Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.

Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.Funding for the project was provided by the Wellcome Trust for UK10K (WT091310) and DDD Study. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund [grant number HICF-1009-003] - see www.ddduk.org/access.html for full acknowledgement. This work was supported in part by the Intramural Research Program of the National Human Genome Research Institute and the Common Fund, NIH Office of the Director. This work was supported in part by the German Ministry of Research and Education (grant nos. 01GS08160 and 01GS08167; German Mental Retardation Network) as part of the National Genome Research Network to A.R. and D.W. and by the Deutsche Forschungsgemeinschaft (AB393/2-2) to A.R. Brain expression data was provided by the UK Human Brain Expression Consortium (UKBEC), which comprises John A. Hardy, Mina Ryten, Michael Weale, Daniah Trabzuni, Adaikalavan Ramasamy, Colin Smith and Robert Walker, affiliated with UCL Institute of Neurology (J.H., M.R., D.T.), King’s College London (M.R., M.W., A.R.) and the University of Edinburgh (C.S., R.W.)

Clown-care reduces pain in children with cerebral palsy undergoing recurrent botulinum toxin injections- A quasi-randomized controlled crossover study

<div><p>Objective</p><p>We investigated the impact of clown-care on pain in 45 children with cerebral palsy who underwent recurrent Botulinum-toxin injections (age 7.04<i>±</i> 4.68 years). Participants were randomized to receive either clown (<i>n</i> = 20) or standard (<i>n</i> = 25) -care.</p><p>Methods</p><p>Pain Visual-Analogue-Scale (range 1–5) was reported before and after procedures. Pain assessment was lower for children undergoing Botulinum-toxin injections with clown-care (2.89± 1.36) compared to standard-care (3.85± 1.39; <i>p</i> = 0.036) even though pain anticipated prior to procedures was similar (~3).</p><p>Findings</p><p>Children who underwent the first procedure with clown-care reported lower pain even after they crossed-over to the following procedure which was standard (<i>p</i> = 0.048). Carryover effect was more prominent in injection-naïve children (<i>p</i> = 0.019) and during multiple procedures (<i>p</i> = 0.009). Prior pain experience correlated with pain in subsequent procedures only when first experience was standard-care (<i>p</i> = 0.001).</p><p>Conclusions</p><p>Clown-care alleviated pain sensation during Botulinum-toxin injections and initial clown-care experience reduced pain during subsequent injections even though clowns were not present.</p><p>Trial registration</p><p>clinicaltrials.gov ID # <a href="https://clinicaltrials.gov/ct2/show/NCT01377883" target="_blank">NCT01377883</a>.</p></div

Carry over effect—Pain levels remained constant despite crossover (with/without clowning).

<p>(A) Pain levels (VAS-after LSmean ±SE) remained stable in each group (grey solid line: clowning 1^st-> standard 2^nd; black dashed line: standard 1^st-> clowning 2^nd) and did not change between the first and second procedure. However, pain was lower for children who received clowning during the first injection (grey) compared to those who received clowning only on the second injection (black). (B) Anticipated pain (before) did not correlate with experienced pain (after) the first procedure for both groups. (C) However, pain experience (after) correlated with anticipated pain (before) of the second injection for those who received standard procedure in the first time (black) but not for those who previously received clowning (grey).</p

Pain (Visual Analogue Scale) after BTX injections with and without clown-care.

<p>Box plots (diamond = mean, solid line in center = median) of pain after the first procedure according to the Visual Analogue Scale (VAS; range 1 = no pain to 5 = severe pain): After the procedure the pain was experienced as moderate for the clown group (black) and severe in controls (grey).</p

Medical clowning effect before, during and after BTX injections.

<p>Before: Clown engaging and distracting the anxious child who pays attention to the scene in front of him. During the injection: Clown and child in a secluded atmosphere at the other end of the table; parent watching with a smile. After: Child is laughing leaving the room empowered.</p

Pain as a function of clown presence during first procedure (longitudinal).

<p>Pain levels (VAS-after LSmean ± SE) were lower for the children receiving clown care during the first injection (grey solid line) and remained low (VAS<4) during second, third and fourth injections. Pain was high (VAS>4) for children who did not receive clown care during the first injections.</p

CONSORT flow diagram.

<p>Study design process: enrollment, randomization, Allocation, follow-up and analysis.</p