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Homozygosity for mutation G212A of the gene for aspartoacylase is associated with atypical form of Canavan’s disease

To the Editor: Canavan’s disease is a severe autosomal recessive leukodystrophy with higher prevalence among the Ashkenazi Jewish population. It is due to deficiency of the enzyme aspartoacylase (ASPA) that leads to accumulation of N-acetylaspartic acid (NAA) in the central nervous system. Disease manifestations typically start at the age of 3–6 months. Dysmyelination and progressive spongial atrophy of the brain lead to death by the age of 5–10 years (1). More than 50 mutations of the ASPA gene were reported to date. Several rare mutations were reported in association with a milder disease course (2–5). Janson et al. (5) recently reported a family in which two individuals were compound heterozygotes for a novel mutation G212A (R71H) and the common non-Jewish mutation C914A (A305E). The phenotype in this family was unusually mild and consisted of only mild developmental delay in the two reported patients, age 19 and 50 months. Their NAA levels were more than 10 times the normal range, but 2–3 times lower than the affected range. The ASPA enzyme activity was very low and was not significantly different from the one in typical Canavan’s disease patients. No mutant G212A homozygotes have been reported to date. Our patient is a 28-month-old girl who was born after an uncomplicated pregnancy. Her parents are originally from Ecuador, are not Jewish, and have no evidence of consanguinity. No other affected family relatives are known. The child was first noted to have mild motor and speech delay at the age of 9 months. Her brain magnetic resonance imaging (MRI) performed at 18 months of age showed symmetrical hyperintensities within the caudate and putamen with no white matter and U fiber changes (Fig. 1). Repeat MRI at the age of 26 months showed the same changes with no significant progression. Proton magnetic resonance spectroscopy through the region of abnormal signal in the caudate head and basal ganglia bilaterally did not show abnormal elevation of the NAA peak. The patient did not have macrocephaly or seizure activity and had a normal electroencephalogram at the age of 17 months. She walked at the age of 19 months. At the age of 25 months, she was able to say about 20 words. She was able to run and play at that time and appeared as a healthy 2-year-old girl. Her neurological exam was essentially normal. Her metabolic testing was normal with the exception of an NAA level of 370 mmol/mol creatinine, which was about 15 times higher than normal, but was significantly lower than the levels observed in classic Canavan’s disease patients and similar to the patients reported by Janson et al. (5). DNA analysis showed homozygosity for the ASPA mutation G212A (R71H). Our patient shows that homozygosity for the G212A mutation is associated with mild but noticeable manifestations of Canavan’s disease, similar to the ones reported by Janson et al. (5). The same authors also reported their results of expression of the G212A mutant ASPA gene in COS cells. The resulting ASPA activity was very low and not significantly different from the one in the expressed common C914A mutation. From these and other studies, it seems that the measured level of ASPA activity does not correlate well with the phenotypic severity of the disorder in atypical cases. One explanation for such findings may be that the assay used to measure ASPA activity is not sensitive enough to detect minor differences in the enzyme activity with possible implication for the disease severity. The NAA levels seem to better correspond to the disease severity in our case and other atypical cases, indicating the possibility of proportional gradient effect of variable elevated NAA concentrations during neurodevelopment, which remains to be fully elucidated (6).