Gaucher disease and parkinsonism: A phenotypic and genotypic characterization

Among the many phenotypes associated with Gaucher disease, the inherited de ficiency of glucocerebrosidase, are reports of patients with parkinsonian s ymptoms. The basis for this association is unknown, but could be due to alt erations in the gene or gene region. The human glucocerebrosidase gene, loc ated on chromosome 1q21, has a nearby pseudogene that shares 96% identity. Immediately adjacent to the glucocerebrosidase pseudogene is a convergently transcribed gene, metaxin, which has a pseudogene that is located just dow nstream to the glucocerebrosidase gene. We describe a patient with mild Gau cher disease but impaired horizontal saccadic eye movements who developed a tremor at age 42, followed by rapid deterioration of her gait. A pallidoto my at age 47 was unsuccessful. Her motor and cognitive deterioration progre ssed despite enzyme replacement therapy. Sequencing of the glucocerebrosida se gene identified mutations L444P and D409H. Southern blot analysis using the enzyme SspI showed that the maternal allele had an additional 17-kb ban d. PCR amplifications and sequencing of this fragment demonstrated a duplic ation which included the glucocerebrosidase pseudogene, metaxin gene, and a pseudometaxin/metaxin fusion. Gene alterations associated with this novel rearrangement, resulting from a crossover between the gene for metaxin and its pseudogene, could contribute to the atypical phenotype encountered in t his patient. (C) 2001 Academic Press.