Novel mutations in KMT2B offer pathophysiological insights into childhood-onset progressive dystonia

Dafsari, Hormos Salimi; Sprute, Rosanne; Wunderlich, Gilbert; Daimagüler, Hülya‐Sevcan; Karaca, Ezgi; Contreras, Adriana; Becker, Kerstin; Schulze-Rhonhof, Mira; Kiening, Karl; Karakulak, Tülay; Kloß, Manja; Horn, Annette; Pauls, K. Amande M.; Nürnberg, Peter; Altmüller, Janine; Thiele, Holger; Assmann, Birgit; Koy, Anne; Çırak, Sebahattin

doi:10.1038/s10038-019-0625-1

Cited by 25 publications

(29 citation statements)

References 49 publications

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“…7 Dafsari et al reported the longest follow-up period (10 years) of a single patient who underwent GPi-DBS and was found to have a 34.9% improvement in BFMDRS values. 6 Mun et al reported an 83.3% improvement in BFMDRS scores after bilateral GPi-DBS at 22-month follow-up. 3 In the present study, there was an 84.1% improvement in the BFM-MS score after bilateral ablation and a 34.4% and 61.0% improvement in the BFM-MS score after unilateral ablations, which corresponded to previous results using GPi-DBS.…”

Section: Discussionmentioning

confidence: 98%

“…Previous studies have shown significant improvements in patients with DYT-28 dystonia after bilateral GPi-DBS, with 5 to 10 years of improvement after the initial procedure. 1,6 However, the majority of these studies did not document outcomes using objective evaluation scales, such as the BFM rating scale or the Toronto Western Spasmodic Torticollis Scale. Only five reports documented the efficacy of GPi-DBS for DYT-28 dystonia using the BFMDRS.…”

Section: Discussionmentioning

confidence: 99%

“…Only five reports documented the efficacy of GPi-DBS for DYT-28 dystonia using the BFMDRS. [3][4][5][6][7] Kawarai et al used the BFMDRS to report post-GPi-DBS outcomes in three patients with DYT-28, showing 70.5%, 45.7%, and 31.1% improvements in BFMDRS values. 7 Dafsari et al reported the longest follow-up period (10 years) of a single patient who underwent GPi-DBS and was found to have a 34.9% improvement in BFMDRS values.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have shown significant improvements in patients with DYT-28 after deep brain stimulation (DBS) of the globus pallidus internus (GPi). [3][4][5][6][7] ; however, the use of ablative treatments for DYT-28 management have not yet been reported. For patients who develop dystonia at a young age, ablative treatments may play a particularly valuable role in disease management because they do not necessitate device implantation or time-consuming and costly postoperative management.…”

Section: Introductionmentioning

confidence: 99%

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Radiofrequency ablation for DYT‐28 dystonia: short term follow‐up of three adult cases

Horisawa

Azuma

Akagawa

et al. 2020

Ann Clin Transl Neurol

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Mutations in the lysine methyltransferase 2B (KMT2B) gene have recently been reported to be associated with childhood-onset generalized dystonia. There have been no studies investigating ablative treatments for the management of this disorder. Three patients underwent either a staged unilateral pallidotomy and contralateral pallidothalamic tractotomy (19-year-old man, 2-year follow-up), a unilateral pallidothalamic tractotomy (34-year-old man, 6-month follow-up) or a simultaneous unilateral pallidothalamic tractotomy and ventro-oral thalamotomy (29-year-old man, 6-month follow-up). The average total patient score on the Burke-Fahn-Marsden Dystonia Rating Scale-Movement Scale improved from 39.5 to 13.2 (66.6%) after the procedures. No significant complications were identified. Ablative treatments appear to be a promising alternative surgical option for generalized dystonia with KMT2B mutation.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Radiofrequency ablation for DYT‐28 dystonia: short term follow‐up of three adult cases

Horisawa

Azuma

Akagawa

et al. 2020

Ann Clin Transl Neurol

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“…Our report describes the phenotype in a family with a previously undescribed KMT2B variant and highlights failure to thrive, an overlooked manifestation. Thus far, 80 additional patients have been described (Additional Table) [5,6,[10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]. A recent report identified KMT2B mutations in 21.5% of patients with previously undiagnosed childhood-onset dystonia suggesting KMT2B mutations may be a relatively common cause of dystonia in children [26].…”

Section: Discussionmentioning

confidence: 99%

Failure to thrive - an overlooked manifestation of KMT2B-related dystonia: a case presentation

Galosi

Salz

et al. 2020

BMC Neurol

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Background: KMT2B-related dystonia is a recently described form of childhood onset dystonia that may improve with deep brain stimulation. Prior reports have focused on neurologic features including prominent bulbar involvement without detailing general health consequences that may result from orolingual dysfunction. We describe a family with novel KMT2B mutation with several members with failure to thrive to highlight this nonneurologic, but consequential impact of mutation in this gene. Case presentation: We present a case of a 15-year old female who was admitted and evaluated for failure to thrive. On exam, she had severe speech dysfluency, limited ability to protrude the tongue, and generalized dystonia involving the oromandibular region, right upper and left lower extremity with left foot inversion contracture. The proband and her parents underwent whole genome sequencing. A previously undescribed variant, c.4960 T > C (p.Cys1654Arg), was identified in the KMT2B gene in the proband and mother, and this variant was subsequently confirmed in two maternal cousins, one with failure to thrive. Literature review identified frequent reports of prominent bulbar involvement but failure to thrive is rarely mentioned. Conclusion: Failure to thrive is a common pediatric clinical condition that has consequences for growth and development. In the presence of an abnormal neurologic exam, a search for a specific underlying genetic etiology should be pursued. With this case series, we highlight an unusual potentially treatable cause of failure to thrive, reinforce the importance of precise molecular diagnosis for patients with failure to thrive and an abnormal neurologic exam, and underscore the importance of cascade screening of family members.

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GPi‐DBS for KMT2B‐Associated Dystonia: Systematic Review and Meta‐Analysis

Rajan

Garg

Saini

et al. 2021

Movement Disord Clin Pract

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Background Early evidence suggests good response to pallidal deep brain stimulation (DBS) in DYT‐KMT2B. Objectives We aimed to conduct a systematic review and meta‐analysis to assess outcomes and identify predictors of good outcome following GPi‐DBS in DYT‐KMT2B. Methods We searched MEDLINE, Cochrane and MDS‐abstracts databases using the MeSH terms “KMT2B and DYT28”. We included studies that reported objective outcomes following GPi‐DBS in DYT‐KMT2B. The BFMDRS‐M (Burke‐Fahn‐Marsden Dystonia Rating Scale‐ Movement) total scores pre‐ and post‐surgery were used to quantify outcomes. We calculated pooled effects using a random effects meta‐analysis and used meta‐regression to identify potential effect modifiers. Multiple linear regression using individual patient data was used to identify predictors of good outcome (>50% improvement from baseline on BFMDRS‐M). Results Initial searches screened 132 abstracts of which 34 full‐text articles were identified to be of potential interest. Ten studies reporting 42 individual patients, met the inclusion/exclusion criteria and were included in the final review. The mean age at onset was 6.4 ± 5.7 years and 40% were male. The median follow‐up was 12 months (range: 1–264 months). GPi‐DBS resulted in median BFMDRS‐M improvement of 42.7% (range: −103.5% to 95.9%) postoperatively. Pooled proportion of patients experiencing clinical improvement >50% on BFMDRS‐M was 41% (95% CI: 27%–57%). Male gender [β: 22.6, 95% CI: 8.0–37.3, P = 0.004), and higher pre‐operative BFMDRS‐M score [β: 0.62, 95% CI: 0.36–0.87, P < 0.001) were independently associated with better outcome. Conclusion KMT2B‐associated dystonia responds effectively to pallidal stimulation. The outcome is better in males and those with more severe dystonia at baseline.

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Novel mutations in KMT2B offer pathophysiological insights into childhood-onset progressive dystonia

Cited by 25 publications

References 49 publications

Radiofrequency ablation for DYT‐28 dystonia: short term follow‐up of three adult cases

Radiofrequency ablation for DYT‐28 dystonia: short term follow‐up of three adult cases

Failure to thrive - an overlooked manifestation of KMT2B-related dystonia: a case presentation

GPi‐DBS for KMT2B‐Associated Dystonia: Systematic Review and Meta‐Analysis

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