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Background: Protein synthesis is a tightly controlled process, involving a host of translation-initiation factors and microRNA-associated repressors. Variants in the translational regulator EIF2AK2 were first linked to neurodevelopmental-delay phenotypes, followed by their implication in dystonia. Recently, de novo variants in EIF4A2, encoding eukaryotic translation initiation factor 4A isoform 2 (eIF4A2), have been described in pediatric cases with developmental delay and intellectual disability., Objective: We sought to characterize the role of EIF4A2 variants in dystonic conditions., Methods: We undertook an unbiased search for likely deleterious variants in mutation-constrained genes among 1100 families studied with dystonia. Independent cohorts were screened for EIF4A2 variants. Western blotting and immunocytochemical studies were performed in patient-derived fibroblasts., Results: We report the discovery of a novel heterozygous EIF4A2 frameshift deletion (c.896_897del) in seven patients from two unrelated families. The disease was characterized by adolescence- to adulthood-onset dystonia with tremor. In patient-derived fibroblasts, eIF4A2 production amounted to only 50% of the normal quantity. Reduction of eIF4A2 was associated with abnormally increased levels of IMP1, a target of Ccr4-Not, the complex that interacts with eIF4A2 to mediate microRNA-dependent translational repression. By complementing the analyses with fibroblasts bearing EIF4A2 biallelic mutations, we established a correlation between IMP1 expression alterations and eIF4A2 functional dosage. Moreover, eIF4A2 and Ccr4-Not displayed significantly diminished colocalization in dystonia patient cells. Review of international databases identified EIF4A2 deletion variants (c.470_472del, c.1144_1145del) in another two dystonia-affected pedigrees., Conclusions: Our findings demonstrate that EIF4A2 haploinsufficiency underlies a previously unrecognized dominant dystonia-tremor syndrome. The data imply that translational deregulation is more broadly linked to both early neurodevelopmental phenotypes and later-onset dystonic conditions. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Most episodic ataxias (EA) are autosomal dominantly inherited and characterized by recurrent attacks of ataxia and other paroxysmal and non-paroxysmal features. EA is often caused by pathogenic variants in the CACNA1A, KCNA1, PDHA1, and SLC1A3 genes, listed as paroxysmal movement disorders (PxMD) by the MDS Task Force on the Nomenclature of Genetic Movement Disorders. Little is known about the genotype-phenotype correlation of the different genetic EA forms., Methods: We performed a systematic review of the literature to identify individuals affected by an episodic movement disorder harboring pathogenic variants in one of the four genes. We applied the standardized MDSGene literature search and data extraction protocol to summarize the clinical and genetic features. All data are available via the MDSGene protocol and platform on the MDSGene website (https://www.mdsgene.org/)., Results: Information on 717 patients (CACNA1A: 491, KCNA1: 125, PDHA1: 90, and SLC1A3: 11) carrying 287 different pathogenic variants from 229 papers was identified and summarized. We show the profound phenotypic variability and overlap leading to the absence of frank genotype-phenotype correlation aside from a few key 'red flags'., Conclusion: Given this overlap, a broad approach to genetic testing using a panel or whole exome or genome approach is most practical in most circumstances., (© 2023 European Academy of Neurology.)

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.)

In 2016, the Movement Disorder Society Task Force for the Nomenclature of Genetic Movement Disorders presented a new system for naming genetically determined movement disorders and provided a criterion-based list of confirmed monogenic movement disorders. Since then, a substantial number of novel disease-causing genes have been described, which warrant classification using this system. In addition, with this update, we further refined the system and propose dissolving the imaging-based categories of Primary Familial Brain Calcification and Neurodegeneration with Brain Iron Accumulation and reclassifying these genetic conditions according to their predominant phenotype. We also introduce the novel category of Mixed Movement Disorders (MxMD), which includes conditions linked to multiple equally prominent movement disorder phenotypes. In this article, we present updated lists of newly confirmed monogenic causes of movement disorders. We found a total of 89 different newly identified genes that warrant a prefix based on our criteria; 6 genes for parkinsonism, 21 for dystonia, 38 for dominant and recessive ataxia, 5 for chorea, 7 for myoclonus, 13 for spastic paraplegia, 3 for paroxysmal movement disorders, and 6 for mixed movement disorder phenotypes; 10 genes were linked to combined phenotypes and have been assigned two new prefixes. The updated lists represent a resource for clinicians and researchers alike and they have also been published on the website of the Task Force for the Nomenclature of Genetic Movement Disorders on the homepage of the International Parkinson and Movement Disorder Society (https://www.movementdisorders.org/MDS/About/Committees--Other-Groups/MDS-Task-Forces/Task-Force-on-Nomenclature-in-Movement-Disorders.htm). © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.)

Background: Neurological disorders comprise a large group of clinically and genetically heterogeneous disorders, many of which have a genetic cause. In addition to a detailed neurological examination, exome sequencing is being increasingly used as a complementary diagnostic tool to identify the underlying genetic cause in patients with unclear, supposedly genetically determined disorders., Objective: To identify the genetic cause of a complex movement disorder in five consanguineous Pakistani families., Methods: We included five consanguineous Pakistani families with complex recessively inherited movement disorders. Clinical investigation including videotaping was carried out in a total of 59 family members (4-21 per family) and MRI in six patients. Exome sequencing was performed in 4-5 family members per pedigree to explore the underlying genetic cause., Results: Patients presented a wide spectrum of neurological symptoms including ataxia and/or dystonia. We identified three novel homozygous, segregating variants in ATCAY (p.Pro200Profs*20), MCOLN1 (p.Ile184Thr), and SACS (p.Asn3040Lysfs*4) in three of the families. Thus, we were able to identify the likely cause of the disease in a considerable number of families (60%) with the relatively simple and nowadays widely available method of exome sequencing. Of note, close collaboration of neurologists and geneticists was instrumental for proper data interpretation., Conclusions: We expand the phenotypic, genotypic, and ethnical spectrum of mutations in these genes. Our findings alert neurologists that rare genetic causes should be considered in complex phenotypes regardless of ethnicity., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Movement disorders are often genetically complex with genetic risk factors playing a major role. For example, monogenic causes of Parkinson's disease (PD) can be found in only 2-5% of patients who often have an early onset (<40 years). In the majority of patients, common genetic variants seem to contribute to the disease risk. To date, 24 genetic risk factors have been identified. For restless legs syndrome (RLS), six different risk variants have been reported but no monogenic cause is known yet. For the genetic risk factors of essential tremor and dystonia, which are less well studied, only five and two candidate variants, respectively, have been described but their roles still require independent confirmation. In this review, we provide an overview on the involved genes, their function, and discuss possible, disease mechanism-driven therapies.

The system of assigning locus symbols to specify chromosomal regions that are associated with a familial disorder has a number of problems when used as a reference list of genetically determined disorders,including (I) erroneously assigned loci, (II) duplicated loci, (III) missing symbols or loci, (IV) unconfirmed loci and genes, (V) a combination of causative genes and risk factor genes in the same list, and (VI) discordance between phenotype and list assignment. In this article, we report on the recommendations of the International Parkinson and Movement Disorder Society Task Force for Nomenclature of Genetic Movement Disorders and present a system for naming genetically determined movement disorders that addresses these problems. We demonstrate how the system would be applied to currently known genetically determined parkinsonism, dystonia, dominantly inherited ataxia, spastic paraparesis, chorea, paroxysmal movement disorders, neurodegeneration with brain iron accumulation, and primary familial brain calcifications. This system provides a resource for clinicians and researchers that, unlike the previous system, can be considered an accurate and criterion-based list of confirmed genetically determined movement disorders at the time it was last updated., (© 2016 International Parkinson and Movement Disorder Society.)

A number of genetic causes of movement disorders including Parkinson disease, dystonia, restless legs syndrome or essential tremor have been elucidated in recent years. This process was accelerated by novel technologies including genome-wide association studies (GWAS) and next generation sequencing (NGS). Although monogenic forms are overall rare, they provide a unique opportunity to investigate mutation carriers who are still in the presymptomatic phase. As these subjects present individuals at risk to develop the disease, they have been included in longitudinal studies to unravel disease mechanisms and elucidate novel therapeutic targets. In addition, cell culture and animal studies have been performed to functionally characterize proteins mutated in different movement disorders to provide further insight into disturbed cellular pathways. In this article, we summarize known monogenic forms and the associated phenotype as well as genetic risk factors and review the function of relevant genes and proteins.

Purpose of Review: We will review the recent advances in the genetics of Parkinson disease and other movement disorders such as dystonia, essential tremor and restless legs syndrome (RLS)., Recent Findings: Mutations in VPS35 were identified as a novel cause of autosomal dominant Parkinson disease using exome sequencing. Next generation sequencing (NGS) was also used to identify PRRT2 mutations as a cause of paroxysmal kinesigenic dyskinesia (DYT10). Using a different technique, that is linkage analysis, mutations in EIF4G1 were implicated as a cause of Parkinson disease and mutations in SLC20A2 as a cause of familial idiopathic basal ganglia calcification. Furthermore, genome-wide association studies (GWAS) and meta-analyses have confirmed known risk genes and identified new risk loci in Parkinson disease, RLS and essential tremor. New models to study genetic forms of Parkinson disease, such as stem cell-derived neurons, have helped to elucidate disease-relevant molecular pathways, such as the molecular link between Gaucher disease and Parkinson disease., Summary: New genes have been implicated in Parkinson disease and other movement disorders through the use of NGS. The identification of risk variants has been facilitated by GWAS and meta-analyses. Furthermore, new models are being developed to study the molecular mechanisms involved in the pathogenesis of these diseases.

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Brüggemann N, Külper W, Hagenah J, Bauer P, Pattaro C, Tadic V, Lohnau T, Winkler S, Tönnies H, Sprenger A, Pramstaller P, Rolfs A, Siebert R, Riess O, Vieregge P, Lohmann K, Klein C. Autosomal dominant Parkinson's disease in a large German pedigree. Acta Neurol Scand: 2012: 126: 129-137. © 2011 John Wiley & Sons A/S. Objective - While several genes have been identified to cause Parkinson′s disease (PD), monogenic forms explain only a small proportion of cases. We report clinical and genetic results in a large family with late-onset autosomal dominant PD. Methods - Thirty-eight family members of a five-generation Northern German PD family underwent a detailed neurologic examination, and transcranial sonography was performed in fifteen of them. Comprehensive mutation analysis of known PD-causing genes and a genome-wide linkage analysis were performed. Results - Late-onset definite PD was found in five subjects with a mean age at onset of 63 years. Another six individuals presented either with probable/possible PD or with subtle parkinsonian signs. Six members with a mean age of 79 years had an essential tremor phenotype. Mode of PD inheritance was compatible with autosomal dominant transmission. One of three examined patients with definite PD demonstrated an increased area of substantia nigra hyperechogenicity upon transcranial sonography. Comprehensive linkage and mutational analysis excluded mutations in known PD-causing genes. Genome-wide linkage analysis suggested a putative disease gene in an 11.3-Mb region on chromosome 7p15-21.1 with a multipoint LOD score of 2.0. Conclusions - The findings in this family further demonstrate genetic heterogeneity in familial autosomal dominant late-onset PD. [ABSTRACT FROM AUTHOR]