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P3‐120: DNA METHYLATION DYNAMICS IN ALZHEIMER'S DISEASE: DEVELOPMENT OF BIOMARKERS AND NOVEL DRUG TARGETS USING ADNI EPIGENETIC DATA
Author(s) -
Vasanthakumar Aparna,
Davis Justin W.,
Idler Kenneth,
Asque Elizabeth,
Riley-Gillis Bridget,
Kim Sungeun,
Nho Kwangsik,
Nudelman Kelly N.H.,
Faber Kelley,
Bai Yuchen,
Sun Yu,
Foroud Tatiana M.,
Estrada Karol,
Apostolova Liana G.,
Li Qingqin S.,
Saykin Andrew J.,
Waring Jeffrey
Publication year - 2018
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2018.06.1477
Subject(s) - dnam , dna methylation , epigenetics , methylation , differentially methylated regions , disease , biology , gene , oncology , bioinformatics , gene expression , medicine , genetics
Background: Mutations in the SPG4/SPAST gene are the major cause of hereditary spastic paraplegias (HSPs), a group of genetic disorders leading to progressive spasticity and weakness of the lower limbs. Alzheimer’s disease (AD) is a degenerative disorder of the central nervous system. Early-onset familial AD (EOFAD) accounts for 3-5% of all AD cases and denotes families in which onset is reliably before age 60 to 65 years and sometimes before age 55 years. Two SPG4/SPAST Italian families with pure HSP and AD and one Japanese family with complicated HSP and AD were previously described by our research team. Methods:Whole exome sequencing (WES), Sanger sequencing, Multiplex Ligation dependent Probe Amplification (MLPA) analysis, bioinformatics, neurological evaluation, diagnostic imaging, and pathological assessment. Results: One Italian man was diagnosed as certainly affected by slowly progressive autosomal dominant HSP, according to the Harding criteria. The age at onset of the first motor symptoms was 32 years. At 57 years, the phenotype was complicated by cognitive impairment; a diagnosis of EOFAD based on the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria was formulated. The case was definite Alzheimer’s disease (autopsy proven): the brain pathology showed plaques with a congophilic core and neuritic pathology. Additional four affected subjects revealed the same initial symptoms of dementia and HSP was diagnosed. Additional clinical signs, such as hearing impairment, seizures, and pes cavus, were present in the affected individuals. WES revealed in all patients a new heterozygous change in SPG4/SPAST. MLPA analysis excluded the presence of deletions/duplications in SPG4/SPAST. Bioinformatic analyses and population study confirm a pathogenetic role of such mutation. Screening of PS1, PS2, and bAPP genes did not reveal any coding mutation. No affected subject carried out APOE genotype ε4/ε3 or ε4/ε4. Conclusions: To our knowledge, this work describes the first Italian family with a new SPG4/SPAST mutation and association of a complicated form of HSP and EOFAD.