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The c.429_452 duplication of the ARX gene: a unique developmental-model of limb kinetic apraxia.

ABSTRACT: BACKGROUND: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. METHODS: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. RESULTS: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. CONCLUSION:These findings suggest that the ARX c.429_452dup24 mutation may be a developmental model for Limb Kinetic Apraxia.

SUBMITTER: Curie A

PROVIDER: S-EPMC4016261 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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The c.429_452 duplication of the ARX gene: a unique developmental-model of limb kinetic apraxia.

Curie Aurore A Nazir Tatjana T Brun Amandine A Paulignan Yves Y Reboul Anne A Delange Karine K Cheylus Anne A Bertrand Sophie S Rochefort Fanny F Bussy Gérald G Marignier Stéphanie S Lacombe Didier D Chiron Catherine C Cossée Mireille M Leheup Bruno B Philippe Christophe C Laugel Vincent V De Saint Martin Anne A Sacco Silvia S Poirier Karine K Bienvenu Thierry T Souville Isabelle I Gilbert-Dussardier Brigitte B Bieth Eric E Kauffmann Didier D Briot Philippe P de Fréminville Bénédicte B Prieur Fabienne F Till Michel M Rooryck-Thambo Caroline C Mortemousque Isabelle I Bobillier-Chaumont Isabelle I Toutain Annick A Touraine Renaud R Sanlaville Damien D Chelly Jamel J Freeman Sonya S Kong Jian J Hadjikhani Nouchine N Gollub Randy L RL Roy Alice A des Portes Vincent V

Orphanet journal of rare diseases 20140214

<h4>Background</h4>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.<h4>Me ...[more]

PMID: 24528893

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Project description:Influential theories of skilled action posit that distinct cognitive mechanisms and neuroanatomic substrates support meaningless gesture imitation and tool use pantomiming, and poor performance on these tasks are hallmarks of limb apraxia. Yet prior research has primarily investigated brain-behavior relations at the group level; thus, it is unclear whether we can identify individuals with isolated impairments in meaningless gesture imitation or tool use pantomiming whose performance is associated with a distinct neuroanatomic lesion profile. The goal of this study was to test the hypothesis that individuals with disproportionately worse performance in meaningless gesture imitation would exhibit cortical damage and white matter disconnection in left fronto-parietal brain regions, whereas individuals with disproportionately worse performance in tool use pantomiming would exhibit cortical damage and white matter disconnection in left temporo-parietal brain regions. Fifty-eight participants who experienced a left cerebrovascular accident took part in a meaningless gesture imitation task, a tool use pantomiming task, and a T1 structural MRI. Two participants were identified who had relatively small lesions and disproportionate impairments on one task relative to the other, as well as below-control-level performance on one task and not the other. Using these criteria, one participant was disproportionately impaired at meaningless gesture imitation, and the other participant was disproportionately impaired at pantomiming tool use. Graph theoretic analysis of each participant's structural disconnectome demonstrated that disproportionately worse meaningless gesture imitation performance was associated with disconnection among the left inferior parietal lobule, the left superior parietal lobule, and the left middle and superior frontal gyri, whereas disproportionately worse tool use pantomiming performance was associated with disconnection between left temporal and parietal regions. Our results demonstrate that relatively focal lesions to specific portions of the Tool Use Network can be associated with distinct limb apraxia subtypes.

Dataset Information

The c.429_452 duplication of the ARX gene: a unique developmental-model of limb kinetic apraxia.

Publications

The c.429_452 duplication of the ARX gene: a unique developmental-model of limb kinetic apraxia.

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