title: Two patients with Canavan disease and structural modeling of a novel mutation.
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.
authors.affiliation: Medical Genetics Unit, Pediatric Department, Faculty of Medicine, Ain Shams University Hospital, Cairo, 11665, Egypt. ozaki@med.asu.edu.eg.
authors.forename: Osama K
authors.initials: OK
authors.lastname: Zaki
authors.affiliation: Division of Experimental Genetics, Sidra Medical and Research Centre, Qatar Foundation, Doha, Qatar.|Heart Science Centre, National Heart and Lung Institute, Imperial College London, Harefield, UK.
authors.forename: Navaneethakrishnan
authors.initials: N
authors.lastname: Krishnamoorthy
authors.affiliation: Medical Genetics Unit, Pediatric Department, Faculty of Medicine, Ain Shams University Hospital, Cairo, 11665, Egypt.
authors.forename: Heba S
authors.initials: HS
authors.lastname: El Abd
authors.affiliation: Department of Biomedical Sciences, College of Health Sciences, Qatar University, Doha, Qatar.
authors.forename: Soumaya A
authors.initials: SA
authors.lastname: Harche
authors.affiliation: Department of Biomedical Sciences, College of Health Sciences, Qatar University, Doha, Qatar.
authors.forename: Reem A
authors.initials: RA
authors.lastname: Mattar
authors.affiliation: Department of Biomedical Sciences, College of Health Sciences, Qatar University, Doha, Qatar.
authors.forename: Rana S
authors.initials: RS
authors.lastname: Al Disi
authors.affiliation: Department of Biomedical Sciences, College of Health Sciences, Qatar University, Doha, Qatar.
authors.forename: Mariam Y
authors.initials: MY
authors.lastname: Nofal
authors.affiliation: Laboratory of Biomedical Research, Virgen de la Victoria Clinical University Hospital, 29010, Málaga, Spain.
authors.forename: Rajaa
authors.initials: R
authors.lastname: El Bekay
authors.affiliation: Medical Genetics Unit, Pediatric Department, Faculty of Medicine, Ain Shams University Hospital, Cairo, 11665, Egypt.
authors.forename: Khalid A
authors.initials: KA
authors.lastname: Ahmed
authors.affiliation: Department of Integrative Biology, School of Biosciences and Technology, VIT- University, Vellore, India.
authors.forename: C
authors.initials: C
authors.lastname: George Priya Doss
authors.affiliation: Department of Biomedical Sciences, College of Health Sciences, Qatar University, Doha, Qatar. hatem.zayed@qu.edu.qa.
authors.forename: Hatem
authors.initials: H
authors.lastname: Zayed
mesh_terms: D001921:Brain / Q000000981:diagnostic imaging*; D017825:Canavan Disease / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D020125:Mutation, Missense; D011487:Protein Conformation
keywords: Aspartoacylase; Canavan disease; In silico mutagenesis; MRI; MRS; Molecular modeling; N-acetyl-aspartate