Deep Brain Stimulation in KMT2B-Related Dystonia: Case Report and Review of the Literature With Special Emphasis on Dysarthria and Speech

Abel, Maria; Pfister, Robert M.; Hussein, Iman; Alsalloum, Fahd; Onyinzo, Christina; Kappl, S.; Zech, Michael; Demmel, Walter; Staudt, Martin; Kudernatsch, Manfred; Berweck, Steffen

doi:10.3389/fneur.2021.662910

Cited by 3 publications

(4 citation statements)

References 17 publications

(45 reference statements)

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“…Several adult and pediatric patients underwent GPi-DBS due to DYT-THAP1 and DYT-KMT2B. Although the number of pediatric patients was lower, the results prove that bilateral GPi-DBS is a valuable therapeutic option for DYT-THAP1 (8)(9)(10)(11)(12)(13)(14)(15)(16) and DYT-KMT2B, particularly for movement disorders and regaining mobility, but less so for speech issues (5,(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37) (Supplementary Tables 1, 2). So far, the aforementioned patients presented with severe dystonic postures, majorly impacting their quality of life, as well as those of their families and caregivers.…”

Section: Discussionmentioning

confidence: 95%

“…Further clinical characteristics, such as cognitive disability, psychiatric comorbidities, and dysmorphic features, have been reported in several patients (27-29). Bilateral GPi-DBS has been reported as an efficient therapeutic option, especially for improving movement disorder and regaining independent mobility (5,(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37). GPi-DBS is sometimes associated with "dramatic" amelioration in gait but more commonly associated with truncal dystonia and scoliosis; it is rarely associated with speech dysfunction in severely affected patients with KMT2B gene mutations prior to DBS (23).…”

Section: Discussionmentioning

confidence: 99%

“…Bilateral GPi-DBS has been reported as an efficient therapeutic option, especially for improving movement disorder and regaining independent mobility ( 5 , 22 – 37 ). GPi-DBS is sometimes associated with “dramatic” amelioration in gait but more commonly associated with truncal dystonia and scoliosis; it is rarely associated with speech dysfunction in severely affected patients with KMT2B gene mutations prior to DBS ( 23 ).…”

Section: Discussionmentioning

confidence: 99%

“…Although it is suggested that DBS should be considered as a treatment approach in pharmacoresistent DYT-THAP1 early in childhood to prevent more severe symptoms, such as disabling motor development and quality of life decline, including emotional and social aspects, the results are missing. Additionally, bilateral GPi-DBS has been reported as a valuable therapeutic option for DYT-KMT2B, especially for regaining motor function and mobility, but less so for speech if significant speech difficulties are developed (5,(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37).…”

Section: Introductionmentioning

confidence: 99%

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GPi DBS treatment outcome in children with monogenic dystonia: a case series and review of the literature

et al. 2023

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IntroductionDystonia is the third most common pediatric movement disorder and is often difficult to treat. Deep brain stimulation (DBS) of the internal pallidum (GPi) has been demonstrated as a safe and effective treatment for genetic dystonia in adolescents and adults. The results of DBS in children are limited to individual cases or case series, although it has been proven to be an effective procedure in carefully selected pediatric cohorts. The aim of our study was to present the treatment outcome for 7- to 9-year-old pediatric patients with disabling monogenic isolated generalized DYT-THAP1 and DYT-KMT2B dystonia after bilateral GPi-DBS.Patients and resultsWe present three boys aged <10 years; two siblings with disabling generalized DYT-THAP1 dystonia and a boy with monogenic-complex DYT-KMT2B. Dystonia onset occurred between the ages of 3 and 6. Significantly disabled children were mostly dependent on their parents. Pharmacotherapy was inefficient and patients underwent bilateral GPi-DBS. Clinical signs of dystonia improved significantly in the first month after the implantation and continued to maintain improved motor functions, which were found to have improved further at follow-up. These patients were ambulant without support and included in everyday activities. All patients had significantly lower Burke–Fahn–Marsden Dystonia Rating Scale (BFMDRS) values, indicating >25% improvement over the first 15 months. However, there was a decline in speech and upper limb function, manifesting with bradylalia, bradykinesia, and dysphonia, which decreased after treatment with trihexyphenidyl.ConclusionAlthough reports of patients with monogenic dystonia, particularly DYT-THAP1, treated with DBS are still scarce, DBS should be considered as an efficient treatment approach in children with pharmacoresistent dystonia, especially with generalized monogenic dystonia and to prevent severe and disabling symptoms that reduce the quality of life, including emotional and social aspects. Patients require an individual approach and parents should be properly informed about expectations and possible outcomes, including relapses and impairments, in addition to DBS responsiveness and related improvements. Furthermore, early genetic diagnosis and the provision of appropriate treatments, including DBS, are mandatory for preventing severe neurologic impairments.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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GPi DBS treatment outcome in children with monogenic dystonia: a case series and review of the literature

et al. 2023

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Directional electrodes in deep brain stimulation: Results of a survey by the European Association of Neurosurgical Societies (EANS)

Krauss,

Duarte-Batista,

Hart

et al. 2024

Brain and Spine

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Diagnostic utility of DNA methylation episignature analysis for early diagnosis of KMT2B-related disorders: case report

Bouhamdani,

McConkey,

Leblanc

et al. 2024

Front. Genet.

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The lysine methyltransferase 2B (KMT2B) gene product is important for epigenetic modifications associated with active gene transcription in normal development and in maintaining proper neural function. Pathogenic variants in KMT2B have been associated with childhood-onset Dystonia-28 and Intellectual developmental disorder, autosomal dominant 68 (MRD 68) for cases of neurodevelopmental impairment without dystonia (DYT28; OMIM 617284 and MRD68; OMIM 619934, respectively). Since its first description in 2016, approximately one hundred KMT2B genetic variants have been reported with heterogeneous phenotypes, including atypical patterns of dystonia evolution and non-dystonic neurodevelopmental phenotypes. KMT2B-related disorders share many overlapping phenotypic characteristics with other neurodevelopmental disorders and delayed dystonia, that can appear later in childhood, often delaying clinical diagnosis. Furthermore, conventional genetic testing may not always provide actionable information (e.g., gene panel selection based on early clinical presentation or variants of uncertain significance), which prevents patients and families from obtaining early access to treatments and support. Herein, we describe the early diagnosis of KMT2B-related neurodevelopmental disorder by DNA methylation episignature testing in a 4-year-old patient without features of dystonia at diagnosis, which is reported to develop in more than 80% of KMT2B-related disorder cases. The proband, a 4-year-old female of Jewish-Israeli descent, presented with speech delay, microcephaly, poor weight gain, attention-deficit and hyperactivity disorder, dysmorphism, intellectual disabilities and joint hyperlaxity, but presented no signs of dystonia at initial evaluation. Episignature screening in this pre-symptomatic patient enabled accurate genetic diagnosis and timely and actionable intervention earlier in the natural history of Childhood-onset Dystonia-28.

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Deep Brain Stimulation in KMT2B-Related Dystonia: Case Report and Review of the Literature With Special Emphasis on Dysarthria and Speech

Cited by 3 publications

References 17 publications

GPi DBS treatment outcome in children with monogenic dystonia: a case series and review of the literature

GPi DBS treatment outcome in children with monogenic dystonia: a case series and review of the literature

Directional electrodes in deep brain stimulation: Results of a survey by the European Association of Neurosurgical Societies (EANS)

Diagnostic utility of DNA methylation episignature analysis for early diagnosis of KMT2B-related disorders: case report

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