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.

• Authors: Aurore Curie, Tatjana Nazir, Amandine Brun, Yves Paulignan, Anne Reboul, Karine Delange, Anne Cheylus, Sophie Bertrand, Fanny Rochefort, Gérald Bussy, Stéphanie Marignier, Didier Lacombe, Catherine Chiron, Mireille Cossée, Bruno Leheup, Christophe Philippe, Vincent Laugel, Anne De Saint Martin, Silvia Sacco, Karine Poirier, Thierry Bienvenu, Isabelle Souville, Brigitte Gilbert-Dussardier, Eric Bieth, Didier Kauffmann, Philippe Briot, Bénédicte de Fréminville, Fabienne Prieur, Michel Till, Caroline Rooryck-Thambo, Isabelle Mortemousque, Isabelle Bobillier-Chaumont, Annick Toutain, Renaud Touraine, Damien Sanlaville, Jamel Chelly, Sonya Freeman, Jian Kong, Nouchine Hadjikhani, Randy L Gollub, Alice Roy, Vincent des Portes
• Journal: Orphanet journal of rare diseases (Orphanet J Rare Dis) Vol. 9 Pg. 25 (Feb 14 2014) ISSN: 1750-1172 [Electronic] England
• PMID: 24528893 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ARX protein, human
• Homeodomain Proteins
• Transcription Factors

Topics

• Adolescent
• Adult
• Apraxias (genetics)
• Biomechanical Phenomena
• Case-Control Studies
• Child
• Down Syndrome (physiopathology)
• Extremities (physiopathology)
• Gene Duplication
• Homeodomain Proteins (genetics)
• Humans
• Models, Biological
• Mutation
• Transcription Factors (genetics)
• Young Adult