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.

Figure 1

Kinematic task (set-up and kinematic parameters).

Figure 2

Oro-lingual and gestural scores in 21 ARX mutated patients compared to 21 age-matched DS patients: 4 ARX patients (red lines) showed the most severe forms, with global scores below 1 for gestural and oro-lingual praxis; 15 ARX patients (blue, green and pink lines) had global scores between 1 and 2.5 with respect to oro-lingual and/or gestural praxis; 3 (green) had a predominantly gestural praxis impairment (difference between the two scores of more than 1), and 2 (pink) had a predominantly oro-lingual praxis impairment; the remaining 2 patients (dark blue) exhibited milder forms with scores just above 3.

Figure 3

Pen holding in ARX patients.

Figure 4

Significant interaction between the factor ‘group’ and the within factor ‘effector’ (fingers vs limb) on the De Renzi scale: ARX patients were much more impaired on independent fingers movements than on global limb movements (*p < 0.05; ****p < 0.0001).

Figure 5

Kinematic results. a: Significant [object orientation*group] interaction on acceleration peak amplitude [F(2,32) = 3.45, p < 0.05]: a significant orientation effect was observed in healthy controls and DS patients but not in ARX patients; b: Significant [Pinch*group] interaction on MGA latency [F(4,64) = 7.06, p < 0.001]: ARX patients were impaired in using the thumb-fourth finger pinch; c: Significant positive correlation between the velocity peak amplitude with the thumb-index pinch at +56° and the De Renzi’s finger score.