LAUSR

Canavan disease is a recessively inherited vacuolar leukodystrophy caused by ASPA mutations [1–3]. ASPA encodes aspartoacylase, an oligodendroglial enzyme required for cleavage of the abundant brain amino acid N-acetyl-l-aspartate (NAA) to acetate and l-aspartate [4]. ASPA mutations are relatively common in Ashkenazi Jews, with carrier frequency estimates ranging between 1:40 and 1:60, but also occur, though substantially less often, in many other human populations [3, 5, 6]. The disease classically presents in infancy with ataxia, hypotonia, and failure to acquire normal developmental milestones, often in association with macrocephaly and seizures [3]. In atypical cases in which some aspartoacylase enzymatic activity remains, disease onset is delayed until several years after birth [2, 7, 8]. Neuroimaging shows brain white matter signal abnormalities, and, at later time-points, ventricular enlargement [9, 10]. In vivo proton nuclear magnetic resonance spectroscopy (1H-MRS) documents a 30% or greater elevation in brain NAA concentration ([NAAB]) [10]. Histological studies reveal brain “spongiform” vacuolation, astrogliosis, and dysmyelination [7, 11–13]. These neuropathological abnormalities are most prominent in superficial white matter and neighboring gray matter of the forebrain, cerebellum, and upper brainstem. In more advanced cases, the cerebral ventricles become enlarged, and numbers of brain neurons diminish [7, 12, 13]. No therapies have yet been proven to be effective in preventing or reversing progression of leukodystrophy in Canavan disease.