Hagerman Randi J, Ono Michele Y, Hagerman Paul J
Department of Pediatrics, University of California at Davis Medical Center, M.I.N.D. Institute, Sacramento, CA 95817, USA.
Curr Opin Psychiatry. 2005 Sep;18(5):490-6. doi: 10.1097/01.yco.0000179485.39520.b0.
This review will describe recent developments in the neurobiology of fragile X syndrome (FXS), the association between FXS and autism, and involvement in premutation carriers.
Metabotropic glutamate receptor 5 (mGluR5)-coupled pathways are dysregulated in individuals with FXS and this is thought to relate to the FXS phenotype. The mGluR5 model suggests that mGluR5 antagonists, including downstream effectors such as lithium, could be useful for treating FXS. Two forms of clinical involvement associated with the fragile X mental retardation 1 (FMR1) gene, autism and fragile X-associated tremor/ataxia syndrome (FXTAS), have received additional attention during the past year. One study has found that approximately 30% of individuals with FXS have autism; those with autism have lowered cognitive abilities, language problems, and behavioral difficulties compared to those with FXS alone. Furthermore, evidence is mounting that autism also occurs in some young males who have premutation alleles. Finally, males and occasional females with premutation alleles may develop a neurological syndrome with aging that consists of tremor, ataxia, peripheral neuropathy, and cognitive deficits. Significant brain atrophy and white-matter disease is usually seen. This new disorder (FXTAS) is thought to be related to elevated levels of abnormal FMR1 mRNA.
Full-mutation forms of the gene (> 200 repeats) can cause autism, learning disabilities, anxiety disorders, and mental retardation. Disorders associated with premutation forms of the gene (55-200 repeats) include, in addition to autism, FXTAS in older males and females, and premature ovarian failure.
本综述将描述脆性X综合征（FXS）神经生物学的最新进展、FXS与自闭症之间的关联以及前突变携带者的情况。
代谢型谷氨酸受体5（mGluR5）偶联通路在FXS患者中失调，这被认为与FXS表型有关。mGluR5模型表明，mGluR5拮抗剂，包括锂等下游效应物，可能对治疗FXS有用。过去一年，与脆性X智力低下1（FMR1）基因相关的两种临床情况，即自闭症和脆性X相关震颤/共济失调综合征（FXTAS），受到了更多关注。一项研究发现，约30%的FXS患者患有自闭症；与仅患有FXS的患者相比，患有自闭症的患者认知能力较低、有语言问题和行为困难。此外，越来越多的证据表明，一些携带前突变等位基因的年轻男性也会出现自闭症。最后，携带前突变等位基因的男性和少数女性可能会随着年龄增长出现一种神经综合征，包括震颤、共济失调、周围神经病变和认知缺陷。通常会出现明显的脑萎缩和白质疾病。这种新疾病（FXTAS）被认为与异常FMR1 mRNA水平升高有关。
该基因的全突变形式（>200次重复）可导致自闭症、学习障碍、焦虑症和智力低下。与该基因前突变形式（55 - 200次重复）相关的疾病，除自闭症外，还包括老年男性和女性的FXTAS以及卵巢早衰。
