CLINICOPATHOLOGIC STUDY OF A SNCA GENE DUPLICATION PATIENT WITH PARKINSON DISEASE AND DEMENTIA

Abstract

There is evidence that α-synuclein gene ( SNCA ) point mutations and gene multiplications play a pivotal role in the development of Lewy bodies (LBs) and Lewy neuritic (LN) pathology. Dysregulation of the production/degradation of the α-synuclein protein, a major component of LBs and LNs, is speculated to result in its accumulation and produce the neuropathological features of SNCA -related neurodegeneration.1 The identification of SNCA multiplications in families with parkinsonism suggests that SNCA gene dosage may play a role in the onset of Parkinson disease (PD).2 Most patients with SNCA triplication develop cognitive and autonomic dysfunction in early stage of the disease.3,4 However, three families with SNCA duplication have been reported with symptoms more reminiscent of typical PD.5,6 Interestingly, a recent study reported that one triplication (a Swedish-American pedigree) and one duplication pedigree have a common ancestor.7 As a common mechanism of multiplications, the area including the SNCA-MMRN1 locus could play a role in multiple copy numbers. Another multiplication family has been reported also to have the rearrangement change in the same region indicating the SNCA-MMRN1 locus may be fragile.2,5–7 With regard to clinical aspects, patients with SNCA duplication tend to have milder symptoms compared to those with triplication.5–7 The onset of disease in SNCA duplication patients occurs approximately 15 years later (50 years of age) than that of SNCA triplication families (35 years of age). These features suggest that differences in genetic copy numbers could influence the clinical features of PD. Recently, we identified two families of Japanese origin with SNCA duplications.8 One patient from Family B (named as B-1) developed severe parkinsonism and dementia. These findings indicate that SNCA duplication also causes PD with dementia (PDD). Three copies of the locus SNCA-MMRN1 were identified in the two duplication families. The length of …