Basuta Kirin, Schneider Andrea, Gane Louise, Polussa Jonathan, Woodruff Bryan, Pretto Dalyir, Hagerman Randi, Tassone Flora
Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Sacramento, California.
MIND Institute, University of California, Davis, Medical Center, Sacramento, California.
Am J Med Genet A. 2015 Sep;167A(9):2154-61. doi: 10.1002/ajmg.a.37125. Epub 2015 Apr 29.
Fragile X syndrome (FXS) affects individuals with more than 200 CGG repeats (full mutation) in the fragile X mental retardation 1 (FMR1) gene. Those born with FXS experience cognitive and social impairments, developmental delays, and some features of autism spectrum disorders. Carriers of a premutation (55-200 CGG repeats) are generally not severely affected early in life; however, are at high risk of developing the late onset neurodegenerative disorder, Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), or Fragile X-associated Primary Ovarian Insufficiency (FXPOI), and may have other medical conditions such as developmental delay, autism spectrum disorders, hypertension, anxiety, and immune-mediated disorders. Here we present a case of a 58-year-old man with a borderline IQ, average memory skills, and executive function deficits. He met criteria for multiple psychiatric diagnoses and presented with tremor and ataxia, meeting criteria for FXTAS. Molecular testing unveiled a completely unmethylated FMR1 full mutation in peripheral blood mononucleated cells with elevated FMR1 mRNA and premutation alleles of different sizes in two other tissues (primary fibroblasts and sperm), indicating the presence of allele instability based on both inter- and intra-tissue mosaicism. The observation of FXTAS in this case of a full mutation mosaic man suggests that the pathogenic mechanism underlying this disorder is not observed exclusively in premutation carriers as it was originally thought. The concomitant presence of features of FXS and late onset neurological deterioration with probable FXTAS likely result from a combined molecular pathology of elevated FMR1 mRNA levels, a molecular hallmark of FXTAS and low FMRP expression that leads to FXS.
脆性X综合征（FXS）影响脆性X智力低下1（FMR1）基因中具有超过200个CGG重复序列（完全突变）的个体。患有FXS的个体存在认知和社交障碍、发育迟缓以及一些自闭症谱系障碍的特征。前突变（55 - 200个CGG重复序列）携带者在生命早期通常不会受到严重影响；然而，他们患迟发性神经退行性疾病脆性X相关震颤/共济失调综合征（FXTAS）或脆性X相关原发性卵巢功能不全（FXPOI）的风险很高，并且可能患有其他疾病，如发育迟缓、自闭症谱系障碍、高血压、焦虑症和免疫介导的疾病。在此，我们报告一例58岁男性病例，其智商处于临界水平，记忆能力平均，但存在执行功能缺陷。他符合多种精神疾病诊断标准，并伴有震颤和共济失调，符合FXTAS的诊断标准。分子检测发现外周血单核细胞中FMR1完全突变且完全未甲基化，FMR1 mRNA水平升高，另外两个组织（原代成纤维细胞和精子）中存在不同大小的前突变等位基因，这表明基于组织间和组织内的嵌合现象存在等位基因不稳定性。在这个完全突变嵌合男性病例中观察到FXTAS表明，这种疾病的致病机制并不像最初认为的那样仅在前突变携带者中出现。FXS特征与可能的FXTAS导致的迟发性神经功能恶化同时存在，可能是由于FMR1 mRNA水平升高（FXTAS的分子标志）和导致FXS的低FMRP表达的联合分子病理学所致。
