Brief CommunicationGlucocerebrosidase mutations in subjects with parkinsonism
Introduction
Gaucher disease (MIM 230800), the most common lysosomal storage disorder, results from the inherited deficiency of glucocerebrosidase (EC 3.2.1.45). There is growing evidence for an association between Gaucher disease and parkinsonism, demonstrated in recent studies of genotypically heterogeneous patients with relatively mild Gaucher disease who developed progressive parkinsonian manifestations, including tremor, bradykinesia and rigidity and often cognitive decline [1], [2], [3], [4], [5]. Neuropathologic studies revealed focal regions of gliosis, especially in the hippocampal C2–C4 region and calcarine cortex, and α-synuclein immunoreactive cortical and brainstem-type Lewy bodies [1], [6]. These shared clinical and neuropathologic features prompted genotyping of the glucocerebrosidase gene (GBA) in autopsy samples from cases classified as Parkinson disease. Here we report that GBA mutations are encountered more often than expected in individuals with parkinsonism.
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Materials and methods
Brain samples from subjects who carried a clinical or pathologic diagnosis of Parkinson disease were requested from five different brain bank repositories without additional prerequisites. Tissues from 57 probands were provided, with the age at death ranging from 54 to 99 years (mean age 76 years). One of the provided samples (Table 1, subject 2) also had the diagnosis of Gaucher disease. Tissues from 44 adult subjects without the diagnosis of Parkinson disease (mean age 70 years) were obtained
Results and discussion
Alterations in GBA were identified in 12 of the 57 subjects with Parkinson disease (21%), including eight with known or novel mutations (two N370S homozygotes, three N370S heterozygotes and one each carrying L444P, K198T, and R329C). The novel mutations K198T and R329C were confirmed on a second PCR product and/or by digestion with the enzyme AciI. Four probands carried alterations that are presumed polymorphisms, T369M in three and E326K in one (Table 1). These changes are considered to be
Acknowledgements
The technical assistance of Michael Eblan, Joann Nguyen, Shira Ziegler, and Barbara Stubblefield and secretarial help of Marie Hall are gratefully acknowledged. We also thank the Massachusetts Alzheimer Disease Research Center, the Harvard Brain Tissue Resource Center, the Cooperative Human Tissue Network, the University of Maryland Brain and Tissue Bank for Developmental Disorders and the Parkinson Institute for providing the tissues and pathology reports used in this study.
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