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通过各种与Ras/MAPK途径相关的基因变异探讨努南综合征谱系障碍中的认知表型和精神病理学

Cognitive Phenotype and Psychopathology in Noonan Syndrome Spectrum Disorders through Various Ras/MAPK Pathway Associated Gene Variants.

作者信息

Wingbermühle Ellen, Roelofs Renée L, Oomens Wouter, Kramer Jennifer, Draaisma Jos M T, Leenders Erika, Kleefstra Tjitske, Kessels Roy P C, Egger Jos I M

机构信息

Center of Excellence for Neuropsychiatry, Vincent van Gogh Institute for Psychiatry, 5803 DM Venray, The Netherlands.

Donders Institute for Brain, Cognition and Behaviour, Radboud University, 6525 GD Nijmegen, The Netherlands.

出版信息

J Clin Med. 2022 Aug 13;11(16):4735. doi: 10.3390/jcm11164735.

Abstract

Cognitive difficulties are argued to be common in patients with Noonan syndrome spectrum disorders (NSSDs), but findings are based on studies in which patients with variants in PTPN11 (prevalence ~50%) were overrepresented. The current study, using a structured clinical approach, describes the cognitive phenotype and psychopathology of 100 patients (aged 6 to 61 years) with nine different gene variants in the Ras/MAPK pathway underlying NSSDs (PTPN11n = 61, PTPN11 Noonan syndrome with multiple lentigines n = 3, SOS1n = 14, KRASn = 7, LZTR1n = 5, RAF1n = 4, SHOC2n = 2, CBLn = 2, SOS2n = 2). After weighted assessment and bootstrapping of the results of individual neuropsychological assessments and measures of psychopathology, cognitive performances in most variant groups were within the ranges of expectation. IQs were significantly lower in patients with variants in PTPN11, KRAS, RAF1, and SHOC2, but no specific cognitive impairments were found. The performances of younger participants (<16 years of age) did not differ from those of adults. Alexithymia and internalizing problems were more frequent in patients with variants in PTPN11 and SOS1, while PTPN11 patients also showed higher levels of externalizing problems. These results stress the need to take intelligence into account when interpreting lower cognitive performances in individual neuropsychological assessments, which is crucial for an adequate understanding and guidance of patients with NSSDs.

摘要

认知困难被认为在努南综合征谱系障碍(NSSD)患者中很常见,但现有研究结果所基于的研究中,携带PTPN11基因变异的患者(患病率约50%)占比过高。本研究采用结构化临床方法,描述了100例(年龄6至61岁)患有NSSD的患者的认知表型和精神病理学特征,这些患者在Ras/MAPK通路中有9种不同的基因变异(PTPN11,n = 61;伴有多发雀斑的努南综合征,n = 3;SOS1,n = 14;KRAS,n = 7;LZTR1,n = 5;RAF1,n = 4;SHOC2,n = 2;CBL,n = 2;SOS2,n = 2)。在对个体神经心理学评估结果和精神病理学测量进行加权评估和自抽样后,大多数变异组的认知表现处于预期范围内。携带PTPN11、KRAS、RAF1和SHOC2基因变异的患者智商显著较低,但未发现特定的认知障碍。较年轻参与者(<16岁)的表现与成年人无差异。述情障碍和内化问题在携带PTPN11和SOS1基因变异的患者中更为常见,而携带PTPN11基因变异的患者还表现出较高水平的外化问题。这些结果强调,在个体神经心理学评估中解释较低的认知表现时需要考虑智力因素,这对于充分理解和指导NSSD患者至关重要。

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