Hori Atsushi, Ai Tomohiko, Isshiki Miwa, Motoi Yumiko, Yano Kouji, Tabe Yoko, Hattori Nobutaka, Miida Takashi
Center for Genomic and Regenerative Medicine, Juntendo University Graduate School of Medicine, Tokyo 113-8424, Japan.
Department of Clinical Laboratory Medicine, Juntendo University Graduate School of Medicine, Tokyo 113-8424, Japan.
Geriatrics (Basel). 2021 Feb 7;6(1):14. doi: 10.3390/geriatrics6010014.
Dementia has an enormous impact on medical and financial resources in aging societies like Japan. Diagnosis of dementia can be made by physical and mental examinations, imaging tests, and findings of high abnormal proteins in cerebrospinal fluids. In addition, genetic tests can be performed in neurodegenerative diseases such as Alzheimer's disease (AD), frontotemporal dementia (FTD), and Parkinson's disease (PD). In this case series, we presented three cases of dementia with unknown causes who carry novel variants in the genes associated with neurodegenerative diseases. Three patients (Patients 1, 2, and 6) were found by screening 18 dementia patients using a gene panel including 63 genes. The age of onset for Patient 1 was 74 years old, and his father had PD and mother had AD. The age of onset for Patient 2 was 75 years old, and her mother had AD. The age of onset for Patient 6 was 83 years old, and her father, two sisters, and daughter had dementia. The Mini-Mental State Examination produced results of 20, 15, and 22, respectively. The suspected diagnosis by neurological examinations and imaging studies for Patients 1 and 2 was AD, and for Patient 6 was FTD. Patient 1 was treated with donepezil; Patient 2 was treated with donepezil and memantine; and Patient 6 was treated with donepezil, galantamine, and rivastigmine. The three rare variants identified were: , encoding a chloride channel, c.2848G>A:p.Glu950Lys (Patient 1); , encoding a calcium releasing ryanodine receptor, c.13175A>G:p.Lys4392Arg (Patient 2); and , encoding a subunit of dynactin, c. 3209G>A:p.Arg1070Gln (Patient 6). The detected variants were interpreted according to the American College of Medical Genetics (ACMG) guidelines. The minor allele frequency for each variant was 0.025%, 0.023%, and 0.0004% in East Asians, respectively. The variant found in Patient 6 might be associated with FTD. Although none of them were previously reported in dementia patients, all variants were classified as variants of unknown significance (VUS). Our report suggests that results of genetic tests in elderly patients with dementia need to be carefully interpreted. Further data accumulation of genotype-phenotype relationships and development of appropriate functional models are warranted.
在日本这样的老龄化社会中，痴呆症对医疗和财政资源产生了巨大影响。痴呆症的诊断可通过身体和精神检查、影像学检查以及脑脊液中高异常蛋白的检测结果来进行。此外，对于神经退行性疾病，如阿尔茨海默病（AD）、额颞叶痴呆（FTD）和帕金森病（PD），可以进行基因检测。在本病例系列中，我们呈现了三例病因不明的痴呆症患者，他们携带与神经退行性疾病相关基因的新型变异。通过使用包含63个基因的基因检测板对18例痴呆症患者进行筛查，发现了三名患者（患者1、2和6）。患者1的发病年龄为74岁，其父亲患有帕金森病，母亲患有阿尔茨海默病。患者2的发病年龄为75岁，其母亲患有阿尔茨海默病。患者6的发病年龄为83岁，其父亲、两个姐妹和女儿都患有痴呆症。简易精神状态检查表的结果分别为20、15和22。通过神经检查和影像学研究，患者1和2的疑似诊断为阿尔茨海默病，患者6的疑似诊断为额颞叶痴呆。患者1接受多奈哌齐治疗；患者2接受多奈哌齐和美金刚治疗；患者6接受多奈哌齐、加兰他敏和卡巴拉汀治疗。鉴定出的三种罕见变异分别为： ，编码一个氯离子通道，c.2848G>A:p.Glu950Lys（患者1）； ，编码一个钙释放兰尼碱受体，c.13175A>G:p.Lys4392Arg（患者2）；以及 ，编码动力蛋白的一个亚基，c.3209G>A:p.Arg1070Gln（患者6）。根据美国医学遗传学学会（ACMG）指南对检测到的变异进行了解释。在东亚人群中，每个变异的次要等位基因频率分别为0.025%、0.023%和0.0004%。在患者6中发现的 变异可能与额颞叶痴呆有关。尽管这些变异在痴呆症患者中以前均未被报道，但所有变异均被归类为意义未明的变异（VUS）。我们的报告表明，老年痴呆症患者的基因检测结果需要仔细解读。有必要进一步积累基因型 - 表型关系的数据并开发合适的功能模型。
