abstract

Canavan disease (CD) is a rare fatal childhood neurological autosomal recessive genetic disease caused by mutations in the ASPA gene, which lead to catalytic deficiency of the ASPA enzyme, which catalyzes the hydrolysis of N-acetyl-L-aspartate (NAA) into aspartate and acetate. CD occurs frequently among Ashkenazi Jewish population, however it has been reported in many other ethnic groups with significantly lower frequency. Here, we report on two Egyptian patients diagnosed with CD, the first patient harbors five missense mutations (c.427 A > G; p. I143V, c.502C > T; p. R168C, c.530 T > C; p. I177T, c.557 T > C; p. V186D c.548C > T; p. P183L) and a silent mutation (c.693 C > T; p. Y231Y). The second patient was found to be homozygous for two missense mutations (c.427 A > G; p. I143V and c.557 T > A; p. V186D). Furthermore, molecular modeling of the novel mutation p. P183L provides an instructive explanation of the mutational impact on the protein structure that can affect the function of the ASPA. Here, the clinical, radiological, and biochemical profile of the two patients are reviewed in details.

Keywords: Aspartoacylase; Canavan disease; In silico mutagenesis; MRI; MRS; Molecular modeling; N-acetyl-aspartate.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain / diagnostic imaging*
  • Canavan Disease / diagnostic imaging
  • Canavan Disease / genetics
  • Canavan Disease / metabolism*
  • Humans
  • Infant
  • Magnetic Resonance Imaging
  • Magnetic Resonance Spectroscopy
  • Male
  • Models, Molecular*
  • Mutation*
  • Mutation, Missense
  • Protein Conformation