title: Mild-onset presentation of Canavan's disease associated with novel G212A point mutation in aspartoacylase gene.
abstract: We describe two sisters with a mild-onset variant of Canavan's disease who presented at age 50 and 19 months with developmental delay but without macrocephaly, hypotonia, spasticity, or seizures. Remarkably, both patients had age-appropriate head control, gross motor development, and muscle tone. There were very mild deficits in fine motor skills, coordination, and gait. Both sisters had a history of strabismus, but otherwise vision was normal. The older child showed evidence of mild cognitive and social impairment, whereas language and behavior were normal for age in the infant. Both patients were found to be compound heterozygotes for C914A (A305E) and G212A (R71H) mutations in ASPA. Like all other known ASPA mutations, this previously unknown G212A mutation appears to have low absolute enzyme activity. Nevertheless, it is associated in these patients with an extremely benign phenotype that is highly atypical of Canavan's disease. Biochemical and clinical data were evaluated using a generalized linear mixed model generated from 25 other subjects with Canavan's disease. There were statistically significant differences in brain chemistry and clinical evaluations, supporting a distinct variant of Canavan's disease. Future studies of ASPA enzyme structure and gene regulation in these subjects could lead to a better understanding of Canavan's pathophysiology and improvements in ASPA gene therapy.
authors.affiliation: Department of Neurology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Camden, NJ, USA. janson@memorymatters.org
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Janson
authors.forename: Edwin H
authors.initials: EH
authors.lastname: Kolodny
authors.forename: Bai-Jin
authors.initials: BJ
authors.lastname: Zeng
authors.forename: Srinivasa
authors.initials: S
authors.lastname: Raghavan
authors.forename: Gregory
authors.initials: G
authors.lastname: Pastores
authors.forename: Paola
authors.initials: P
authors.lastname: Torres
authors.forename: Mitra
authors.initials: M
authors.lastname: Assadi
authors.forename: Scott
authors.initials: S
authors.lastname: McPhee
authors.forename: Olga
authors.initials: O
authors.lastname: Goldfarb
authors.forename: Beth
authors.initials: B
authors.lastname: Saslow
authors.forename: Andrew
authors.initials: A
authors.lastname: Freese
authors.forename: D J
authors.initials: DJ
authors.lastname: Wang
authors.forename: Larissa
authors.initials: L
authors.lastname: Bilaniuk
authors.forename: David
authors.initials: D
authors.lastname: Shera
authors.forename: Paola
authors.initials: P
authors.lastname: Leone
mesh_terms: D000328:Adult; D000409:Alanine / Q000235:genetics*; D000581:Amidohydrolases / Q000235:genetics*; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D017825:Canavan Disease / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D005998:Glycine / Q000235:genetics*; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008875:Middle Aged; D017354:Point Mutation; D035781:Siblings
chemical_list: D001224:Aspartic Acid; C000179:N-acetylaspartate; D000581:Amidohydrolases; C019751:aspartoacylase; D000409:Alanine; D005998:Glycine