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Home arrow Health arrow Cognitive impairment and dementia in Parkinson disease
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Dementias with parkinsonism

The clinical expression of mutations in genes proven to be associated with different dementias is variable. Some of these mutations may give rise to parkinsonian syndromes and thus these genes may be of potential importance in the development of PD-D. For example, mutations of PSEN1 and PSEN2 cause a familial form of young-onset AD. In PSEN1 the p.G217D mutation was found in a Japanese family affected by a disease characterized by dementia, parkinsonism, a stooped posture, and an antiflexion gait with an onset in the fourth decade of life. Neuropathologically, the disease was characterized by the presence of ‘cotton wool’ plaques, senile plaques, severe amyloid angiopathy, neurofibrillary tangles, neuronal rarefaction, and gliosis [62]. In PSEN2, the p.A85V mutation was found in an Italian family in which the proband was diagnosed with DLB. All the other affected members exhibited a clinical phenotype typical of AD. Neuropathologically, the proband presented with unusually abundant and widespread cortical Lewy bodies in addition to the hallmark lesions of AD [63]. To clarify the role of mutations in the major dementia (APP, PSEN1, PSEN2, MAPT, GRN, TARDBP) and PD (SNCA, LRRK2, PARK2, PINK1, PARK7, GBA) genes in DLB and PD-D, Meeus et al. [53] performed sequencing and dosage analyses in 99 DLB and 75 PD-D patients from Belgium. They identified 14 known or novel variants in these genes, but most were associated with a diagnosis of DLB, with only three variants (PSEN2 p.V191E, LRRK2 p.R1441C, and PARK2 p.P37L) being found in PD-D or probable PD-D cases. From these three, only the LRRK2 p.R1441C mutation was considered as definitely pathogenic. Interestingly, the sequencing of GBA revealed five rare and two common heterozygous variants in the studied cohort. The five rare mutations were found in seven patients, six of whom had a diagnosis of PD-D and only one of DLB. One of these mutations was a novel frameshift mutation (p.Q256SfX9), predicted to create a premature stop codon, in a familial early onset PD-D patient whose father also suffered from early onset PD. Even though this study analysed a small series of patients, the results suggest that rare variants in dementia genes have a more pronounced role in the genetics of DLB, while variants in PD genes seem to be more frequently associated with PD-D.

 
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