Urine <i>N</i> -Acetylaspartate Distinguishes Phenotypes in Canavan Disease

Canavan disease (CD) is an ultra-rare autosomal recessive leukodystrophy caused by loss-of-function mutations in <i>ASPA,</i> which encodes aspartoacylase (ASPA), leading to accumulation of <i>N</i>-acetylaspartate (NAA). Patients with CD typically present with profound psychomotor deficits within the first 6 months of life and meet few motor milestones. Within CD a subset of patients exhibits a milder phenotype with more milestone acquisition, possibly related to greater residual ASPA activity. An ongoing CD natural history study and a literature search were leveraged to compare urine NAA levels and associated genotypes in patients classified with mild or typical CD, with the hypothesis that urine NAA levels reflect ASPA activity and therefore can distinguish between the two phenotypes. Urine NAA levels were lower, on average (<i>p</i> < 0.0001), in individuals with mild (mean 525.3, range 25.2-1,335 mmol/mol creatinine [Cr]) compared with typical CD (mean 1,369, range 391.7-2,420 mmol/mol Cr). Mutations R71H and Y288C, variants that may harbor residual ASPA activity, were unique to the mild phenotype population (56%, 14/25) and not found in individuals with a typical phenotype (0%, 0/39). In aggregate, urine NAA levels can distinguish between mild and typical CD phenotypes, suggesting the ability to reflect ASPA activity.