CANAVAN-DISEASE IN COMPOUND HETEROZYGOTE WITH NOVEL MUTATION (C-914-]A) IN ASPARTOACYLASE GENE (VOL 11, PG 145, 1994)

Canavan disease (CD) is an autosomal-recessive leukodystrophy characte rized by macrocephaly, hypotonia, and psychomotor retardation with dea th usually occurring in the first decade of life. It is caused by the deficiency of N-acetylaspartoacylase (ASP) which hydrolyses N-acetyl-L -aspartic acid and is most prevalent among Ashkenazim. Recently, a com mon mutation (A(854) --> C) in the ASP coding region has been found in 85% of Ashkenazic Jewish patients [Nature Genet 1993;5:118]. In this study we present an 18-year-old male of Creek and Ashkenazic Jewish or igin with CD whose clinical features and low levels of aspartoacylase activity in fibroblasts suggested a variant form of the disease. He ha s had progressive spastic quadriparesis, loss of visual function, and marked volumetric reduction of cerebral and cerebellar cortex and whit e matter by cranial CT and MRI. Molecular analysis showed the proband as a compound heterozygote carrying in the maternal allele the A(854) --> C Ashkenazic mutation and a new mutation in the paternal allele. D NA sequencing and allele-specific oligonucleotide (ASO) analyses revea led a novel mutation, C-914 --> A, resulting in the missense Ala(305) --> Glu in the paternal Greek allele. This novel mutation may be respo nsible for the less severe involvement and slower progression of the d isease in this patient than in classical CD.