Aspartoacylase Deficiency (Canavan Disease)

ABSTRACT

The disorder now identified as aspartoacylase deficiency is equivalent to the condition variously called spongy degeneration of the brain, spongy degeneration of the central nervous system in infancy, or spongy degeneration of infancy, and many publications have used the eponymic designation, Canavan disease. The first definition of this condition as a distinct clinical entity is properly credited to van Bogaert and Bertrand in 1949.^1,2 In retrospect, the first clinical description is attributed to Globus and Strauss in 1928.³ In 1931, Canavan described an infant with prominent enlargement of the head and cerebral and cerebellar spongy degeneration under the designation “Schilder's encephalitis periaxialis diffusa.”⁴ Eiselsberg is credited with the recognition of the familial nature of the disorder in 1937,⁵ but, like Jervis,^6,7 she described the condition as Krabbe disease. The reports of von Bogaert and Bertrand^1,2 were comprehensive and described the essential pathologic and clinical features as well as the predilection for the occurrence of the disorder in Ashkenazic infants. In a more detailed review of the historical literature,⁸ Banker et al. pointed out that the Canavan eponym is hardly justified, because her report was not the first clinical description, did not recognize the familial or ethnic aspect to the disorder, and did not recognize spongy degeneration as the unique pathologic feature; the designation aspartoacylase deficiency may be most appropriate, but the eponym is widely used.

Unraveling of the biochemical basis of infantile spongy degeneration began with the description of urinary excretion of N-acetylaspartic acid (NAA) by Kvittingen et al.,⁹ but aspartoacylase was reported to be normal in cultured fibroblasts; presumably the failure to demonstrate the enzyme deficiency was due to the choice of conditions for enzyme analysis. In 1987, Hagenfeldt et al. reported N-acetylaspartic aciduria and identified aspartoacylase deficiency,¹⁰ but neither of these biochemical reports recognized the association with infantile spongy degeneration. Matalon et al.,^11,12 and Divry et al.^13,14 are credited with the recognition that aspartoacylase deficiency correlated with infantile spongy degeneration (Canavan disease). Kaul et al. went on to isolate a cDNA clone for human aspartoacylase and identified the common mutation in Jewish patients.¹⁵ Matalon and colleagues have contributed extensively to observations in recent years as reviewed elsewhere.¹⁶

CLINICAL FEATURES

In addition to the landmark descriptions of von Bogaert and Bertrand,^1,2 Banker and colleagues, and others have provided excellent reviews of the clinical and pathologic features of infantile spongy degeneration.^8,17-19 Ungar and Goodman reviewed cases of infantile spongy degeneration in Israel from 1965 to 1980.²⁰ Although infants are usually normal in the first month of life, they may exhibit poor visual fixation, irritability, and poor suck at birth.¹⁹ They demonstrate poor head control, poor eye contact, seizures, and abnormal muscle tone beginning in the second to fourth month, and all those with the classic phenotype are clearly neurologically abnormal ...