Frequency and phenotypic spectrum of KMT2B dystonia in childhood: A single‐center cohort study

Background: Childhood-onset dystonia is often genetically determined. Recently, KMT2B variants have been recognized as an important cause of childhood-onset dystonia. Objective: To define the frequency of KMT2B mutations in a cohort of dystonic patients aged less than 18 years at onset, the associated clinical and radiological phenotype, and the natural history of disease. Methods: Whole-exome sequencing or customized gene panels were used to screen a cohort of sixty-five patients who had previously tested negative for all other known dystonia-associated genes. Results: We identified fourteen patients (21.5%) carrying KMT2B variants, of which one was classified as a Variant of Unknown Significance (VUS). We also identified two additional patients carrying pathogenic mutations in GNAO1 and ATM. Overall, we established a definitive genetic diagnosis in 23% of cases. We observed a spectrum of clinical manifestations in KMT2B variant carriers, ranging from generalized dystonia to short stature or intellectual disability alone, even within the same family. In 78.5% of cases, dystonia involved the lower limbs at onset, with later caudo-cranial generalization. Eight patients underwent pallidal Deep Brain Stimulation with a median decrease of BFMDRS-M score of 38.5% in the long term. We also report four asymptomatic carriers, suggesting that some KMT2B mutations may be associated with incomplete disease penetrance. Conclusions: KMT2B mutations are frequent in childhood-onset dystonia and cause a complex neurodevelopmental syndrome often featuring growth retardation and intellectual disability as additional phenotypic features. A dramatic and long-lasting response to Deep Brain Stimulation is characteristic of DYT-KMT2B dystonia

Use of botulinum toxin type A in the management of patients with neurological disorders: a national survey.

The aim of this survey was to provide an overview of important issues relating to therapeutic strategies based on botulinum toxin type A injection for the treatment of patients with neurological disorders. Two hundred and ten physicians from neurology and neurorehabilitation units in Italian hospitals answered a questionnaire exploring some clinical aspects of the use of botulinum toxin type A in patients with spasticity/dystonia. 66% of the physicians treated patients with dystonia, 80% treated adults with spasticity, and 35% treated children with cerebral palsy. Palpation with no instrumental guidance was the injection technique most commonly used for treating patients with dystonia, spasticity and cerebral palsy; 57% of the physicians evaluated patients instrumentally before toxin injection, while 45% assessed postinjection improvements by instrumental means; 78% of the physicians prescribed (when appropriate) rehabilitation procedures after toxin injection. Our results seem to show that the routine use of botulinum toxin in clinics is far from standardized

Bilateral high frequency subthalamic stimulation in Parkinson's disease: long-term neurological follow-up.

High frequency stimulation of the subthalamic nucleus (STN) is gaining recognition as a new symptomatic treatment for Parkinson's disease (PD). The first available long-term observations show the stability of the efficacy of this procedure in time.Quadripolar leads were implanted bilaterally under stereotactic conditions in the STN of patients with advanced PD. High frequency stimulation was applied for 24 hours a day. Following implant, antiparkinsonian medication was reduced as much as possible and stimulation was gradually increased. The patients were evaluated in the practically defined "off" condition and in the "on" condition using the unified PD rating scale (UPDRS) and the Schwab & England scale. Neuropsychological testing was performed before and after the implant. Thirty-three patients were followed up for at least 3 months and 13 among them until 36 months.The patients had a mean age of 56.8+/-7.1 years and a mean disease duration of 13.8+/-5.5 years; they were followed-up for an average of 25.7+/-13.5 months. At the time of the last available visit, the stimulation amplitude was 2.47+/-0.40 V (the total energy delivered averaged 1.57+/-0.8 microW). The levodopa-equivalent daily dose was reduced by 56.2\% (p<0.001). Parkinsonian features were improved in all patients, the greatest changes were seen for tremor, gait, bradykinesia and postural stability, then rigidity and limb akinesia. Compared with the pre-implant conditions, the UPDRS motor score in the "off" condition was improved by 51.6\% at the time of the last visit (p<0.001), the UPDRS activities of daily living score was improved by 68.5\% (p<0.001), the Schwab & England scale was improved by 196.8\% (p<0.001). The neuropsychological data did not show significant changes. Night sleep improved in all patients, due to increased mobility at night. In almost all patients insomnia was resolved. All patients gained weight after surgery with an increase of 11.1\% (p<0.001) compared to their pre-implant weight. The most common permanent side effects consisted in hypophonia and dysarthria, transient side effects were increased sexuality and mania, the most common side effects related to stimulation were ballic or choreic dyskinesias. The most common adverse event related to the surgical procedure was transient psychosis; unexplained switching-off of the stimulator was the most common device-related effect.This study extends our recently published 3-years FU series. It confirms again that symptomatic efficacy of STN stimulation is retained during the 2(nd) and 3(rd) years following the implant, without any obvious decay of efficacy or need for increase of energy delivered. Improvement of dyskinesias also persists and the procedure is well tolerated. Side effects and adverse events are sometimes severe, but can be managed in most cases. The improvement of daily living activities outweighs by far the motor benefit, indicating that the use of this procedure significantly improves the patients' lifestyle

Freezing of gait in Parkinson's disease: the paradoxical interplay between gait and cognition

Item does not contain fulltextBACKGROUND: Freezing of gait is a disabling episodic gait disturbance common in patients with Parkinson's disease. Recent evidences suggest a complex interplay between gait impairment and executive functions. Aim of our study was to evaluate whether specific motor conditions (sitting or walking) influence cognitive performance in patients with or without different types of freezing. METHODS: Eight healthy controls, eight patients without freezing, nine patients with levodopa-responsive and nine patients with levodopa-resistant freezing received a clinical and neuropsychological assessment during two randomly performed conditions: at rest and during walking. Results : At rest, patients with levodopa-resistant freezing performed worse than patients without freezing on tests of phonological fluency (p = 0.01). No differences among the four groups were detected during walking. When cognitive performances during walking were compared to the performance at rest, there was a significant decline of verbal episodic memory task (Rey Auditory Verbal Learning Test) in patients without freezing and with levodopa-responsive freezing. Interestingly, walking improved performance on the phonological fluency task in patients with levodopa-resistant freezing (p = 0.04). CONCLUSIONS: Compared to patients without freezing, patients with levodopa-resistant freezing perform worse when tested while seated in tasks of phonological verbal fluency. Surprisingly, gait was associated with a paradoxical improvement of phonological verbal fluency in the patients with levodopa-resistant freezing whilst walking determined a worsening of episodic memory in the other patient groups

Aristotle's illusion reveals interdigit functional somatosensory alterations in focal hand dystonia.

In focal hand dystonia, the cortical somatosensory representation of the fingers is abnormal, with overlapping receptive fields and reduced interdigit separation. These abnormalities are associated with deficits in sensory perception, as previously demonstrated by applying tactile stimuli to one finger at a time. What is still unknown is whether the sensory deficits can be observed when tactile perception involves more than one finger. To address this issue, we applied 'Aristotle's illusion' to 15 patients with focal hand dystonia, 15 patients with dystonia not affecting the hand (blepharospasm and cervical dystonia) and 15 healthy control subjects. In this illusion, one object touching the contact point of two crossed fingertips is perceived as two objects by a blindfolded subject. The same object placed between two parallel fingertips is correctly perceived as one. The illusory doubling sensation is because of the fact that the contact point between the crossed fingers consists of non-adjacent and functionally unrelated skin regions, which usually send sensory signals to separate spots in the somatosensory cortex. In our study, participants were touched by one sphere between the second-third digits, the second-fourth digits and the fourth-fifth digits of both hands, either in crossed or in parallel position, and had to refer whether they felt one or two stimuli. The percentage of 'two stimuli' responses was an index of the illusory doubling. Both healthy control subjects and dystonic patients presented Aristotle's illusion when the fingers were crossed. However, patients with focal hand dystonia presented a significant reduction of the illusion when the sphere was placed between the crossed fourth and fifth digits of the affected hand. This reduction correlated with the severity of motor disease at the fingers. Similar findings were not observed in non-hand dystonia and control groups. The reduction of Aristotle's illusion in non-affected fingers and its preservation in affected fingers suggests dissociation between the abnormal processing of sensory signals and the motor impairment. Based on previous evidence showing that the sensory signals coming from the fourth digit determine lower activation in the somatosensory cortex than those coming from the fifth digit, we suggest that in the crossed position, the tactile information conveyed by the fifth digit prevailed over the fourth digit, thus resulting in the perception of one stimulus. The reduction of the illusory doubling perception, therefore, may represent the functional correlate of the different level of activation between the fourth and the fifth digit in the somatosensory cortex

How motor, behavioral and cognitive symptoms affect functional abilities in Huntington's disease?

Neurological Motor Disorder

Better global and cognitive functioning in choreatic versus hypokinetic-rigid Huntington's disease

Neurological Motor Disorder