Centre de Référence Déficiences Intellectuelles de Causes Rares, Hôpital Femmes Mères Enfants, Hospices Civils de Lyon, Bron, France; CNRS UMR5304, Institut des Sciences Cognitives, Bron, France; Université Claude Bernard Lyon 1, France; Psychiatric Neuroimaging Program, Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.
Inserm UMR1078, Université de Brest, IBSAM, Brest, France; Etablissement Français du Sang (EFS), Bretagne, France; CHU Brest, Brest, France.
Neuroimage Clin. 2018 Apr 5;19:454-465. doi: 10.1016/j.nicl.2018.04.001. eCollection 2018.
The () gene was identified in 2002 as responsible for XLAG syndrome, a lissencephaly characterized by an almost complete absence of cortical GABAergic interneurons, and for milder forms of X-linked Intellectual Disability (ID) without apparent brain abnormalities. The most frequent mutation found in the gene, a duplication of 24 base pairs (c.429_452dup24) in exon 2, results in a recognizable syndrome in which patients present ID without primary motor impairment, but with a very specific upper limb distal motor apraxia associated with a pathognomonic hand-grip, described as developmental Limb Kinetic Apraxia (LKA). In this study, we first present expression during human fetal brain development showing that it is strongly expressed in GABAergic neuronal progenitors during the second and third trimester of pregnancy. We show that although expression strongly decreases towards the end of gestation, it is still present after birth in some neurons of the basal ganglia, thalamus and cerebral cortex, suggesting that ARX also plays a role in more mature neuron functioning. Then, using morphometric brain MRI in 13 patients carrying c.429_452dup24 mutation and in 13 sex- and age-matched healthy controls, we show that patients have a significantly decreased volume of several brain structures including the striatum (and more specifically the caudate nucleus), hippocampus and thalamus as well as decreased precentral gyrus cortical thickness. We observe a significant correlation between caudate nucleus volume reduction and motor impairment severity quantified by kinematic parameter of precision grip. As basal ganglia are known to regulate sensorimotor processing and are involved in the control of precision gripping, the combined decrease in cortical thickness of primary motor cortex and basal ganglia volume in dup24 patients is very likely the anatomical substrate of this developmental form of LKA.
ARX 基因于 2002 年被确定为 XLAG 综合征的致病基因，该综合征表现为脑回无脑回畸形，皮质 GABA 能中间神经元几乎完全缺失，并伴有轻度 X 连锁智力障碍（ID），无明显的脑异常。在 ARX 基因中发现的最常见的突变是外显子 2 中的 24 个碱基对（c.429_452dup24）重复，导致可识别的综合征，患者表现为 ID 而无主要运动障碍，但存在非常特异性的上肢远端运动性失用症，伴有特征性的手抓握，称为发育性肢体运动性失用症（LKA）。在这项研究中，我们首先展示了人类胎儿大脑发育过程中的 ARX 表达，表明它在妊娠的第二和第三个三个月强烈表达于 GABA 能神经元祖细胞。我们表明，尽管 ARX 表达在妊娠末期强烈下降，但它在出生后仍存在于基底节、丘脑和大脑皮层的一些神经元中，这表明 ARX 也在更成熟的神经元功能中发挥作用。然后，我们使用携带 c.429_452dup24 突变的 13 名患者和 13 名性别和年龄匹配的健康对照者的形态计量脑 MRI，表明 ARX 患者的几个脑结构的体积明显减小，包括纹状体（特别是尾状核）、海马体和丘脑，以及中央前回皮质厚度减小。我们观察到尾状核体积减少与运动障碍严重程度之间存在显著相关性，该运动障碍严重程度通过精准抓握的运动学参数来量化。由于基底节已知调节感觉运动处理并参与精准抓握的控制，因此 ARX dup24 患者的初级运动皮层和基底节体积的皮质厚度的联合减少很可能是这种发育性 LKA 的解剖学基础。
