Amano Eiichiro, Yoshida Tomokatsu, Mizuta Ikuko, Oyama Jun, Sakashita Shingo, Ueyama Syunsuke, Machida Akira, Yokota Takanori
Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (E.A., T. Yokota); Department of Neurology, Tsuchiura Kyodo General Hospital (E.A., A.M.), Ibaraki; Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine (T. Yoshida, I.M.); Department of Radiology, Tokyo Medical and Dental University (J.O.); Department of Pathology, Tsuchiura Kyodo General Hospital (S.S.), Ibaraki; Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center (S.S.), Chiba; and Department of Gastroenterology, Tsuchiura Kyodo General Hospital (S.U.), Ibaraki, Japan.
Neurol Genet. 2021 Oct 1;7(6):e626. doi: 10.1212/NXG.0000000000000626. eCollection 2021 Dec.
Alexander disease (ALXDRD) is an autosomal dominant neurologic disorder caused by mutations in the glial fibrillary acidic protein () gene and is pathologically defined by Rosenthal fiber accumulation. Most mutations are exonic missense mutations, and splice site mutations are rare. We report a very-late-onset autopsied case of adult-onset ALXDRD with a novel splice site mutation.
Genetic testing of was performed by Sanger sequencing. Using autopsied brain tissues, transcript analysis was performed.
The patient presented mild upper motor neuron symptoms in contrast to the severe atrophy of spinal cord and medulla oblongata. The patient had c.619-1G>A mutation, which is located in the canonical splice acceptor site of intron 3. The brain RNA analysis identified the r.619_621del (p.Glu207del) mutation, which is explained by the activation of the cryptic splice acceptor site in the second and third nucleotides from the 5' end of the exon 4.
gene expression analysis is necessary to clarify the effects of intronic mutations on splicing, even if they are in canonical splice sites. This case showed a much milder phenotype than those in previous cases with missense mutations at Glu207, thereby expanding the clinical spectrum of ALXDRD with Glu207 mutation.
亚历山大病（ALXDRD）是一种常染色体显性神经疾病，由胶质纤维酸性蛋白（）基因突变引起，其病理特征为罗森塔尔纤维积聚。大多数突变是外显子错义突变，剪接位点突变较为罕见。我们报告一例成人起病的ALXDRD极晚发尸检病例，该病例存在一种新的剪接位点突变。
采用桑格测序法对进行基因检测。利用尸检脑组织进行转录本分析。
与脊髓和延髓严重萎缩形成对比的是，该患者表现出轻度上运动神经元症状。患者存在c.619-1G>A突变，该突变位于内含子3的典型剪接受体位点。脑RNA分析确定了r.619_621del（p.Glu207del）突变，这是由外显子4 5'端第二个和第三个核苷酸处的隐蔽剪接受体位点激活所导致的。
即使内含子突变位于典型剪接位点，进行基因表达分析对于阐明其对剪接的影响也是必要的。该病例表现出的表型比先前Glu207处存在错义突变的病例要温和得多，从而扩展了Glu207突变型ALXDRD的临床谱。
