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

Curie A, Nazir T, Brun A, Paulignan Y, Reboul A, Delange K, Cheylus A, Bertrand S, Rochefort F, Bussy G, Marignier S, Lacombe D, Chiron C, Cossée M, Leheup B, Philippe C, Laugel V, De Saint Martin A, Sacco S, Poirier K, Bienvenu T, Souville I, Gilbert-Dussardier B, Bieth E, Kauffmann D, Briot P, de Fréminville B, Prieur F, Till M, Rooryck-Thambo C, Mortemousque I, Bobillier-Chaumont I, Toutain A, Touraine R, Sanlaville D, Chelly J, Freeman S, Kong J, Hadjikhani N, Gollub RL, Roy A, des Portes V - Orphanet J Rare Dis (2014)

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Centre de Référence « Déficiences Intellectuelles de Causes Rares », Hôpital Femme Mère Enfant, Hospices Civils de Lyon, F-69677 Bron, France. aurorecurie@yahoo.fr.

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.

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Related in: MedlinePlus

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).
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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).

Mentions: A statistically significant group effect between ARX and DS patients was seen for the global score and all sub-tests of the De Renzi upper-limb apraxia scale with better scores for DS patients (Table 1). The ANOVA showed a significant effect of the factor ‘group’ (ARX vs. DS) but also an interaction between the factor ‘group’ and the within factor ‘effector’ (finger vs. limb), emphasizing a particular difficulty that ARX patients have with distal movements that require independent movement of the fingers, compared to limb movements (Figure 4, p = 0.016). The analysis of the type of error made for this test revealed that both groups of patients made sequential gesture errors, but ARX patients were significantly more clumsy (p < 0.05) and made more spatial errors (p < 0.001). Interestingly, ARX patients exhibited similar impairment when performing symbolic and non symbolic gestures, as well as when holding a position or executing motor sequences. Family-weighted ‘Global’, ‘Fingers’ and ‘Limb’ scores for the de Renzi scale were also significantly higher for DS patients than for ARX patients (Mann and Whitney, p = 0.007, p = 0.009 and p = 0.03 respectively).


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

Curie A, Nazir T, Brun A, Paulignan Y, Reboul A, Delange K, Cheylus A, Bertrand S, Rochefort F, Bussy G, Marignier S, Lacombe D, Chiron C, Cossée M, Leheup B, Philippe C, Laugel V, De Saint Martin A, Sacco S, Poirier K, Bienvenu T, Souville I, Gilbert-Dussardier B, Bieth E, Kauffmann D, Briot P, de Fréminville B, Prieur F, Till M, Rooryck-Thambo C, Mortemousque I, Bobillier-Chaumont I, Toutain A, Touraine R, Sanlaville D, Chelly J, Freeman S, Kong J, Hadjikhani N, Gollub RL, Roy A, des Portes V - Orphanet J Rare Dis (2014)

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).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4016261&req=5

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).
Mentions: A statistically significant group effect between ARX and DS patients was seen for the global score and all sub-tests of the De Renzi upper-limb apraxia scale with better scores for DS patients (Table 1). The ANOVA showed a significant effect of the factor ‘group’ (ARX vs. DS) but also an interaction between the factor ‘group’ and the within factor ‘effector’ (finger vs. limb), emphasizing a particular difficulty that ARX patients have with distal movements that require independent movement of the fingers, compared to limb movements (Figure 4, p = 0.016). The analysis of the type of error made for this test revealed that both groups of patients made sequential gesture errors, but ARX patients were significantly more clumsy (p < 0.05) and made more spatial errors (p < 0.001). Interestingly, ARX patients exhibited similar impairment when performing symbolic and non symbolic gestures, as well as when holding a position or executing motor sequences. Family-weighted ‘Global’, ‘Fingers’ and ‘Limb’ scores for the de Renzi scale were also significantly higher for DS patients than for ARX patients (Mann and Whitney, p = 0.007, p = 0.009 and p = 0.03 respectively).

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Centre de Référence « Déficiences Intellectuelles de Causes Rares », Hôpital Femme Mère Enfant, Hospices Civils de Lyon, F-69677 Bron, France. aurorecurie@yahoo.fr.

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.

Show MeSH
Related in: MedlinePlus