Curie Aurore, Nazir Tatjana, Brun Amandine, Paulignan Yves, Reboul Anne, Delange Karine, Cheylus Anne, Bertrand Sophie, Rochefort Fanny, Bussy Gérald, Marignier Stéphanie, Lacombe Didier, Chiron Catherine, Cossée Mireille, Leheup Bruno, Philippe Christophe, Laugel Vincent, De Saint Martin Anne, Sacco Silvia, Poirier Karine, Bienvenu Thierry, Souville Isabelle, Gilbert-Dussardier Brigitte, Bieth Eric, Kauffmann Didier, Briot Philippe, de Fréminville Bénédicte, Prieur Fabienne, Till Michel, Rooryck-Thambo Caroline, Mortemousque Isabelle, Bobillier-Chaumont Isabelle, Toutain Annick, Touraine Renaud, Sanlaville Damien, Chelly Jamel, Freeman Sonya, Kong Jian, Hadjikhani Nouchine, Gollub Randy L, Roy Alice, des Portes Vincent
Centre de Référence « Déficiences Intellectuelles de Causes Rares », Hôpital Femme Mère Enfant, Hospices Civils de Lyon, F-69677 Bron, France.
Orphanet J Rare Dis. 2014 Feb 14;9:25. doi: 10.1186/1750-1172-9-25.
The c.429_452dup24 of the ARX gene is a rare genetic anomaly, leading to X-Linked Intellectual Disability without brain malformation. While in certain cases c.429_452dup24 has been associated with specific clinical patterns such as Partington syndrome, the consequence of this mutation has been also often classified as "non-specific Intellectual Disability". The present work aims at a more precise description of the clinical features linked to the c.429_452dup24 mutation.
We clinically reviewed all affected patients identified in France over a five-year period, i.e. 27 patients from 12 different families. Detailed cognitive, behavioural, and motor evaluation, as well as standardized videotaped assessments of oro-lingual and gestural praxis, were performed. In a sub-group of 13 ARX patients, kinematic and MRI studies were further accomplished to better characterize the motor impairment prevalent in the ARX patients group. To ensure that data were specific to the ARX gene mutation and did not result from low-cognitive functioning per se, a group of 27 age- and IQ-matched Down syndrome patients served as control.
Neuropsychological and motor assessment indicated that the c.429_452dup24 mutation constitutes a recognizable clinical syndrome: ARX patients exhibiting Intellectual Disability, without primary motor impairment, but with a very specific upper limb distal motor apraxia associated with a pathognomonic hand-grip. Patients affected with the so-called Partington syndrome, which involves major hand dystonia and orolingual apraxia, exhibit the most severe symptoms of the disorder. The particular "reach and grip" impairment which was observed in all ARX patients, but not in Down syndrome patients, was further characterized by the kinematic data: (i) loss of preference for the index finger when gripping an object, (ii) major impairment of fourth finger deftness, and (iii) a lack of pronation movements. This lack of distal movement coordination exhibited by ARX patients is associated with the loss of independent digital dexterity and is similar to the distortion of individual finger movements and posture observed in Limb Kinetic Apraxia.
These findings suggest that the ARX c.429_452dup24 mutation may be a developmental model for Limb Kinetic Apraxia.
ARX基因的c.429_452dup24是一种罕见的基因异常，会导致无脑部畸形的X连锁智力障碍。虽然在某些情况下，c.429_452dup24与特定的临床模式相关，如帕廷顿综合征，但这种突变的后果也常被归类为“非特异性智力障碍”。本研究旨在更精确地描述与c.429_452dup24突变相关的临床特征。
我们对法国在五年期间确诊的所有受影响患者进行了临床评估，即来自12个不同家庭的27名患者。进行了详细的认知、行为和运动评估，以及对口-舌和手势运用的标准化录像评估。在13名ARX患者的亚组中，进一步完成了运动学和MRI研究，以更好地描述ARX患者组中普遍存在的运动障碍特征。为确保数据是ARX基因突变所特有的，而非源于本身认知功能低下，一组年龄和智商匹配的27名唐氏综合征患者作为对照。
神经心理学和运动评估表明，c.429_452dup24突变构成一种可识别的临床综合征：ARX患者表现出智力障碍，无原发性运动障碍，但伴有非常特殊的上肢远端运动失用症，并伴有特征性的握力异常。患有所谓帕廷顿综合征（涉及严重手部肌张力障碍和口-舌失用症）的患者表现出该疾病最严重的症状。在所有ARX患者中观察到但在唐氏综合征患者中未观察到的特殊“抓握”障碍，通过运动学数据进一步表征为：（i）抓握物体时对食指的偏好丧失，（ii）无名指灵活性严重受损，以及（iii）旋前运动缺乏。ARX患者表现出的这种远端运动协调缺乏与独立手指灵活性丧失有关，并且类似于肢体运动性失用症中观察到的单个手指运动和姿势的扭曲。
这些发现表明，ARX基因的c.429_452dup24突变可能是肢体运动性失用症的一种发育模型。
