Deep brain stimulation for dystonia: a novel perspective on the value of genetic testing

Jinnah, Hyder A.; Alterman, Ron L.; Klein, Christine; Krauss, Joachim K.; Moro, Elena; Vidailhet, Marie; Raike, Robert S.

doi:10.1007/s00702-016-1656-9

Cited by 72 publications

(54 citation statements)

References 102 publications

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“…Our data confirm that carriers of KMT2B mutations show an excellent, long-lasting motor response to pallidal DBS, and that improvement is rapidly observed particularly in the limbs and trunk, but not in the larynx. Different genetic causes of isolated and combined dystonia are emerging as poor or favorable prognostic factors for DBS outcome 39,40 ; our series fully supports KMT2B mutations as a positive prognostic factor for a good functional outcome after DBS, similarly to DYT-TOR1A patients. Aside from dystonia, KMT2B variants were frequently associated with additional neurological features, such as mild intellectual disability, short stature, brisk reflexes in the lower limbs, and minor facial dysmorphic features.…”

Section: Discussionsupporting

confidence: 76%

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

et al. 2019

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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 <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 65 patients who had previously tested negative for all other known dystonia‐associated genes. Results We identified 14 patients (21.5%) carrying KMT2B variants, of which 1 was classified as a variant of unknown significance. We also identified 2 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 caudocranial generalization. Eight patients underwent pallidal DBS with a median decrease of Burke‐Fahn‐Marsden Dystonia Rating Scale‐Motor score of 38.5% in the long term. We also report on 4 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 DBS is characteristic of DYT‐KMT2B dystonia. © 2019 International Parkinson and Movement Disorder Society

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Section: Discussionsupporting

confidence: 76%

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

et al. 2019

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“…In addition, the pathomechanisms of newly discovered gene loci in disease development are also unknown 1,2. Thus, despite the presence of this gene mutation in many previously reported DBS cases, the positive response in both cases with and without this mutation,1,2 like ours, and the small number of total MD cases with DBS suggest that, at this time, it is difficult to utilize gene status in predicting surgical outcomes, unlike in those with DYT-1 or DYT-6 mutations 14. It is possible, however, that those without the mutation may have only a moderate reduction in myoclonus compared with those with positive mutation status,1 but as seen in our report the myoclonus may respond in mutation-negative patients with low-frequency stimulation.…”

Section: Discussioncontrasting

confidence: 51%

A Case of Myoclonus–Dystonia Responding to Low-frequency Pallidal Stimulation

Sarva

Miravite

Swan

et al. 2017

Tremor and Other Hyperkinetic Movements

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“…All variables in this group were evaluated in a crosssectional manner. Based on MMSE and daily functioning, all patients had normal cognitive function (mean MMSE, 28.6 ± 1.9; range, [25][26][27][28][29][30] and no frontal lobe dysfunction (mean FAB, 16.6 ± 1.3; range, [15][16][17][18]. With the exception of 1 patient with self-reported depression and anxiety, none of the patients were depressed or anxious (mean BDI-II, 5.7 ± 6.1; range, 0-19; mean HADS-A, 7.7 ± 3.7; range, 2-14; mean HADS-D, 3.3 ± 2.8; range, 0-8).…”

Section: Nonmotor Symptoms and Quality Of Lifementioning

confidence: 99%

Long‐term GPi‐DBS improves motor features in myoclonus‐dystonia and enhances social adjustment

et al. 2018

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Background Good short‐term results of pallidal deep brain stimulation have been reported in myoclonus‐dystonia. Efficacy and safety in the long term remain to be established. In addition, the actual impact of DBS treatment on social inclusion is unknown. The objective of this study was to assess the long‐term clinical outcome, quality of life, and social adjustment of GPi‐DBS in patients with ε‐sarcoglycan (DYT11)‐positive myoclonus‐dystonia. Methods Consecutive myoclonus‐dystonia patients with ε‐sarcoglycan mutations who underwent GPi‐DBS were evaluated at least 5 years postoperatively. Motor symptoms were assessed using the Burke‐Fahn‐Marsden Dystonia Rating Scale including the Disability Scale, a composite score combining the rest and action parts of the Unified Myoclonus Rating Scale and modified Abnormal Involuntary Movement Scale. Standardized video‐protocols were assessed by a blinded and external movement disorder specialist. Social adjustment, cognition, and mood were evaluated. Results Nine patients (5 women) with long‐term GPi‐DBS (8.7 ± 3.1 years) were included. There was significant improvement in the composite myoclonus score (94.1% ± 4% improvement; P = 0.008). Dystonia severity was also markedly improved (71.4% ± 28.33% improvement; P = 0.008) as well as motor disability (88.3% ± 20% improvement; P = 0.008) and abnormal involuntary movement score (71.1% ± 15.0% improvement; P = 0.008). No patients experienced postoperative speech or gait problems or any permanent adverse effects. Eight of the 9 patients had fully enhanced social adjustment and personal achievement, with little or no mood or behavioral disorders. Conclusions GPi‐DBS seems to be a safe and efficacious treatment for medically refractory ɛ‐sarcoglycan myoclonus‐dystonia, with sustained motor benefit, good quality of life, and social adjustment in long‐term follow‐up. © 2018 International Parkinson and Movement Disorder Society

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Deep brain stimulation for dystonia: a novel perspective on the value of genetic testing

Cited by 72 publications

References 102 publications

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

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

A Case of Myoclonus–Dystonia Responding to Low-frequency Pallidal Stimulation

Long‐term GPi‐DBS improves motor features in myoclonus‐dystonia and enhances social adjustment

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