Analysis The Characteristics Of Genetic Mutation And Clinical Manifestations In Familial Alzheimer’s Disease Associated With A Novel PSEN2 Mutation

BackgroundAlzheimer’s disease(AD) is a genetically complex and heterogeneous neurodegenerative disorder characterized by memory impairment, behavioral disturbances, and multiple cognitive deficits. Three genes have been associated with early-onset familial AD: amyloid β protein precursor(APP), the presenilin 1(PSEN1),and presenilin 2(PSEN2) genes. Until now, genetic mutations were reported only in >500 families with a positive family history. In 3 or more generations of these families with dementia, 86% were associated with a younger onset(<60 years) with a mutation in the APP, PSEN1, or PSEN2 gene. PSEN1 mutations account for approximately 60% of these families. APP mutations accounts for 15% of these families. PSEN2 mutations are rarely. The research of FAD in China is mostly focus on PSEN1 gene mutation. Mutations in PSEN2 were rarely reported. In this research,we mainly analysis the characteristics of genetic mutation and clinical manifestations in a familial Alzheimer’s disease associated with a novel PSEN2 mutation.ObjectiveInvestigate the characteristics of genetic mutation and clinical manifestations in familial Alzheimer’s disease associated with a novel PSEN2 mutation and expand the PSEN2 mutation clinical phenotype.Materials and methods1. The clinical data and blood sample of four generations of a 16 member including the proband and other patients Alzheimer’s disease family were evaluated at the Department of Neurology of Henan Provincial People’s Hospital. Polymerase chain reaction(PCR) and DNA sanger sequencing technology were performed to confirm whether there exists mutations in PSEN1、PSEN2、MAPT genes and exon16 and exon17 of APP gene in the proband and normal members of this family.2. For the novel mutation which was yielded by Sanger sequencing was also verified on the 100 normal controls using the same technology and confirmed whether it is a novel missense mutation or a single nucleotide polymorphism(SNP)by searching dementia associated database.3. The pathogenicity of the mutation was predicted by using Poly Phen2、SIFT and Mutation Taster online program. The structures of PSEN2 were generated by Raptor 3D prediction program. Evolutionary conservation analysis of the novel mutation on many species were retrieved from NCBI Gen Bank.4. The proband underwent systemic clinical and neurological imaging assessment, including magnetic resonance imaging(MRI) sequences and18F-fludeoxyglucose positron emission tomography(18F-FDG-PET).Results1. Sanger sequencing yielded a novel missense mutation in the proband and other 6 members at codon 123(P123L) which is a heterozygous C to T point mutation at position 368(c.368C>T) in exon 5 of the presenilin 2 leading to a proline-to-leucine substitution.2. This missense mutation was not reported according to the dementia Mutation Database and also not found in the other 9 unaffected family members and 100 control subjects. Multiple gene variants databases excluded known single nucleotide polymorphisms.3. Online programs predicted the novel mutation is probably damaging. Multiple sequence alignment for PSEN2 was performed in comparison with different organisms and evolutionary conservation analysis indicated that the novel mutation p.P123 L resulted in a highly conserved amino acid change. Raptor 3D program indicated that the mutation altered the side chain of residue in the codon 123.4. The mainly clinical manifestations of the proband are progressive memory loss, cognitive impairment, and parkinsonism and myoclonic jerks. MRI revealed diffuse cortical atrophy in the frontotemporal lobe, parietal lobe, and hippocampal atrophy(R > L). Hypoperfusion in right temporal and parietal regions were also observed on ASL images sequence. The FDG-PET showed right temporoparietal and precuneus hypometabolism.Conclusion1. We found a novel PSEN2 mutation Pro123 Leu which is probably damaging in familial Alzheimer’s disease.2. Parkinsonism and myoclonic jerks are probably the new clinical phenotype of the novel PSEN2 mutation.