Abstract Cerebral palsy (CP) is the most common cause for acquired dystonia in childhood. Pharmacological treatment is often unsatisfactory and side effects are frequently dose-limiting. Data on ...outcome of DBS in paediatric patients with dyskinetic CP is very limited and heterogeneous. Reasons for the variability in responses are not entirely known yet. Interestingly, some CP-patients seem to improve subjectively on pallidal stimulation but without measurable changes in impairment scales. Besides dystonia scales, the use of sensitive age-dependent assessments tools is therefore reasonable to capture the full effect. As the course of disease duration as well as the age at operation seem to correlate with DBS outcome in patients with dystonia, DBS at an early stage of development might be beneficial for some of these patients. For the future, well-conducted trials as well as data collection in the international registry is of major importance to increase knowledge about DBS in CP patients, especially those implanted at a young age. Furthermore, selection criteria and guidelines or treatment standards are needed to improve the service for children with dyskinetic CP - especially in light of unsatisfactory medical treatment options.
Summary Movement disorders in children are causally and clinically heterogeneous and present in a challenging developmental context. Treatment options are broad ranging, from pharmacotherapy to ...invasive neuromodulation and experimental gene and stem cell therapies. The clinical effects of these therapies are variable and often poorly sustained, and only a few of the management strategies used in paediatric populations have been tested in randomised controlled studies with age-appropriate cohorts. Identification of the most appropriate treatment is uniquely challenging in children because of the incomplete knowledge about the pathophysiology of movement disorders and their influence on normal motor development; thus, effective therapeutic options for these children remain an unmet need. It is vital to transfer the expanding knowledge of the movement disorders into the development of novel symptomatic or, ideally, disease-modifying treatments, and to assess these therapeutic strategies in appropriately designed and well done trials.
•Mono-center trial investigating imaging data of exclusively patients with dystonia during childhood and adolescence.•Diffusion parameters differ between patients with acquired and inherited dystonia ...in several brain regions.•Higher fiber density between GPi and putamen of patients with acquired dystonia.
Background: Childhood-onset dystonia is often progressive and severely impairs a child´s life. The pathophysiology is very heterogeneous and treatment responses vary in patients with dystonia. Factors influencing treatment effects remain to be elucidated. We hypothesize that differences in brain connectivity and fiber coherence contribute to the heterogeneity in treatment response among pediatric patients with inherited and acquired dystonia.
Methods: Twenty patients with childhood-onset dystonia were retrospectively recruited including twelve patients with inherited or idiopathic, and eight patients with acquired dystonia (mean age 10 years; 8 female/12 male). Fiber density between the internal part of the globus pallidus and selective target regions, as well as the diffusion measures of fractional anisotropy (FA) and mean diffusivity (MD) were analyzed and compared between different etiologies.
Results: Patients with acquired dystonia presented higher fiber density to the premotor cortex and putamen and lower FA values in the thalamus compared to patients with inherited/idiopathic dystonia. MD in the premotor cortex was higher in patients with acquired dystonia, while it was lower in the thalamus.
Conclusion: Diffusion MRI reveals microstructural and network alterations in patients with dystonia of different etiologies.
PNPT1 mutations may cause Aicardi-Goutières-Syndrome Bamborschke, Daniel; Kreutzer, Mona; Koy, Anne ...
Brain & development (Tokyo. 1979),
February 2021, 2021-Feb, 2021-02-00, Volume:
43, Issue:
2
Journal Article
Peer reviewed
Aicardi-Goutières syndrome (AGS) is a clinically and genetically heterogenous autoinflammatory disorder caused by constitutive activation of the type I interferon axis. It has been associated with ...the genes TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, IFIH1. The clinical diagnosis of AGS is usually made in the context of early-onset encephalopathy in combination with basal ganglia calcification or white matter abnormalities on cranial MRI and laboratory prove of interferon I activation.
We report a patient with early-onset encephalopathy, severe neurodevelopmental regression, progressive secondary microcephaly, epilepsy, movement disorder, and white matter hyperintensities on T2 weighted MRI images. Via whole-exome sequencing, we identified a novel homozygous missense variant (c.1399C > T, p.Pro467Ser) in PNPT1 (NM_033109). Longitudinal assessment of the interferon signature showed a massively elevated interferon score and chronic type I interferon-mediated autoinflammation.
Bi-allelic mutations in PNPT1 have been reported in early-onset encephalopathy. Insufficient nuclear RNA import into mitochondria with consecutive disruption of the respiratory chain was proposed as the main underlying pathomechanism. Recent studies have shown that PNPT1 deficiency causes an accumulation of double-stranded mtRNAs in the cytoplasm, leading to aberrant type I interferon activation, however, longitudinal assessment has been lacking. Here, we present a case of AGS with continuously elevated type I interferon signature with a novel likely-pathogenic homozygous PNTP1 variant. We highlight the clinical value of assessing the interferon signature in children with encephalopathy of unknown origin and suggest all patients presenting with a phenotype of AGS should be screened for mutations in PNPT1.
Biallelic variants in the Golgi SNAP receptor complex member 2 gene (GOSR2) have been reported in progressive myoclonus epilepsy with neurodegeneration. Typical clinical features include ataxia and ...areflexia during early childhood, followed by seizures, scoliosis, dysarthria, and myoclonus. Here, we report two novel patients from unrelated families with a GOSR2-related disorder and novel genetic and clinical findings. The first patient, a male compound heterozygous for the GOSR2 splice site variant c.336+1G>A and the novel c.364G>A,p.Glu122Lys missense variant showed global developmental delay and seizures at the age of 2 years, followed by myoclonus at the age of 8 years with partial response to clonazepam. The second patient, a female homozygous for the GOSR2 founder variant p.Gly144Trp, showed only mild fine motor developmental delay and generalized tonic–clonic seizures triggered by infections during adolescence, with seizure remission on levetiracetam. The associated movement disorder progressed atypically slowly during adolescence compared to its usual speed, from initial intention tremor and myoclonus to ataxia, hyporeflexia, dysmetria, and dystonia. These findings expand the genotype–phenotype spectrum of GOSR2-related disorders and suggest that GOSR2 should be included in the consideration of monogenetic causes of dystonia, global developmental delay, and seizures.
Rapid progress has recently been made in the elucidation of the genetic basis of childhood-onset inherited generalized dystonia (IGD) due to the implementation of genomic sequencing methodologies. We ...identified four patients with childhood-onset IGD harboring novel disease-causing mutations in lysine-specific histone methyltransferase 2B gene (KMT2B) by whole-exome sequencing. The main focus of this paper is to gain novel pathophysiological insights through understanding the molecular consequences of these mutations. The disease course is mostly progressive, evolving from lower limbs into generalized dystonia, which could be associated with dysarthria, dysphonia, intellectual disability, orofacial dyskinesia, and sometimes distinct dysmorphic facial features. In two patients, motor performances improved after bilateral implantation of deep brain stimulation in the globus pallidus internus (GPi-DBS). Pharmacotherapy with trihexyphenidyl reduced dystonia in two patients. We discovered three novel KMT2B mutations. Our analyses revealed that the mutation in patient 1 (c.7463A > G, p.Y2488C) is localized in the highly conserved FYRC domain of KMT2B. This mutation holds the potential to alter the inter-domain FYR interactions, which could lead to KMT2B instability. The mutations in patients 2 and 3 (c.3596_3697insC, p.M1202Dfs*22; c.4229delA, p.Q1410Rfs*12) lead to predicted unstable transcripts, likely to be subject to degradation by non-sense-mediated decay. Childhood-onset progressive dystonia with orofacial involvement is one of the main clinical manifestations of KMT2B mutations. In all, 26% (18/69) of the reported cases have T2 signal alterations of the globus pallidus internus, mostly at a younger age. Anticholinergic medication and GPi-DBS are promising treatment options and shall be considered early.
GNAO1-related disorders (GNAO1-RD) encompass a diverse spectrum of neurodevelopmental and movement disorders arising from variants in the GNAO1 gene. Dyskinetic crises, marked by sudden and intense ...exacerbations of abnormal involuntary movements, present a significant challenge in GNAO1-RD.BackgroundGNAO1-related disorders (GNAO1-RD) encompass a diverse spectrum of neurodevelopmental and movement disorders arising from variants in the GNAO1 gene. Dyskinetic crises, marked by sudden and intense exacerbations of abnormal involuntary movements, present a significant challenge in GNAO1-RD.This study aimed to establish a standardized framework for understanding dyskinetic crises, addressing crucial aspects such as definition, triggers, diagnostic criteria, complications, and management strategies.ObjectivesThis study aimed to establish a standardized framework for understanding dyskinetic crises, addressing crucial aspects such as definition, triggers, diagnostic criteria, complications, and management strategies.A Delphi consensus process was conducted involving international experts in GNAO1-RD. The panel of thirteen experts participated in three voting rounds, discussing 90 statements generated through a literature review and clinical expertise.MethodsA Delphi consensus process was conducted involving international experts in GNAO1-RD. The panel of thirteen experts participated in three voting rounds, discussing 90 statements generated through a literature review and clinical expertise.Consensus was achieved on 31 statements, defining dyskinetic crises as abrupt, paroxysmal episodes involving distinct abnormal movements in multiple body regions, triggered by emotional stress or infections. Dyskinetic crises may lead to functional impairment and complications, emphasizing the need for prompt recognition. While individualized pharmacological recommendations were not provided, benzodiazepines and clonidine were suggested for acute crisis management. Chronic treatment options included tetrabenazine, benzodiazepines, gabapentin, and clonidine. Deep brain stimulation should be considered early in the treatment of refractory or prolonged dyskinetic crisis.ResultsConsensus was achieved on 31 statements, defining dyskinetic crises as abrupt, paroxysmal episodes involving distinct abnormal movements in multiple body regions, triggered by emotional stress or infections. Dyskinetic crises may lead to functional impairment and complications, emphasizing the need for prompt recognition. While individualized pharmacological recommendations were not provided, benzodiazepines and clonidine were suggested for acute crisis management. Chronic treatment options included tetrabenazine, benzodiazepines, gabapentin, and clonidine. Deep brain stimulation should be considered early in the treatment of refractory or prolonged dyskinetic crisis.This consensus provides a foundation for understanding and managing dyskinetic crises in GNAO1-RD for clinicians, caregivers, and researchers. The study emphasizes the importance of targeted parental and caregiver education, which enables early recognition and intervention, thereby potentially minimizing both short- and long-term complications. Future research should concentrate on differentiating dyskinetic crises from other neurological events and investigating potential risk factors that influence their occurrence and nature. The proposed standardized framework improves clinical management, stakeholder communication, and future GNAO1-RD research.ConclusionThis consensus provides a foundation for understanding and managing dyskinetic crises in GNAO1-RD for clinicians, caregivers, and researchers. The study emphasizes the importance of targeted parental and caregiver education, which enables early recognition and intervention, thereby potentially minimizing both short- and long-term complications. Future research should concentrate on differentiating dyskinetic crises from other neurological events and investigating potential risk factors that influence their occurrence and nature. The proposed standardized framework improves clinical management, stakeholder communication, and future GNAO1-RD research.
•Pediatric neuroimaging resources were assembled and implemented to assist deep brain stimulation imaging-based analyses.•Local sweetspot analysis was performed in a group of pediatric patients with ...dystonia treated with pallidal DBS.•Connectomic analysis was performed to demonstrate a distributed network correlate of DBS effect.
Deep brain stimulation (DBS) is an established treatment in patients of various ages with pharmaco-resistant neurological disorders. Surgical targeting and postoperative programming of DBS depend on the spatial location of the stimulating electrodes in relation to the surrounding anatomical structures, and on electrode connectivity to a specific distribution pattern within brain networks. Such information is usually collected using group-level analysis, which relies on the availability of normative imaging resources (atlases and connectomes). Analysis of DBS data in children with debilitating neurological disorders such as dystonia would benefit from such resources, especially given the developmental differences in neuroimaging data between adults and children. We assembled pediatric normative neuroimaging resources from open-access datasets in order to comply with age-related anatomical and functional differences in pediatric DBS populations. We illustrated their utility in a cohort of children with dystonia treated with pallidal DBS. We aimed to derive a local pallidal sweetspot and explore a connectivity fingerprint associated with pallidal stimulation to exemplify the utility of the assembled imaging resources.
An average pediatric brain template (the MNI brain template 4.5–18.5 years) was implemented and used to localize the DBS electrodes in 20 patients from the GEPESTIM registry cohort. A pediatric subcortical atlas, analogous to the DISTAL atlas known in DBS research, was also employed to highlight the anatomical structures of interest. A local pallidal sweetspot was modeled, and its degree of overlap with stimulation volumes was calculated as a correlate of individual clinical outcomes. Additionally, a pediatric functional connectome of 100 neurotypical subjects from the Consortium for Reliability and Reproducibility was built to allow network-based analyses and decipher a connectivity fingerprint responsible for the clinical improvements in our cohort.
We successfully implemented a pediatric neuroimaging dataset that will be made available for public use as a tool for DBS analyses. Overlap of stimulation volumes with the identified DBS-sweetspot model correlated significantly with improvement on a local spatial level (R = 0.46, permuted p = 0.019). The functional connectivity fingerprint of DBS outcomes was determined to be a network correlate of therapeutic pallidal stimulation in children with dystonia (R = 0.30, permuted p = 0.003).
Local sweetspot and distributed network models provide neuroanatomical substrates for DBS-associated clinical outcomes in dystonia using pediatric neuroimaging surrogate data. Implementation of this pediatric neuroimaging dataset might help to improve the practice and pave the road towards a personalized DBS-neuroimaging analyses in pediatric patients.
