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In neurodegenerative diseases, the characterization of the prodromal phase is essential for the future application of disease-modifying therapies. X-linked dystonia-parkinsonism is a hereditary neurodegenerative movement disorder characterized by severe adult-onset dystonia accompanied by parkinsonism. Distinct striatal and pallidal atrophy is present already in early disease stages indicating a long-lasting presymptomatic degenerative process. To gain insight into the prodromal phase of X-linked dystonia-parkinsonism, structural and iron-sensitive magnetic resonance imaging (MRI) was performed in 10 non-manifesting carriers and 24 healthy controls in a double-blind fashion. Seventeen patients with X-linked dystonia-parkinsonism were recruited to replicate previous findings of basal ganglia pathology and iron accumulation. Age at onset was estimated in non-manifesting carriers and patients using the repeat length of the hexanucleotide expansion and 3 single-nucleotide polymorphisms associated with age at onset. Voxel-based morphometry and subcortical volumetry showed striatal and pallidal atrophy in non-manifesting carriers (~10%) and patients (~40%). Substantia nigra volume was similarly reduced in patients (~40%). Caudate volume correlated with time to estimated onset in non-manifesting carriers. Susceptibility-weighted imaging confirmed iron deposition in the anteromedial putamen in patients. Non-manifesting carriers also showed small clusters of iron accumulation in the same area after lowering the statistical threshold. In conclusion, basal ganglia atrophy and iron accumulation precede the clinical onset of X-linked dystonia-parkinsonism and can be detected years before the estimated disease manifestation. It thereby highlights the potential of multimodal imaging to identify clinically unaffected mutation carriers with incipient neurodegeneration and to monitor disease progression independent of clinical measures. Longitudinal studies are needed to further elucidate the onset and progression rate of neurodegeneration in prodromal X-linked dystonia-parkinsonism. ANN NEUROL 2023;93:999-1011., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Introduction: Dystonia is a movement disorder of variable etiology and clinical presentation and is accompanied by tremor in about 50% of cases. Monogenic causes in dystonia are rare, but also in the group of non-monogenic dystonias 10-30% of patients report a family history of dystonia. This points to a number of patients currently classified as idiopathic that have at least in part an underlying genetic contribution. The present study aims to identify clinical and demographic features associated with heritability of yet idiopathic dystonia., Methods: Seven hundred thirty-three datasets were obtained from the DysTract dystonia registry, patients with acquired dystonia or monogenic causes were excluded. Affected individuals were assigned to a familial and sporadic group, and clinical features were compared across these groups. Additionally, the history of movement disorders was also counted in family members., Results: 18.2% of patients reported a family history of dystonia. Groups differed in age at onset, disease duration and presence of tremor on a descriptive level. Logistic regression analysis revealed that tremor was the only predictor for a positive family history of dystonia (OR 2.49, CI = 1.54-4.11, p < 0.001). Tremor turned out to be the most common movement disorder in available relatives of patients, and presence of tremor in relatives was associated with tremor in index patients (X 2 (1) = 16.2, p < 0.001)., Conclusions: Tremor is associated with an increased risk of familial clustering of dystonia and with a family history of tremor itself. This indicates a hereditable dystonia-tremor syndrome with a clinical spectrum ranging from tremor-predominant diseases to dystonia., Competing Interests: Declaration of competing interest This work was supported by the Federal Ministry of Education and Research(BMBF) through a research grant to the DysTract Research Consortium (Grant No 01GM1514B. The DysTract registry is currently supported by Pharm Allergan, Ipsen Pharma and Merz Pharmaceuticals. The funding sources were not involved in the design of the study, or in the acquisition, analysis or interpretation of the data. The authors report no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Study Objectives: Recently, IMPDH2 has been linked to dystonia. However, no replication study from other cohorts has been conducted to confirm the association. We aimed to systematically evaluate the genetic associations of IMPDH2 with dystonia in a large dystonia cohort., Methods: We analyzed rare variants (minor allele frequency < 0.01) of IMPDH2 in 688 Chinese dystonia patients with whole exome sequencing. The over-representation of rare variants in patients was examined with Fisher's exact test at allele and gene levels., Results: Four rare variants were detected in IMPDH2 in four patients with dystonia in our cohort, including three missense variants (p.Ser508Leu, p.Ala396Thr, and p.Phe24Val) and one splice acceptor variant (c.1296-1G>T). Two of them (c.1296-1G>T and p.Ser508Leu) were co-segregated in the family co-segregation analysis and were classified as pathogenic and likely pathogenic variant according to the American College of Medical Genetics and Genomics (ACMG) guidelines, respectively. Gene burden analysis revealed enrichment of rare variants in IMPDH2 in dystonia., Conclusions: Our work supplemented the evidence on the role of IMPDH2 in autosomal dominant dystonia in Chinese population, and expanded the genetic and phenotypic spectrum of IMPDH2, paving way for future studies., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

The relationship between genotype and phenotype in DYT-TOR1A dystonia as well as the associated motor circuit alterations are still insufficiently understood. DYT-TOR1A dystonia has a remarkably reduced penetrance of 20-30%, which has led to the second-hit hypothesis emphasizing an important role of extragenetic factors in the symptomatogenesis of TOR1A mutation carriers. To analyze whether recovery from a peripheral nerve injury can trigger a dystonic phenotype in asymptomatic hΔGAG3 mice, which overexpress human mutated torsinA, a sciatic nerve crush was applied. An observer-based scoring system as well as an unbiased deep-learning based characterization of the phenotype showed that recovery from a sciatic nerve crush leads to significantly more dystonia-like movements in hΔGAG3 animals compared to wildtype control animals, which persisted over the entire monitored period of 12 weeks. In the basal ganglia, the analysis of medium spiny neurons revealed a significantly reduced number of dendrites, dendrite length and number of spines in the naïve and nerve-crushed hΔGAG3 mice compared to both wildtype control groups indicative of an endophenotypical trait. The volume of striatal calretinin + interneurons showed alterations in hΔGAG3 mice compared to the wt groups. Nerve-injury related changes were found for striatal ChAT + , parvalbumin + and nNOS + interneurons in both genotypes. The dopaminergic neurons of the substantia nigra remained unchanged in number across all groups, however, the cell volume was significantly increased in nerve-crushed hΔGAG3 mice compared to naïve hΔGAG3 mice and wildtype littermates. Moreover, in vivo microdialysis showed an increase of dopamine and its metabolites in the striatum comparing nerve-crushed hΔGAG3 mice to all other groups. The induction of a dystonia-like phenotype in genetically predisposed DYT-TOR1A mice highlights the importance of extragenetic factors in the symptomatogenesis of DYT-TOR1A dystonia. Our experimental approach allowed us to dissect microstructural and neurochemical abnormalities in the basal ganglia, which either reflected a genetic predisposition or endophenotype in DYT-TOR1A mice or a correlate of the induced dystonic phenotype. In particular, neurochemical and morphological changes of the nigrostriatal dopaminergic system were correlated with symptomatogenesis., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Dystonia is a genetically and phenotypically heterogeneous disorder that occurs in isolation (isolated dystonia) or in combination with other movement disorders. To determine the genetic spectrum in isolated dystonia, we enrolled 88 patients with isolated dystonia for whole-exome sequencing (WES). Seventeen mutations, including nine novel ones, were identified in 19 of the 88 patients, providing a 21.59% positive molecular diagnostic rate. Eleven distinct genes were involved, of which TOR1A and THAP1 accounted for 47.37% (9/19) of the positive cases. A novel missense variant, p.S225R in TOR1A, was found in a patient with adolescence-onset generalized dystonia. Cellular experiments revealed that p.S255R results in the abnormal aggregation of Torsin-1A encoding by TOR1A. In addition, we reviewed the clinical and genetic features of the isolated dystonia patients carrying TOR1A, THAP1, ANO3, and GNAL mutations in the Chinese population. Our results expand the genetic spectrum and clinical profiles of patients with isolated dystonia and demonstrate WES as an effective strategy for the molecular diagnosis of isolated dystonia., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The human dopaminergic system is vital for a broad range of neurological processes, including the control of voluntary movement. Here we report a proband presenting with clinical features of dopamine deficiency: severe infantile parkinsonism-dystonia, characterised by frequent oculogyric crises, dysautonomia and global neurodevelopmental impairment. CSF neurotransmitter analysis was unexpectedly normal. Triome whole-genome sequencing revealed a homozygous variant (c.110C>A, (p.T37K)) in DRD1 , encoding the most abundant dopamine receptor (D 1 ) in the central nervous system, most highly expressed in the striatum. This variant was absent from gnomAD, with a CADD score of 27.5. Using an in vitro heterologous expression system, we determined that DRD1 -T37K results in loss of protein function. Structure-function modelling studies predicted reduced substrate binding, which was confirmed in vitro. Exposure of mutant protein to the selective D 1 agonist Chloro APB resulted in significantly reduced cyclic AMP levels. Numerous D 1 agonists failed to rescue the cellular defect, reflected clinically in the patient, who had no benefit from dopaminergic therapy. Our study identifies DRD1 as a new disease-associated gene, suggesting a crucial role for the D 1 receptor in motor control.

While many genetic causes of movement disorders have been identified, modifiers of disease expression are largely unknown. X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disease caused by a SINE-VNTR-Alu(AGAGGG)n retrotransposon insertion in TAF1, with a polymorphic (AGAGGG)n repeat. Repeat length and variants in MSH3 and PMS2 explain ∼65% of the variance in age at onset (AAO) in XDP. However, additional genetic modifiers are conceivably at play in XDP, such as repeat interruptions. Long-read nanopore sequencing of PCR amplicons from XDP patients (n = 202) was performed to assess potential repeat interruption and instability. Repeat-primed PCR and Cas9-mediated targeted enrichment confirmed the presence of identified divergent repeat motifs. In addition to the canonical pure SINE-VNTR-Alu-5'-(AGAGGG)n, we observed a mosaic of divergent repeat motifs that polarized at the beginning of the tract, where the divergent repeat interruptions varied in motif length by having one, two, or three nucleotides fewer than the hexameric motif, distinct from interruptions in other disease-associated repeats, which match the lengths of the canonical motifs. All divergent configurations occurred mosaically and in two investigated brain regions (basal ganglia, cerebellum) and in blood-derived DNA from the same patient. The most common divergent interruption was AGG [5'-SINE-VNTR-Alu(AGAGGG)2AGG(AGAGGG)n], similar to the pure tract, followed by AGGG [5'-SINE-VNTR-Alu(AGAGGG)2AGGG(AGAGGG)n], at median frequencies of 0.425 (IQR: 0.42-0.43) and 0.128 (IQR: 0.12-0.13), respectively. The mosaic AGG motif was not associated with repeat number (estimate = -3.8342, P = 0.869). The mosaic pure tract frequency was associated with repeat number (estimate = 45.32, P = 0.0441) but not AAO (estimate = -41.486, P = 0.378). Importantly, the mosaic frequency of the AGGG negatively correlated with repeat number after adjusting for age at sampling (estimate = -161.09, P = 3.44 × 10-5). When including the XDP-relevant MSH3/PMS2 modifier single nucleotide polymorphisms into the model, the mosaic AGGG frequency was associated with AAO (estimate = 155.1063, P = 0.047); however, the association dissipated after including the repeat number (estimate = -92.46430, P = 0.079). We reveal novel mosaic divergent repeat interruptions affecting both motif length and sequence (DRILS) of the canonical motif polarized within the SINE-VNTR-Alu(AGAGGG)n repeat. Our study illustrates: (i) the importance of somatic mosaic genotypes; (ii) the biological plausibility of multiple modifiers (both germline and somatic) that can have additive effects on repeat instability; and (iii) that these variations may remain undetected without assessment of single molecules., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Introduction: Genetically inherited ataxic disorders are classified by their age of disease presentation into early- and late-onset ataxia (EOA and LOA, presenting before or after the 25th year-of-life). In both disease groups, comorbid dystonia co-occurs frequently. Despite overlapping genes and pathogenetic features, EOA, LOA and dystonia are considered as different genetic entities with a separate diagnostic approach. This often leads to diagnostic delay. So far, the possibility of a disease continuum between EOA, LOA and mixed ataxia-dystonia has not been explored in silico. In the present study, we analyzed the pathogenetic mechanisms underlying EOA, LOA and mixed ataxia-dystonia., Methods: We analyzed the association of 267 ataxia genes with comorbid dystonia and anatomical MRI lesions in literature. We compared anatomical damage, biological pathways, and temporal cerebellar gene expression between EOA, LOA and mixed ataxia-dystonia., Results: The majority (≈65%) of ataxia genes were associated with comorbid dystonia in literature. Both EOA and LOA gene groups with comorbid dystonia were significantly associated with lesions in the cortico-basal-ganglia-pontocerebellar network. EOA, LOA and mixed ataxia-dystonia gene groups were enriched for biological pathways related to nervous system development, neural signaling and cellular processes. All genes revealed similar cerebellar gene expression levels before and after 25 years of age and during cerebellar development., Conclusion: In EOA, LOA and mixed ataxia-dystonia gene groups, our findings show similar anatomical damage, underlying biological pathways and temporal cerebellar gene expression patterns. These findings may suggest the existence of a disease continuum, supporting the diagnostic use of a unified genetic approach., Competing Interests: Declaration of competing interest D.A. Sival and D.S. Verbeek are members of the European Reference Network for Rare Neurological Diseases. The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: None

Infantile striatonigral degeneration is caused by a homozygous variant of the nuclear-pore complex (NPC) gene NUP62, involved in nucleo-cytoplasmic trafficking. By querying sequencing-datasets of patients with dystonia and/or Leigh(-like) syndromes, we identified 3 unrelated individuals with biallelic variants in NUP54. All variants clustered in the C-terminal protein region that interacts with NUP62. Associated phenotypes were similar to those of NUP62-related disease, including early-onset dystonia with dysphagia, choreoathetosis, and T2-hyperintense lesions in striatum. In silico and protein-biochemical studies gave further evidence for the argument that the variants were pathogenic. We expand the spectrum of NPC component-associated dystonic conditions with localized basal-ganglia abnormalities. ANN NEUROL 2023;93:330-335., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Since the first European-wide evaluation of dystonia management in 2016, several efforts have been made to improve dystonia-care. One of these was the development of the Dystonia Disease Group as a part of the European Reference Network for Rare Neurological Diseases (ERN-RND) that implemented several initiatives based on the recommendations made in 2016., Aim: To evaluate the current state of dystonia management across Europe., Methods: Twenty-four countries were surveyed via 62 dystonia-experts from 44 ERN-RND-related centers., Results: Dystonia-experts for adult patients were available in all surveyed countries. However, almost half of the countries evaluated accessibility as merely 'satisfactory'. Access to genetic and neurophysiological testing was challenging to varying degrees in over half of countries. Main oral medications and botulinum toxin were available in all countries. Deep brain stimulation (DBS) was easily accessible in one-third of the countries. Dystonia research was conducted in 20/24 countries. Trainings on dystonia for general practitioners (GPs) were available in 11/24 countries. However, lack of trainings for other professionals was almost general. For pediatric dystonia, experts and specific training were available in over half of the countries., Conclusions: In this overview, we present the current state of dystonia management within ERN-RND. Management has slightly improved since 2016 in several fields, including diagnostics, availability of DBS, and research. The results highlight that future challenges in dystonia management are accessibility of experts, and diagnostic tools and treatments, education on adult and childhood dystonia, and optimization of referral pathways. These findings are important for improving dystonia care across Europe., (© 2022. The Author(s).)

SGCE myoclonus-dystonia is a monogenic form of dystonia with an autosomal dominant mode of inheritance that co-occurs with a myoclonic jerk. In this study, we present 12 Japanese patients from nine families with this disease. Targeted next-generation sequencing covering major causative genes for monogenic dystonias identified nine distinct SGCE mutations from each of the families: three nonsense, two frameshift, two missense, one in-frame 15 bp deletion, and one splice donor site mutations, of which four were previously unreported. One missense mutation (c.662G>T, p.Gly221Val) was located at the 3' end of exon 5 (NM&#95;001099400), which was predicted to cause aberrant splicing according to in silico predictions. Minigene assays performed together with the c.825+1G>C mutation demonstrated complete skipping of exon 5 and 6, respectively, in their transcripts. The other missense (c.1345A>G, p.Met449Val) and 15 bp deletion (c.168&#95;182del, p.Phe58&#95;Leu62del) mutations showed a significant reduction in cell membrane expression via HiBiT bioluminescence assay. Therefore, we concluded that all the detected mutations were disease-causing. Unlike the other detected mutations, p.Met449Val affects only isoform 3 (NP&#95;001092870 encoded by NM&#95;001099400) among the variously known isoforms of SGCE. This isoform is brain-specific and is mostly expressed in the cerebellum, which supports recent studies showing that cerebellar dysfunction is a key element in the pathophysiology of SGCE myoclonus-dystonia., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Dystonia is characterized by sustained or intermittent muscle contractions, leading to abnormal posturing and twisting movements. In pediatric patients, dystonia often negatively influences quality of life. Pharmacological treatment for dystonia is often inadequate and causes adverse effects. Deep brain stimulation (DBS) appears to be a valid therapeutic option for pharmacoresistant dystonia in children., Methods: To illustrate the current clinical practice, we hereby describe two pediatric cases of monogenetic movement disorders presenting with dystonia and treated with DBS. We provide a literature review of similar previously described cases and on different clinical aspects of DBS in pediatric dystonia., Results: The first patient, a 6-year-old girl with severe dystonia, chorea, and myoclonus due to an ADCY5 gene mutation, received DBS in an elective setting. The second patient, an 8-year-old boy with GNAO1 -related dystonia and chorea, underwent emergency DBS due to a pharmacoresistant status dystonicus. A significant amelioration of motor symptoms (65% on the Burke-Fahn-Marsden Dystonia Rating Scale) was observed postoperatively in the first patient and her personal therapeutic goals were achieved. DBS was previously reported in five patients with ADCY5 -related movement disorders, of which three showed objective improvement. Emergency DBS in our second patient resulted in the successful termination of his GNAO1 -related status dystonicus, this being the eighth case reported in the literature., Conclusion: DBS can be effective in monogenetic pediatric dystonia and should be considered early in the disease course. To better evaluate the effects of DBS on patients' functioning, patient-centered therapeutic goals should be discussed in a multidisciplinary approach., Competing Interests: M.B. was awarded the TKI-PPP grant in 2021. A.I.B. is the chair of the board of the Dutch Academy of Childhood Disability. J.M.D. was awarded the Netherlands Organization for Health Research and Development grant and a Medtronic grant. J.M.D. is the president of the Netherlands workgroup for Movement Disorders. P.R.S. was awarded consulting fees from Boston Scientific, Medtronic, Elekta and lecture fees from Boston Scientific and Elekta. P.R.S. is the treasurer of the European Society for Stereotactic and Functional Neurosurgery, an associate editor of the Journal of Parkinson's Disease and is in the advisory board of Boston Scientific and Insightec., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Dystonia is currently ranked as the third most prevalent motor disorder. It is typically characterized by involuntary muscle over- or co-contractions that can cause painful abnormal postures and jerky movements. Dystonia is a heterogenous disorder-across patients, dystonic symptoms vary in their severity, body distribution, temporal pattern, onset, and progression. There are also a growing number of genes that are associated with hereditary dystonia. In addition, multiple brain regions are associated with dystonic symptoms in both genetic and sporadic forms of the disease. The heterogeneity of dystonia has made it difficult to fully understand its underlying pathophysiology. However, the use of animal models has been used to uncover the complex circuit mechanisms that lead to dystonic behaviors. Here, we summarize findings from animal models harboring mutations in dystonia-associated genes and phenotypic animal models with overt dystonic motor signs resulting from spontaneous mutations, neural circuit perturbations, or pharmacological manipulations. Taken together, an emerging picture depicts dystonia as a result of brain-wide network dysfunction driven by basal ganglia and cerebellar dysfunction. In the basal ganglia, changes in dopaminergic, serotonergic, noradrenergic, and cholinergic signaling are found across different animal models. In the cerebellum, abnormal burst firing activity is observed in multiple dystonia models. We are now beginning to unveil the extent to which these structures mechanistically interact with each other. Such mechanisms inspire the use of pre-clinical animal models that will be used to design new therapies including drug treatments and brain stimulation., (Copyright © 2023. Published by Elsevier Inc.)

Dystonia syndromes encompass a heterogeneous group of movement disorders which might be differentiated by several clinical-historical features. Among the latter, age-at-onset is probably the most important in predicting the likelihood both for the symptoms to spread from focal to generalized and for a genetic cause to be found. Accordingly, dystonia syndromes are generally stratified into early-onset and late-onset forms, the former having a greater likelihood of being monogenic disorders and the latter to be possibly multifactorial diseases, despite being currently labeled as idiopathic. Nonetheless, there are several similarities between these two groups of dystonia, including shared pathophysiological and biological mechanisms. Moreover, there is also initial evidence of age-related modifiers of early-onset dystonia syndromes and of critical periods of vulnerability of the sensorimotor network, during which a combination of genetic and non-genetic insults is more likely to produce symptoms. Based on these lines of evidence, we reappraise the double-hit hypothesis of dystonia, which would accommodate both similarities and differences between early-onset and late-onset dystonia in a single framework., (Copyright © 2023. Published by Elsevier Inc.)

Background: Cerebral Palsy (CP) represents a frequent cause of disability in childhood. Early in life, genetic disorders may present with motor dysfunction and diagnosed as CP. Establishing the primary, genetic etiology allows more accurate prognosis, genetic counselling, and planning for symptomatic interventions in homogeneous etiological groups. Deep brain stimulation (DBS) is recommended in refractory movement disorders, including isolated pediatric dystonias. For dystonia evolving in more complex associations in genetic CP, the effect of DBS is still understudied and currently only sporadically described., Objectives: To report the effect of DBS applied to the globus pallidus pars interna (GPi) in children with complex movement disorders caused by pathogenic ADCY5 variants, diagnosed as dyskinetic CP previous to genetic diagnostic., Methods: We conducted a retrospective study on evolution of treatment with DBS in ADCY5-related disease. A standardized proforma including the different type of movement disorders and associated neurological signs was completed at each follow-up time, based on video recordings, as well as functional assessments used in children with CP., Results: Four children (mean of age, 13 ± 2.9 years) received GPi-DBS. The same de novo pathogenic missense variant (c.1252C > T, p.R418W) was identified in three out of four and a splice site variant (c.2088 + 2G > T) in one subject. Developmental delay and overlapping features including axial hypotonia, chorea, dystonic attacks, myoclonus, and cranial dyskinesia were present. The median age at DBS was 9 years and follow-up with DBS, 2.6 years. We identified a pattern of clinical response with early suppression of dystonic attacks, followed by improvement of myoclonus and facial dyskinesia. Effect on chorea was delayed and more limited. Two patients gained notable functional benefit related to sitting, standing, gait, use of upper limbs and speech., Conclusion: ADCY5-related disease may benefit from GPi-DBS. The most significant clinical response relates to the early and sustained benefit on dystonic attacks and a variable but still positive response on the other hyperkinetic features. Genetic etiology of CP will contribute to further elucidate genotype-phenotype correlations and to refine DBS indication as network-related symptomatic interventions., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest related to this manuscript., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Dystonia is a hyperkinetic movement disorder with a unique motor phenomenology that can manifest as an isolated clinical syndrome or combined with other neurological features. This chapter reviews the characteristic features of dystonia phenomenology and the syndromic approach to evaluating the disorders that may allow us to differentiate the isolated and combined syndromes. We also present the most common types of isolated and combined dystonia syndromes. Since accelerated gene discoveries have increased our understanding of the molecular mechanisms of dystonia pathogenesis, we also present isolated and combined dystonia syndromes by shared biological pathways. Examples of these converging mechanisms of the isolated and combined dystonia syndromes include (1) disruption of the integrated response pathway through eukaryotic initiation factor 2 alpha signaling, (2) disease of dopaminergic signaling, (3) alterations in the cerebello-thalamic pathway, and (4) disease of protein mislocalization and stability. The discoveries that isolated and combined dystonia syndromes converge in shared biological pathways will aid in the development of clinical trials and therapeutic strategies targeting these convergent molecular pathways., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Since the discovery of the treatment for Wilson disease a growing number of treatable inherited dystonias have been identified and their search and treatment have progressively been implemented in the clinics of patients with dystonia. While waiting for gene therapy to be more widely and adequately translated into the clinical setting, the efforts to divert the natural course of dystonia reside in unveiling its pathogenesis. Specific metabolic treatments can rewrite the natural history of the disease by preventing neurotoxic metabolite accumulation or interfering with the cell accumulation of damaging metabolites, restoring energetic cell fuel, supplementing defective metabolites, and supplementing the defective enzyme. A metabolic derangement of cell homeostasis is part of the progression of many non-metabolic genetic lesions and could be the target for possible metabolic approaches. In this chapter, we provided an update on treatment strategies for treatable inherited dystonias and an overview of genetic dystonias with new experimental therapeutic approaches available or close to clinical translation., (Copyright © 2023. Published by Elsevier Inc.)

Background: Dystonia is a rare movement disorder, in which patients suffer from involuntary twisting movements or abnormal posturing. Next to these motor symptoms, patients have a high prevalence of psychiatric comorbidity, suggesting a role for serotonin in its pathophysiology. This study investigates the percentage of DNA methylation of the gene encoding for the serotonin reuptake transporter (SLC6A4) in dystonia patients and the associations between methylation levels and presence and severity of psychiatric symptoms., Methods: Patients with cervical dystonia (n = 49), myoclonus dystonia (n = 41) and dopa-responsive dystonia (DRD) (n = 27) and a group of healthy controls (n = 56) were included. Psychiatric comorbidity was evaluated with validated questionnaires. Methylation levels of 20 CpG sites situated 69 to 213 base pairs upstream of the start codon of SLC6A4 were investigated. Methylation in dystonia patients was compared to healthy controls, correcting for age, and correlated with psychiatric comorbidity., Results: Bootstrapped quantile regression analysis showed that being a dystonia patient compared to a healthy control significantly explains the methylation level at two CpG sites (CpG 24: pseudo-R 2  = 0.05, p = 0.04, CpG 32: pseudo-R 2  = 0.14, p = 0.03). Subgroup analysis revealed that being a DRD patient significantly explained a part of the variance of methylation levels at two CpG sites (CpG 21: pseudo-R 2  = 0.03, p = 0.00, CpG 24: pseudo-R 2  = 0.06, p = 0.03). Regression analysis showed that methylation level at CpG 38 significantly explained a small proportion of the variance of severity score for anxiety (R 2  = 0.07, p = 0.04) and having a diagnosis of depression (Nagelkerke R 2 : 0.11, p = 0.00). Genotype of the 5-HTTLPR polymorphism had no additional effect on these associations., Conclusions: This study showed an association between percentage of methylation at several specific sites of the promoter region of SLCA64 and (dopa-responsive) dystonia patients compared to healthy controls. Furthermore, methylation levels were associated with severity of anxiety and presence of a depressive disorder in the dystonia group. This study suggests alterations in the serotonergic metabolism in dystonia patients, and its relation with the non-motor symptoms., (© 2022. The Author(s).)

The spectrum of non-motor symptoms in dystonia remains unclear. Using UK Biobank data, we analysed clinical phenotypic and genetic information in the largest dystonia cohort reported to date. Case-control comparison of dystonia and matched control cohort was undertaken to identify domains (psychiatric, pain, sleep and cognition) of increased symptom burden in dystonia. Whole exome data were used to determine the rate and likely pathogenicity of variants in Mendelian inherited dystonia causing genes and linked to clinical data. Within the dystonia cohort, phenotypic and genetic single-nucleotide polymorphism (SNP) data were combined in a mixed model analysis to derive genetically informed phenotypic axes. A total of 1572 individuals with dystonia were identified, including cervical dystonia (n = 775), blepharospasm (n = 131), tremor (n = 488) and dystonia, unspecified (n = 154) groups. Phenotypic patterns highlighted a predominance of psychiatric symptoms (anxiety and depression), excess pain and sleep disturbance. Cognitive impairment was limited to prospective memory and fluid intelligence. Whole exome sequencing identified 798 loss of function variants in dystonia-linked genes, 67 missense variants (MPC > 3) and 305 other forms of non-synonymous variants (including inframe deletion, inframe insertion, stop loss and start loss variants). A single loss of function variant (ANO3) was identified in the dystonia cohort. Combined SNP and clinical data identified multiple genetically informed phenotypic axes with predominance of psychiatric, pain and sleep non-motor domains. An excess of psychiatric, pain and sleep symptoms were evident across all forms of dystonia. Combination with genetic data highlights phenotypic subgroups consistent with the heterogeneity observed in clinical practice., (© 2022. The Author(s).)

Background: Mutations in SOX6 have recently been recognized as a new molecular cause of neurodevelopmental disorders characterized by intellectual disability, behavioral changes, and nonspecific facial and digital skeletal abnormalities. To date, <25 cases have been reported in the literature., Methods and Findings: Here we report a new case of SOX6-associated neurodegeneration and expand the phenotype to include ceratoconus. The clinical picture consisted of early onset mildly reduced intellectual function, facial asymmetry, and dystonic tremor of hands and neck, substantially improved by levodopa. Skeletal abnormalities included scoliosis and hypertrophy of the mandibular coronoid process. A heterozygous de novo loss-of-function variant in SOX6 (c.277 C>T. p.Arg93*) was molecularly confirmed which leads to truncation of the SOX6 protein in its N-terminus, upstream of any known functional domain., Conclusion: SOX6-associated neurodevelopmental delayis ultrarare with less than 25 cases described in the literature. We report a new case who presented with early-onset mildly reduced intellectual function, facial asymmetry, skeletal abnormalities and dystonic tremor of hands and neck, substantially improved by levodopa. Given the therapeutic implications, SOX6 mutations should be considered in patients with complex dystonia parkinsonism., (© 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

The patient exhibited plantarflexion during walking at the age of five. He then developed writer's cramp at the age of six, dysphonia at 15 years, and action-induced dystonia with left knee elevation and trunk swinging when walking at 16 years, which subsequently spread to the right leg at 19 years. Levodopa therapy was ineffective for dystonia. Brain MRI showed no abnormalities. He was diagnosed with DYT28 after detecting a novel heterozygous mutation (c.433C>T, p.Arg145*) in the KMT2B gene using whole-exome sequencing at age 39. Furthermore, the patient's parents exhibited normal alleles, confirming the de novo status of KMT2B gene mutation. We should consider DYT28 in addition to DYT1 and DYT5 in patients who developed leg dystonia in childhood.

DYT6 dystonia is caused by mutations in the transcription factor THAP1. THAP1 knock-out or knock-in mouse models revealed complex gene expression changes, which are potentially responsible for the pathogenesis of DYT6 dystonia. However, how THAP1 mutations lead to these gene expression alterations and whether the gene expression changes are also reflected in the brain of THAP1 patients are still unclear. In this study we used epigenetic and transcriptomic approaches combined with multiple model systems [THAP1 patients' frontal cortex, THAP1 patients' induced pluripotent stem cell (iPSC)-derived midbrain dopaminergic neurons, THAP1 heterozygous knock-out rat model, and THAP1 heterozygous knock-out SH-SY5Y cell lines] to uncover a novel function of THAP1 and the potential pathogenesis of DYT6 dystonia. We observed that THAP1 targeted only a minority of differentially expressed genes caused by its mutation. THAP1 mutations lead to dysregulation of genes mainly through regulation of SP1 family members, SP1 and SP4, in a cell type dependent manner. Comparing global differentially expressed genes detected in THAP1 patients' iPSC-derived midbrain dopaminergic neurons and THAP1 heterozygous knock-out rat striatum, we observed many common dysregulated genes and 61 of them were involved in dystonic syndrome-related pathways, like synaptic transmission, nervous system development, and locomotor behaviour. Further behavioural and electrophysiological studies confirmed the involvement of these pathways in THAP1 knock-out rats. Taken together, our study characterized the function of THAP1 and contributes to the understanding of the pathogenesis of primary dystonia in humans and rats. As SP1 family members were dysregulated in some neurodegenerative diseases, our data may link THAP1 dystonia to multiple neurological diseases and may thus provide common treatment targets., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Purpose: HIBCH and ECHS1 genes encode two enzymes implicated in the critical steps of valine catabolism, 3-hydroxyisobutyryl-coenzyme A (CoA) hydrolase (HIBCH) and short-chainenoyl-CoA hydratase (ECHS1), respectively. HIBCH deficiency (HIBCHD) and ECHS1 deficiency (ECHS1D) generate rare metabolic dysfunctions, often revealed by neurological symptoms. The aim of this study was to describe movement disorders spectrum in patients with pathogenic variants in ECHS1 and HIBC., Methods: We reviewed a series of 18 patients (HIBCHD: 5; ECHS1D: 13) as well as 105 patients from the literature. We analysed the detailed phenotype of HIBCHD (38 patients) and ECHS1D (85 patients), focusing on MDs., Results: The two diseases have a very similar neurological phenotype, with an early onset before 10 years of age for three clinical presentations: neonatal onset, Leigh-like syndrome (progressive onset or acute neurological decompensation), and isolated paroxysmal dyskinesia. Permanent or paroxysmal MDs were recorded in 61% of HIBCHD patients and 72% of ECHS1D patients. Patients had a variable combination of either isolated or combined MD, and dystonia was the main MD. These continuous MDs included dystonia, chorea, parkinsonism, athetosis, myoclonus, tremors, and abnormal eye movements. Patients with paroxysmal dyskinesia (HIBCHD: 4; ECHS1D: 9) usually had pure paroxysmal dystonia with normal clinical examination and no major impairment in psychomotor development. No correlation could be identified between clinical pattern (especially MD) and genetic pathogenic variants., Conclusions: Movement disorders, including abnormal ocular movements, are a hallmark of HIBCHD and ECHS1D. MDs are not uniform; dystonia is the most frequent, and various types of MD are combined in single patient., (© 2022 European Academy of Neurology.)

Background and Objective: The objective of this study was to better delineate the genetic landscape and key clinical characteristics of complex, early-onset, monogenic hyperkinetic movement disorders., Methods: Patients were recruited from 14 international centers. Participating clinicians completed standardized proformas capturing demographic, clinical, and genetic data. Two pediatric movement disorder experts reviewed available video footage, classifying hyperkinetic movements according to published criteria., Results: One hundred forty patients with pathogenic variants in 17 different genes (ADCY5, ATP1A3, DDC, DHPR, FOXG1, GCH1, GNAO1, KMT2B, MICU1, NKX2.1, PDE10A, PTPS, SGCE, SLC2A1, SLC6A3, SPR, and TH) were identified. In the majority, hyperkinetic movements were generalized (77%), with most patients (69%) manifesting combined motor semiologies. Parkinsonism-dystonia was characteristic of primary neurotransmitter disorders (DDC, DHPR, PTPS, SLC6A3, SPR, TH); chorea predominated in ADCY5-, ATP1A3-, FOXG1-, NKX2.1-, SLC2A1-, GNAO1-, and PDE10A-related disorders; and stereotypies were a prominent feature in FOXG1- and GNAO1-related disease. Those with generalized hyperkinetic movements had an earlier disease onset than those with focal/segmental distribution (2.5 ± 0.3 vs. 4.7 ± 0.7 years; P = 0.007). Patients with developmental delay also presented with hyperkinetic movements earlier than those with normal neurodevelopment (1.5 ± 2.9 vs. 4.7 ± 3.8 years; P &lt; 0.001). Effective disease-specific therapies included dopaminergic agents for neurotransmitters disorders, ketogenic diet for glucose transporter deficiency, and deep brain stimulation for SGCE-, KMT2B-, and GNAO1-related hyperkinesia., Conclusions: This study highlights the complex phenotypes observed in children with genetic hyperkinetic movement disorders that can lead to diagnostic difficulty. We provide a comprehensive analysis of motor semiology to guide physicians in the genetic investigation of these patients, to facilitate early diagnosis, precision medicine treatments, and genetic counseling. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Episodic ataxia type 1 and 2 (EA1 and EA2) are the most well-described of the episodic ataxias. They are autosomal dominantly inherited early-onset diseases characterized by attacks of cerebellar dysfunction. EA1 is clinically characterized by short episodes of ataxia with interictal myokymia, whereas EA2 is characterized by longer-lasting recurrent ataxia, slurred speech, and interictal nystagmus. We report on a patient with EA2 with interictal focal dystonia and also interictal myokymia, which is hitherto not reported as an interictal feature associated to EA2. The patient carries a previously described heterozygous pathogenic de novo frameshift variant in the CACNA1A gene, establishing the diagnosis of EA2. She had symptom onset at age 13 and from age 48 she developed interictal myokymia and focal dystonia as illustrated in Supplemental Movie S1. We conclude that interictal myokymia and focal dystonia may be interictal features associated to EA2 caused by the cerebellar pathophysiology of EA2. Episodes of ataxia were successfully treated with acetazolamide in low dose, whereas the interictal features were unresponsive to acetazolamide., (© 2022 Nielsen et al.; Published by Cold Spring Harbor Laboratory Press.)

Over the last decade, several clinical reports have outlined cases of childhood-onset manganese (Mn)-induced dystonia-parkinsonism, resulting from loss-of-function mutations in the Mn influx transporter gene SLC39A14 . These clinical cases have provided a wealth of knowledge on Mn toxicity and homeostasis. However, our current understanding of the underlying neuropathophysiology is severely lacking. The recent availability of Slc39a14 knockout (KO) murine and zebrafish animal models provide a powerful platform to investigate the neurological effects of elevated blood and brain Mn concentrations in vivo. As such, the objective of this review was to organize and summarize the current clinical literature and studies utilizing Slc39a14 -KO animal models and assess the validity of the animal models based on the clinical presentation of the disease in human mutation carriers.

Background and Objectives: ATP1A3 is associated with a broad spectrum of predominantly neurologic disorders, which continues to expand beyond the initially defined phenotypes of alternating hemiplegia of childhood, rapid-onset dystonia parkinsonism, and cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss syndrome. This phenotypic variability makes it challenging to assess the pathogenicity of an ATP1A3 variant found in an undiagnosed patient. We describe the phenotypic features of individuals carrying a pathogenic/likely pathogenic ATP1A3 variant and perform a literature review of all ATP1A3 variants published thus far in association with human neurologic disease. Our aim is to demonstrate the heterogeneous clinical spectrum of the gene and look for phenotypic overlap between patients that will streamline the diagnostic process., Methods: Undiagnosed individuals with ATP1A3 variants were identified within the cohort of the Deciphering Developmental Disorders study with additional cases contributed by collaborators internationally. Detailed clinical data were collected with consent through a questionnaire completed by the referring clinicians. PubMed was searched for publications containing the term "ATP1A3" from 2004 to 2021., Results: Twenty-four individuals with a previously undiagnosed neurologic phenotype were found to carry 21 ATP1A3 variants. Eight variants have been previously published. Patients experienced on average 2-3 different types of paroxysmal events. Permanent neurologic features were common including microcephaly (7; 29%), ataxia (13; 54%), dystonia (10; 42%), and hypotonia (7; 29%). All patients had cognitive impairment. Neuropsychiatric diagnoses were reported in 16 (66.6%) individuals. Phenotypes were extremely varied, and most individuals did not fit clinical criteria for previously published phenotypes. On review of the literature, 1,108 individuals have been reported carrying 168 different ATP1A3 variants. The most common variants are associated with well-defined phenotypes, while more rare variants often result in very rare symptom correlations, such as are seen in our study. Combined Annotation-Dependent Depletion (CADD) scores of pathogenic and likely pathogenic variants were significantly higher and variants clustered within 6 regions of constraint., Discussion: Our study shows that looking for a combination of paroxysmal events, hyperkinesia, neuropsychiatric symptoms, and cognitive impairment and evaluating the CADD score and variant location can help identify an ATP1A3 -related condition, rather than applying diagnostic criteria alone., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Despite advances in next generation sequencing technologies, the identification of variants of uncertain significance (VUS) can often hinder definitive diagnosis in patients with complex neurodevelopmental disorders., Objective: The objective of this study was to identify and characterize the underlying cause of disease in a family with two children with severe developmental delay associated with generalized dystonia and episodic status dystonicus, chorea, epilepsy, and cataracts., Methods: Candidate genes identified by autozygosity mapping and whole-exome sequencing were characterized using cellular and vertebrate model systems., Results: Homozygous variants were found in three candidate genes: MED27, SLC6A7, and MPPE1. Although the patients had features of MED27-related disorder, the SLC6A7 and MPPE1 variants were functionally investigated. SLC6A7 variant in vitro overexpression caused decreased proline transport as a result of reduced cell-surface expression, and zebrafish knockdown of slc6a7 exhibited developmental delay and fragile motor neuron morphology that could not be rescued by L-proline transporter-G396S RNA. Lastly, patient fibroblasts displayed reduced cell-surface expression of glycophosphatidylinositol-anchored proteins linked to MPPE1 dysfunction., Conclusions: We report a family harboring a homozygous MED27 variant with additional loss-of-function SLC6A7 and MPPE1 gene variants, which potentially contribute to a blended phenotype caused by multilocus pathogenic variants. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Adult-onset dystonia can be acquired, inherited or idiopathic. The dystonia is usually focal or segmental and for a limited number of cases causal treatment is available. In recent years, rapid developments in neuroimmunology have led to increased knowledge on autoantibody-related dystonias. At the same time, genetic diagnostics in sequencing technology have evolved and revealed several new genes associated with adult-onset dystonia. Furthermore, new phenotype-genotype correlations have been elucidated. Consequently, clinicians face the dilemma of which additional investigations should be performed and whether to perform genetic testing or not. To ensure early diagnosis and to prevent unnecessary investigations, integration of new diagnostic strategies is needed.We designed a new five-step diagnostic approach for adult-onset dystonia. The first four steps are based on a broad literature search and expert opinion, the fifth step, on when to perform genetic testing, is based on a detailed systematic literature review up to 1 December 2021.The basic principle of the algorithm is that genetic testing is unlikely to lead to changes in management in three groups: (1) patients with an acquired form of adult-onset dystonia; (2) patients with neurodegenerative disorders, presenting with a combined movement disorder including dystonic symptoms and (3) patients with adult-onset isolated focal or segmental dystonia. Throughout the approach, focus lies on early identification of treatable forms of dystonia, either acquired or genetic.This novel diagnostic approach for adult-onset dystonia can help clinicians to decide when to perform additional tests, including genetic testing and facilitates early aetiological diagnosis, to enable timely treatment., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose of Review: This article discusses the most recent findings regarding the diagnosis, classification, and management of genetic and idiopathic dystonia., Recent Findings: A new approach to classifying dystonia has been created with the aim to increase the recognition and diagnosis of dystonia. Molecular biology and genetic studies have identified several genes and biological pathways involved in dystonia., Summary: Dystonia is a common movement disorder involving abnormal, often twisting, postures and is a challenging condition to diagnose. The pathophysiology of dystonia involves abnormalities in brain motor networks in the context of genetic factors. Dystonia has genetic, idiopathic, and acquired forms, with a wide phenotypic spectrum, and is a common feature in complex neurologic disorders. Dystonia can be isolated or combined with another movement disorder and may be focal, segmental, multifocal, or generalized in distribution, with some forms only occurring during the performance of specific tasks (task-specific dystonia). Dystonia is classified by clinical characteristics and presumed etiology. The management of dystonia involves accurate diagnosis, followed by treatment with botulinum toxin injections, oral medications, and surgical therapies (mainly deep brain stimulation), as well as pathogenesis-directed treatments, including the prospect of disease-modifying or gene therapies., (Copyright © 2022 American Academy of Neurology.)

Background: DYT6 dystonia belongs to a group of isolated, genetically determined, generalized dystonia associated with mutations in the THAP1 gene., Case Presentation: We present the case of a young patient with DYT6 dystonia associated with a newly discovered c14G>A (p.Cys5Tyr) mutation in the THAP1 gene. We describe the clinical phenotype of this new mutation, effect of pallidal deep brain stimulation (DBS), which was accompanied by two rare postimplantation complications: an early intracerebral hemorrhage and delayed epileptic seizures. Among the published case reports of patients with DYT6 dystonia, the mentioned complications have not been described so far., Conclusions: DBS in the case of DYT6 dystonia is a challenge to thoroughly consider possible therapeutic benefits and potential risks associated with surgery. Genetic heterogeneity of the disease may also play an important role in predicting the development of the clinical phenotype as well as the effect of treatment including DBS. Therefore, it is beneficial to analyze the genetic and clinical relationships of DYT6 dystonia., (© 2022. The Author(s).)

Introduction: KMT2B-related dystonia is a recently described subtype of focal-onset dystonia in the lower limbs, evolving into a generalized form with cervical, oropharyngeal involvement, dysarthria, swallowing disorder and intellectual disability. Clinical case: We describe the case of a 10-year-old female patient, without a history of consanguinity or neurological disease. She manifested abnormal gait and dystonia with focal onset and progressive course with evolution into generalized dystonia, affecting orofacial and bulbar muscles, significant alteration of language and swallowing. Metabolic and systemic studies, including neuroimaging, were found to be normal. A complete genomic sequencing study was performed identifying a new, probably pathogenic, heterozygous variant in the KMT2B gene, c.1205delC, p. (Pro402Hisfs*5), causing displacement in the reading frame, a finding that explains the patient’s phenotype and it is associated to autosomal dominant childhood-onset dystonia-28. Conclusion: We report a new heterozygous mutation in the KMT2B gene as a cause of generalized early-onset dystonia not reported in the literature until the date. The diagnosis of this pathology has implications for the treatment and prognosis of patients, given that therapeutic strategies implemented early can prevent the fast deterioration and severe course of this disease.

Introduction: Although shared genetic factors have been previously reported between dystonia and other neurologic conditions, no sequencing study exploring such links is available. In a large dystonic cohort, we aimed at analyzing the proportions of causative variants in genes associated with disease categories other than dystonia., Methods: Gene findings related to whole-exome sequencing-derived diagnoses in 1100 dystonia index cases were compared with expert-curated molecular testing panels for ataxia, parkinsonism, spastic paraplegia, neuropathy, epilepsy, and intellectual disability., Results: Among 220 diagnosed patients, 21% had variants in ataxia-linked genes; 15% in parkinsonism-linked genes; 15% in spastic-paraplegia-linked genes; 12% in neuropathy-linked genes; 32% in epilepsy-linked genes; and 65% in intellectual-disability-linked genes. Most diagnosed presentations (80%) were related to genes listed in ≥1 studied panel; 71% of the involved loci were found in the non-dystonia panels but not in an expert-curated gene list for dystonia., Conclusions: Our study indicates a convergence in the genetics of dystonia and other neurologic phenotypes, informing diagnostic evaluation strategies and pathophysiological considerations., Competing Interests: Declaration of competing interest None of the authors report disclosures concerning the present manuscript., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Animal and human brain-imaging studies have suggested a role for neurodevelopmental abnormalities in the pathophysiology of dystonia. Variants in neurodevelopmental genes have also been sporadically implicated, although no systematic investigation has been undertaken before the more widespread availability of genome-wide sequencing techniques. Here, we review findings from recent whole-exome and whole-genome sequencing approaches in individuals with dystonic conditions, indicating that more than 50% of molecularly diagnosed cases may have variants in neurodevelopmental disorder-associated genes. We describe how genomic sequencing has contributed to phenotypic expansions of several known hereditary forms of dystonia to include classical neurodevelopmental features. Moreover, we demonstrate that many of the newly reported monogenic neurodevelopmental disorders can manifest with prominent dystonic presentations, including isolated generalized dystonia, paroxysmal dystonia, and dopa-responsive dystonia-parkinsonism. Considering the published evidence, we argue that the clinical feature dystonia might be regarded as an expression of developmental brain dysfunction, a status referring to the common etiological basis of many neurodevelopmental disease traits. Finally, we provide a view into clinical implications, including the necessity to integrate the interrogation of neurodevelopmental disorder-associated genes into the molecular analysis process of patients with dystonia. Recognizing the relationship between dystonia and neurodevelopmental disorders is important to improve patient counseling and management and develop novel therapeutic strategies., Competing Interests: Declaration of competing interest None of the authors report disclosures concerning the present manuscript., (Copyright © 2022 Elsevier Ltd. All rights reserved.)