BackgroundAdenylyl cyclase 5 (ADCY5) mutations is associated with heterogenous syndromes: familial dyskinesia and facial myokymia; paroxysmal chorea and dystonia; autosomal‐dominant chorea and dystonia; and benign hereditary chorea. We provide detailed clinical data on 7 patients from six new kindreds with mutations in the ADCY5 gene, in order to expand and define the phenotypic spectrum of ADCY5 mutations.MethodsIn 5 of the 7 patients, followed over a period of 9 to 32 years, ADCY5 was sequenced by Sanger sequencing. The other 2 unrelated patients participated in studies for undiagnosed pediatric hyperkinetic movement disorders and underwent whole‐exome sequencing.ResultsFive patients had the previously reported p.R418W ADCY5 mutation; we also identified two novel mutations at p.R418G and p.R418Q. All patients presented with motor milestone delay, infantile‐onset action‐induced generalized choreoathetosis, dystonia, or myoclonus, with episodic exacerbations during drowsiness being a characteristic feature. Axial hypotonia, impaired upward saccades, and intellectual disability were variable features. The p.R418G and p.R418Q mutation patients had a milder phenotype. Six of seven patients had mild functional gain with clonazepam or clobazam. One patient had bilateral globus pallidal DBS at the age of 33 with marked reduction in dyskinesia, which resulted in mild functional improvement.ConclusionWe further delineate the clinical features of ADCY5 gene mutations and illustrate its wide phenotypic expression. We describe mild improvement after treatment with clonazepam, clobazam, and bilateral pallidal DBS. ADCY5‐associated dyskinesia may be under‐recognized, and its diagnosis has important prognostic, genetic, and therapeutic implications. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society

Writer's cramp is a focal hand dystonia that specifically affects handwriting. Though writer's cramp has been attributed to a dysfunction of the basal ganglia, the role of the basal ganglia in the pathogenesis of writer's cramp remains to be determined. Seventeen patients with writer's cramp (nine females; age range: 24-71 years) and 17 healthy individuals (six females; age range: 27-68 years) underwent functional MRI (fMRI) while they discriminated the orientation of gratings delivered to the tip of the right index finger. Statistical parametric mapping was used to analyse the fMRI data. The significance level was set at a corrected P-value of 0.05. Relative to healthy controls, patients with writer's cramp showed a widespread bilateral increase in task-related activity in the putamen, caudate nucleus, internal globus pallidus and lateral thalamus. In these areas, hyperactivity was more pronounced in patients who had recently developed writer's cramp. The enhanced response of the basal ganglia to tactile input from the affected hand is compatible with the concept of impaired centre-surround inhibition within the basal ganglia-thalamic circuit and may lead to an excessive activation of sensorimotor cortical areas during skilled movements affected by dystonia. Outside the basal ganglia, dystonic patients showed task-related overactivity in visual cortical areas, left anterior insula and right intraparietal sulcus, but not in the primary or secondary sensory cortex. In addition, task-related activity in the cerebellar nuclei, posterior vermis, right paramedian cerebellar hemisphere and dorsal pons was inversely related with the severity of hand dystonia. Regional activity in these areas may reflect secondary adaptive reorganization at the systems level to compensate for the dysfunction in the basal ganglia-thalamic loop.

Objectives-To characterise the pattern of and risk factors for degenerative changes of the cervical spine in patients with spasmodic torticollis and to assess whether these changes aVect outcome after selective peripheral denervation. Methods-Preoperative CT of the upper cervical spine of 34 patients with spasmodic torticollis referred for surgery were reviewed by two radiologists blinded to the clinical findings. Degenerative changes were assessed for each joint separately and rated as absent, minimal, moderate, or severe. Patients were clinically assessed before surgery and 3 months postoperatively by an independent examiner using standardised clinical rating scales. For comparison of means a t test was carried out. To determine whether an association exists between the side of degenerative changes and type of spasmodic torticollis a 2 test was used. Changes in severity, disability, and pain before and after surgery were calculated using a Wilcoxon matched pairs signed ranks test. Results-Fourteen out of 34 patients had moderate or severe degenerative changes. They were predominantly found at the C2/C3 and C3/C4 level and were significantly more likely to occur on the side of the main direction of the spasmodic torticollis (p=0.015). There was no significant diVerence in age, sex, duration of torticollis, overall severity, degree of disability, or pain between the group with either no or minimal changes and the group with moderate or severe changes. However, in the second group the duration of inadequate treatment was longer (10.1 v 4.8 years; p=0.009), head mobility was more restricted (p=0.015), and head tremor was more severe (p=0.01). At 3 months postoperatively, patients with no or minimal degenerative changes showed a significant improvement in pain and severity whereas no diVerence was found in those with moderate or severe changes. Conclusions-Patients with spasmodic torticollis have an increased risk of developing premature degenerative changes of the upper cervical spine that tend to be on the side towards which the head is turned or tilted and compromise outcome after surgery. EVective early treatment of spasmodic torticollis with botulinum toxin seems to have a protective eVect. Patients with spasmodic torticollis and restricted head mobility who do not adequately respond to treatment should undergo imaging of the upper cervical spine. Patients with imaging evidence of moderate or severe degenerative changes seem to respond poorly to selective peripheral denervation. (J Neurol Neurosurg Psychiatry 2000;68:465-471)

It was reported recently that specific features in the frequency analysis of electromyographic (EMG) activity in the sternocleidomastoid (SCM) and splenius (SPL) muscles were able to distinguish between rotational idiopathic cervical dystonia (CD) and voluntary torticollis in individual subjects. Those with CD showed an abnormal drive to muscles at 5 to 7 Hz and an absence of the normal 10 to 12 Hz peak in the autospectrum of SPL. We sought to determine whether the same abnormalities in the frequency domain are found in complex CD, in which the head is displaced in more than two planes. EMG activity was recorded in the SCM, SPL, trapezius, and levator scapulae muscles bilaterally in 10 patients with complex CD. Frequency analysis of EMG was compared with conventional clinical and polymyographic assessment. The autospectrum of SPL during free dystonic contraction showed an absence of a significant peak at 10 to 12 Hz in 8 of the 10 patients. The presence of a 5 to 7 Hz frequency drive showed a significant association with muscle pairs determined as dystonic by means of polymyography (P< 0.005). The neck posture predicted blindly, based on the low-frequency drive, correlated significantly with the clinical assessment of posture (P < 0.01). Conventional assessment and the results of frequency analysis correlated, suggesting that a low-frequency drive to neck muscle may be a general feature of simple rotational and more complex cervical dystonia. The pattern of coherence between the EMG in different neck muscles may provide a means of identifying leading dystonic muscles, especially in patients with complex cervical dystonia.

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