The Partington syndrome: a clinically recognizable disorder that includes all patients with a c.429_452dup24 of the ARX gene
The present study provides detailed clinical and neuropsychological data on 27 patients from 12 French families; all patients have been diagnosed with the same c.429_452dup24 mutation in the
ARX gene between 2002 and 2006. The clinical features described in this series constitute a recognizable clinical syndrome specific to the c.429_452dup24 of
ARX, which is useful for the diagnosis of unexplained mental retardation, even in sporadic cases. The present series is the first to describe the cognitive profile and specific motor impairments shared by all 27
ARX patients and demonstrates the existence of a pleiotropy. Patients with milder forms, who were erroneously labelled “non specific ID”, exhibit atypical handling and/or articulation impairment. Patients with the most severe form, already known as Partington syndrome, exhibit hand dystonia and/or anarthria [
21]. In light of this spectrum of severity, we propose to consider the term of “Partington syndrome” for all patients affected with this mutation, to acknowledge M.W. Partington who first described the more severely impaired patients.
We report slightly lower epilepsy prevalence in our group (33%) compared to 45% in the Australian series [
24]. The seizures exhibited by
ARX patients in our study were of various types: tonic-clonic or complex partial seizures, mainly sensitive to current antiepileptic drugs. The frequency of infantile spasms (West syndrome) was 11% in our series, which is concordant with the 12.5% rate observed in the Australian series [
24]. Response to corticosteroids appeared to be good if treated early, in contrast with infantile spasms associated with the c.333ins(GCG)
7, which are usually drug resistant [
14,
15].
All ARX patients exhibited mild to severe orolingual dyspraxia. A fifth of ARX patients had very severe language impairment, either due to low cognitive level or to speech apraxia.
With regard to motor assessment, no true pyramidal syndrome was observed in ARX patients. This clinical sparing of the pyramidal tracts, contrasting with the major dystonic posture in some patients, is concordant with the expression pattern of ARX. Indeed, ARX is expressed in GABAergic neurons and is involved in tangential migration of GABAergic neurons from the telencephalon but not in radially migrating neurons, which gives rise to pyramidal neurons in the cortical plate.
As there is a positive correlation between the handedness of a child and the handedness of its biological parents [
43], we chose to compare the
ARX patients to the healthy controls (males) from their families. We reported a higher frequency of strong left-handedness in
ARX patients compared to healthy controls and DS patients. In the literature, the great majority (90%) of the human population is right-handed [
44]. This percentage contrasts with the one found in
ARX patients (70%). The ontogenesis of handedness is usually thought as a multifactorial model [
45]. ARX being a transcription factor expressed early in brain during the development, it could be interesting to test if ARX can regulate some of the 27 genes identified as asymmetrically expressed in the left and right hemisphere of 12-week-old human fetal brains [
46].
The particular “reach and grip” impairment, which was observed in all ARX patients, was further characterized by the videotaped scale and kinematic data. Comparison of ARX patients and age-matched DS patients was useful in distinguishing between motor problems due to intellectual deficit and distortions linked to a specific ARX profile. For instance, both ARX and DS patients had lower acceleration and velocity peak amplitudes compared to age-matched healthy controls. This finding was most likely related to the Intellectual Disability of ARX and DS patients. However, all other parameters that were impaired in ARX patients were spared in DS patients.
Three key features affecting digits, hands, wrist and forearm movements are shared by
ARX patients:
(i)
Loss of preference of the index finger for grasping.
Ninety-five percent of the
ARX patients in our series held a pen in a very specific way, between the lateral sides of the index and middle fingers, with the pen leaning upon the thumb’s proximal phalanx, without directly contacting the pulp of the fingers. Turner described this way of holding the pen as an “odd posture” of the hand in two unrelated families [
30]. When they were presented with our kinematic task,
ARX patients had significantly greater velocity peak amplitudes with the thumb-middle finger pinch than with the thumb-index finger pinch. This preference for the middle finger instead of the index was not observed in age-matched healthy controls and DS patients.
By studying the precision grasps of small beads of different sizes in 48 healthy children and 90 adults, Wong and Whishaw [
47] described a high degree of variability in digit contact strategies, purchase patterns, and posture of the non grasping digits, depending on bead and hand size. However, a lateral grip missing any pulp contact of either the index or the thumb, such as observed in our
ARX population, was never noticed. Similarly, among the various purchase strategies described, the use of the thumb and the middle finger, skipping the index, was very uncommon and considered improper. Conversely, the thumb-index pincer was used in more than 90% when grasping smaller beads, which were much more difficult to purchase [
47].
(ii)
Major impairment of fourth and fifth fingers deftness
It is interesting to note that the unusual grip posture spontaneously observed during the infancy of
ARX patients by their parents (“pinch with three fingers” with a more important use of the major and no use of the 4
th and 5
th finger), persisted during adulthood, in an even more discrete way, as demonstrated in the kinematic study. In age-matched healthy controls and DS patients, the difficulty induced by the use of the thumb- fourth finger pinch, which is unusual, did not have any impact on the movement duration. By contrast,
ARX patients took significantly more time to perform the movement with the thumb-fourth finger pinch than with the thumb-middle finger. Furthermore, the MGA latency for the thumb-fourth finger pinch was much more pronounced in
ARX patients than in controls. In addition, only nine out of the thirteen
ARX patients were able to complete the task with the thumb- fourth finger pinch though they completed the task utilizing the two other types of pinch without much trouble.
(iii)
Lack of pronation/supination movements of the wrist and forearm.
In age-matched healthy controls and DS patients, but not in
ARX patients, we found an orientation effect on both transport and grasp components. The +56° condition has been shown to be the easiest orientation for grasping an object [
48]. At −56°, the movement duration was longer, the MGA occurred later and was smaller. This data suggests that the −56° condition was a more difficult orientation for grasping and required more fine motor control [
49‐
51]. Acceleration and velocity peak amplitudes were higher at −56°. It is likely that the increase of acceleration and velocity peak amplitudes at −56° in healthy controls and DS patients compared to
ARX patients is related to the pronation movement used by the DS and healthy controls to grasp the object at −56°.
ARX patients did not show such an effect on either transport parameters or grasp parameters. In fact,
ARX patients elevated their elbows rather than pronating their wrist in order to grasp the object at −56°. This observation is consistent with the finding that
ARX patients exhibited impaired performances of rapid movements of pronation and supination of the wrist.
The term “focal dystonia” has often been used to describe the very specific hand grip of patients affected with Partington syndrome. However, the general definition of dystonia requires simultaneous co-contraction of agonist and antagonist muscles, leading to sustained hypertonia. In
ARX patients, by contrast, weakness of muscles has been seen (but not stiffness) with a spontaneous position of the wrist at rest in a limp flexed position, both in the present and in past studies [
24]. This awkward position at rest, which could have been mistaken for unusual hand mannerisms, does not fit with the definition of focal dystonia, which occurs during voluntary movement.
Partington syndrome, a developmental model of Limb Kinetic Apraxia (LKA)
The term apraxia indicates an inability to perform purposeful movements in the absence of sensory-motor deficits or impaired understanding of what is required [
52]. Classically, three types of limb apraxia have been identified: the ideational apraxia (patients do not know what to do), the ideomotor apraxia (patients know what to do but not how to do it), and Limb-Kinetic Apraxia (LKA) [
52‐
54]. LKA was defined one century ago by Kleist, as “a loss of hand and finger dexterity resulting from inability to connect or isolate individual finger movements” [
55]. The De Renzi upper-limb apraxia scale has been developed to distinguish LKA from ideomotor apraxia [
35]. In our study, DS and
ARX patients both exhibited a significant rate of ‘sequence’ errors, likely related to a common disability in motor programming resulting from their Intellectual Disability. Specifically, DS patients had significantly higher scores on the De Renzi scale than the
ARX patients, and no DS patient scored below the pathological range for apraxia. Conversely, none of the
ARX patients reached the minimum normal score, and 75% scored in the pathological range for apraxia. Furthermore, only
ARX patients exhibited a high rate of awkwardness and spatial errors, similar to patients affected with LKA associated with CorticoBasal Degeneration (CBD) [
35]. Interestingly,
ARX patients fulfil two major clinical criteria for LKA diagnosis [
54]: (i) impaired, coarse execution of simple movements of the hand, more evident distally than proximally and most notable for incoordination between fingers. It is striking to see how
ARX patients were much more impaired in assessment of distal movement, which demanded independent finger movements, compared with more global movement, which involved the whole superior limb; (ii) impairment of all movements, i.e. symbolic/non symbolic, transitive/intransitive.
ARX patients were similarly impaired in their performance of symbolic or non-symbolic gestures, and in holding a position or carrying out motor sequences. The core deficit in LKA is a distortion of individual finger movements and posture, similar to the peculiar
ARX patients’ grasping behaviour. In addition,
ARX patients exhibit buccofacial apraxia or at least tongue and lips movement impairment, as observed in patients with corticobasal degeneration [
56,
57].
The so called “LKA” observed in
ARX subjects is a unique form of LKA for several reasons:
ARX-related apraxia is (i) a “pure” LKA, without bradykinesia, rigidity and dystonia, three movement impairments commonly seen in corticobasal degeneration [
54], allowing a better analysis of LKA pathophysiology; (ii) a bilateral LKA, by contrast with LKA in CBD which is mainly unilateral [
54]; (iii) a developmental impairment observed as soon as in infancy, without obvious worsening with aging on retrospective data.
The pathophysiology of LKA suggests an impaired cortical inhibition for selection and control of hand muscular activity [
53] and may be the result of loss of cortical inhibitory interneurons either in the frontal lobe or in the basal ganglia in CBD [
53]. In Parkinson disease, the LKA seems also to be related to cortico-basal ganglia network dysfunction [
58]. Since ARX is mainly expressed in inhibitory GABAergic interneurons of the developing cortex and striatum [
59], a similar mechanism might be suggested in
ARX mutated patients.
Visual inspection of the brain MRI of
ARX patients did not reveal major basal ganglia abnormalities. The mild cystic images observed in most
ARX patients located just beneath the putamen have the signal characteristics of CSF on MRI (Hyper T2, Hypo T1 and FLAIR images) and represent most probably a simple enlargement of the Virshow-Robin spaces along the lenticulo-striatal vessels. Nevertheless, it is questionable that obvious prominent cysts were already described in the posterior putamen of patients carrying the c.333ins(GCG)
7 in the first polyalanine tract of the
ARX gene [
14]. Moreover, neuropathologic studies of the brain in newborn males affected with the XLAG syndrome (lack of ARX protein) show poorly delineated and atrophic basal ganglia and multiple small cavitations [
5]. Besides, ARX has a major role in regulating basal ganglia differentiation in mice [
60,
61]. Interestingly, there was no difference in vermis height between
ARX patients and healthy controls, while DS had a significantly smaller vermis compared to both groups. The normal cerebellar structure is concordant with the lack of expression of the
ARX gene in the cerebellum [
1] and good gross motor skills of
ARX patients.