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Mild Elevation of N-Acetylaspartic Acid and Macrocephaly: Diagnostic Problem

Department of Pediatrics University of Texas Medical Branch Galveston, Texas

Fiona J. Bamforth, MD, FRCPC

Department of Laboratory Medicine and Pathology University of Alberta Edmonton, Alberta

Alicia Chan, MD, FRCPC

Department of Medical Genetics University of Alberta Edmonton, Alberta

Stephen K. Tyring, MD, PhD

Department of Microbiology and Immunology University of Texas Medical Branch Galveston, Texas

Stephen I. Goodman, MD, CM

Department of Pediatrics University of Colorado Health Science Center Denver, Colorado

Reuben Matalon, MD, PhD

Department of Pediatrics University of Texas Medical Branch Galveston, Texas, rmatalon{at}utmb.edu

Patients with slightly increased excretion of N-acetylaspartic acid in urine, together with macrocephaly, present a dignostic dilemma for Canavan's disease. We describe a 13-year-old male patient with macrocephaly, mild developmental delay, increased signal intensity in the basal ganglia bilaterally, partial cortical blindness, and retinitis pigmentosa. Although the clinical course and magnetic resonance imaging findings did not resemble typical Canavan's disease, N-acetylaspartic acid excretion in the patient's urine was slightly elevated, 99.90 ± 4.00 µg/mg creatinine, whereas the normal control range was < 83 µg/mg creatinine. Cultured skin fibroblasts from the patient showed no aspartoacylase activity. Cloning of genomic DNA isolated from the patient's fibroblasts showed an intronic mutation, specifically deletion of -2A and -3C at the acceptor site of exon 3 and disrupting the normal splicing of the gene. A second mutation was found in exon 6, 863 AG in aspartoacylase complementary DNA, causing a tyrosine-to-cysteine (Y288C) amino acid substitution. Expression of the mutation on exon 6 showed normal aspartoacylase activity. These data suggest that expression of the mutation may help to understand the enzyme defect in a patient with slightly increased N-acetylaspartic acid excretion. (J Child Neurol 2003;18:809—812).

Journal of Child Neurology, Vol. 18, No. 11, 809-812 (2003)
DOI: 10.1177/08830738030180111601


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