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The ability to sequence entire exomes and genomes has revolutionized molecular testing in rare movement disorders, and genomic sequencing is becoming an integral part of routine diagnostic workflows for these heterogeneous conditions. However, interpretation of the extensive genomic variant information that is being generated presents substantial challenges. In this Perspective, we outline multidimensional strategies for genetic diagnosis in patients with rare movement disorders. We examine bioinformatics tools and computational metrics that have been developed to facilitate accurate prioritization of disease-causing variants. Additionally, we highlight community-driven data-sharing and case-matchmaking platforms, which are designed to foster the discovery of new genotype-phenotype relationships. Finally, we consider how multiomic data integration might optimize diagnostic success by combining genomic, epigenetic, transcriptomic and/or proteomic profiling to enable a more holistic evaluation of variant effects. Together, the approaches that we discuss offer pathways to the improved understanding of the genetic basis of rare movement disorders., (© 2024. Springer Nature Limited.)

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.)

Biallelic variants of the gene encoding for the zinc-finger protein 142 (ZNF142) have recently been associated with intellectual disability (ID), speech impairment, seizures, and movement disorders in nine individuals from five families. In this study, we obtained phenotype and genotype information of 26 further individuals from 16 families. Among the 27 different ZNF142 variants identified in the total of 35 individuals only four were missense. Missense variants may give a milder phenotype by changing the local structure of ZF motifs as suggested by protein modeling; but this correlation should be validated in larger cohorts and pathogenicity of the missense variants should be investigated with functional studies. Clinical features of the 35 individuals suggest that biallelic ZNF142 variants lead to a syndromic neurodevelopmental disorder with mild to moderate ID, varying degrees of delay in language and gross motor development, early onset seizures, hypotonia, behavioral features, movement disorders, and facial dysmorphism. The differences in symptom frequencies observed in the unpublished individuals compared to those of published, and recognition of previously underemphasized facial features are likely to be due to the small sizes of the previous cohorts, which underlines the importance of larger cohorts for the phenotype descriptions of rare genetic disorders., (© 2022 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

Motor complications arising after long-term treatment with levodopa remain one of the main challenges in the treatment of patients with Parkinson's disease (PD). Monotherapy with dopamine agonists may delay the onset of motor complications or reduce their severity when added to levodopa treatment. Here, we retrospectively analyzed data from 62 patients with advanced PD who presented with moderate to severe response fluctuations in whom we increased the dose of oral treatment with pergolide beyond 4.5mg daily. Patients had been treated with levodopa for 10.7+/-4.8 years. Pergolide was increased to 8.2+/-4.3 mg per day over a median titration period of 13.5 weeks. Mean daily dose of levodopa prior to pergolide high-dose treatment was 733+/-468 mg and decreased to 348+/-186 mg after pergolide titration. The duration of OFF times decreased from 7.3+/-3.8 to 1.7+/-0.9 h per day (p < 0.001) measured by patients' diaries. Dyskinesias, present for 5.0+/-3.3 h per day at baseline, were reduced to 1.4+/-0.8 h per day (p < 0.001) and the total daily duration of motor fluctuations (off-time duration plus dyskinesia duration) decreased from 10.5+/-7.0 to 2.8+/-2.2 h (p < 0.001). There was a significant improvement in parkinsonian symptoms (baseline to endpoint reduction of UPDRS III from a median of 36 to 8; p < 0.001). To reduce gastrointestinal side effects 23 patients required concomitant treatment with domperidone. Seven patients developed hallucinations during the titration period, six patients required treatment with clozapine. Our data indicate that increasing the dose of pergolide above 5mg per day can dramatically reduce the need for levodopa, motor fluctuations and severity of clinical symptoms. Controlled trials are needed to further substantiate the efficacy and safety of this treatment strategy.

This article, published in the Journal of Neurology, examines the relationship between dystonia and mitochondrial disease in 900 genetically diagnosed patients. Dystonia is a movement disorder characterized by excessive muscle contractions, and it often occurs alongside other movement disorders or neurological signs. The study analyzes two large groups of patients with dystonia and suspected mitochondrial disease to determine the frequency of mitochondrial gene defects and the prevalence of dystonia as a clinical feature. The study identifies 57 nuclear-encoded mitochondrial disease genes associated with dystonia, with the greatest overlap found in genes related to neurodegeneration with brain iron accumulation. The findings have implications for clinical practice and further research into the causes of dystonia. [Extracted from the article]

A study published in Movement Disorders Clinical Practice discusses a case of adult-onset parkinsonism as a late manifestation of HIVEP2-associated developmental disorder. The patient, a 57-year-old male, presented with gait disturbances, balance difficulties, and tremor of the lower limbs. Genetic investigation revealed a loss-of-function variant in the HIVEP2 gene, which has been linked to intellectual developmental disorder. The study suggests that neurodevelopmental genes may play a role in late-onset movement disorders and highlights the importance of genetic testing and long-term outcomes assessment in individuals with neurodevelopmental disorders. [Extracted from the article]

ATP5F1B is a subunit of the mitochondrial ATP synthase or complex V of the mitochondrial respiratory chain. Pathogenic variants in nuclear genes encoding assembly factors or structural subunits are associated with complex V deficiency, typically characterized by autosomal recessive inheritance and multisystem phenotypes. Movement disorders have been described in a subset of cases carrying autosomal dominant variants in structural subunits genes ATP5F1A and ATP5MC3. Here, we report the identification of two different ATP5F1B missense variants (c.1000A>C; p.Thr334Pro and c.1445T>C; p.Val482Ala) segregating with early-onset isolated dystonia in two families, both with autosomal dominant mode of inheritance and incomplete penetrance. Functional studies in mutant fibroblasts revealed no decrease of ATP5F1B protein amount but severe reduction of complex V activity and impaired mitochondrial membrane potential, suggesting a dominant-negative effect. In conclusion, our study describes a new candidate gene associated with isolated dystonia and confirms that heterozygous variants in genes encoding subunits of the mitochondrial ATP synthase may cause autosomal dominant isolated dystonia with incomplete penetrance, likely through a dominant-negative mechanism. [ABSTRACT FROM AUTHOR]

In view of the NGS-identified c.649del variant-call, neuropediatricians considered the possibility of an atypical manifestation of I PRRT2 i -related disease for patient-2, but simultaneously initiated Sanger-sequencing characterized c.649del as a false-positive NGS hit, so that in the end no erroneous diagnosis was made. Challenges in Establishing the Diagnosis of PRRT2-Related Dystonia: Recurrent Pathogenic Variants in a Homopolymeric Stretch Re-analysis of next-generation sequencing (NGS) data can help to resolve undiagnosed cases.[1] We report on two patients with dystonia to illustrate how stringent NGS-variant filtering criteria can lead to missed diagnoses in the context of variants lying in a homopolymeric nucleotide tract; at the same time, relaxing bioinformatic-filter settings can yield false-positive pathogenic variant-hits in the same homopolymeric stretch, further complicating the NGS-based diagnostic process. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

An association between movement disorders and immune‐system dysfunction has been described in the context of rare genetic diseases such as ataxia telangiectasia as well as infectious encephalopathies. We encountered a male patient who presented immunodeficiency of unknown etiology since childhood. A medication‐refractory, progressive choreodystonic movement disorder emerged at the age of 42 years and prompted an exome‐wide molecular testing approach. This revealed a pathogenic hemizygous variant in CD40LG, the gene implicated in X‐linked hyper‐IgM syndrome. Only two prior reports have specifically suggested a causal relationship between CD40LG mutations and involuntary hyperkinetic movements. Our findings thus confirm the existence of a particular CD40LG‐related condition, combining features of compromised immunity with neurodegenerative movement abnormalities. Establishing the diagnosis is crucial because of potential life‐threatening immunological complications. [ABSTRACT FROM AUTHOR]

Essential tremor (ET) is the most common adult-onset movement disorder. In the present study, we performed whole exome sequencing of a large ET-affected family (10 affected and 6 un-affected family members) and identified a TUB p.V431I variant (rs75594955) segregating in a manner consistent with autosomal-dominant inheritance. Subsequent targeted re-sequencing of TUB in 820 unrelated individuals with sporadic ET and 630 controls revealed significant enrichment of rare nonsynonymous TUB variants (e.g. rs75594955: p.V431I, rs1241709665: p.Ile20Phe, rs55648406: p.Arg49Gln) in the ET cohort (SKAT-O test p-value = 6.20e-08). TUB encodes a transcription factor predominantly expressed in neuronal cells and has been previously implicated in obesity. ChIP-seq analyses of the TUB transcription factor across different regions of the mouse brain revealed that TUB regulates the pathways responsible for neurotransmitter production as well thyroid hormone signaling. Together, these results support the association of rare variants in TUB with ET. Author summary: Essential tremor (ET) is the most common adult-onset movement disorder and in most affected families it appears to be inherited in an autosomal dominant pattern. The causes of essential tremor are unknown. Although many genetic studies in affected families and sporadic cases of ET have shown that genes may play a role, it has proven quite challenging to identify the specific genetic variants involved. Here, we use state-of-the-art technologies to identify the role of genetic variants on ET through exome sequencing of a large affected ET family and subsequent validation in a large population of cases and controls. We show that rare nonsynonymous variants of the TUB gene are significantly enriched in ET cases versus healthy controls. Further studies of biological pathways regulated by TUB in the mouse brain reveal key pathways related to ET. Our work expands our knowledge of the genetic basis of ET. [ABSTRACT FROM AUTHOR]

Background: Serum metabolite profiling can be used to identify pathways involved in the pathogenesis of and potential biomarkers for a given disease. Both restless legs syndrome (RLS) and Parkinson`s disease (PD) represent movement disorders for which currently no blood-based biomarkers are available and whose pathogenesis has not been uncovered conclusively. We performed unbiased serum metabolite profiling in search of signature metabolic changes for both diseases. Methods: 456 metabolites were quantified in serum samples of 1272 general population controls belonging to the KORA cohort, 82 PD cases and 95 RLS cases by liquid-phase chromatography and gas chromatography separation coupled with tandem mass spectrometry. Genetically determined metabotypes were calculated using genome-wide genotyping data for the 1272 general population controls. Results: After stringent quality control, we identified decreased levels of long-chain (polyunsaturated) fatty acids of individuals with PD compared to both RLS (PD vs. RLS: p = 0.0001 to 5.80x10-9) and general population controls (PD vs. KORA: p = 6.09x10-5 to 3.45x10-32). In RLS, inositol metabolites were increased specifically (RLS vs. KORA: p = 1.35x10-6 to 3.96x10-7). The impact of dopaminergic drugs was reflected in changes in the phenylalanine/tyrosine/dopamine metabolism observed in both individuals with RLS and PD. Conclusions: A first discovery approach using serum metabolite profiling in two dopamine-related movement disorders compared to a large general population sample identified significant alterations in the polyunsaturated fatty acid metabolism in PD and implicated the inositol metabolism in RLS. These results provide a starting point for further studies investigating new perspectives on factors involved in the pathogenesis of the two diseases as well as possible points of therapeutic intervention. [ABSTRACT FROM AUTHOR]

Knowledge of restless legs syndrome (RLS) has greatly increased in recent years due to the many advances that have been made in diagnosis, management and genetics. Tools have been developed that facilitate the diagnosis and treatment of RLS, in particular the essential diagnostic criteria for RLS have been refined, severity scales (IRLS, RLS-6, JHSS) have been developed, as have instruments that improve diagnostic accuracy and assess for specific aspects of RLS such as augmentation. These newly developed tools have been used in recent population-based studies, which have provided a greater understanding of the epidemiology of RLS, and also within patient-based trials. As far as the genetics of RLS is concerned, linkage studies in RLS families have revealed eight loci but no causally related sequence variant has yet been identified using this approach. Recent genome-wide association studies have identified variants within intronic or intergenic regions of MEIS1, BTBD9, and MAP2K5/LBXCOR1, and PTPRD, raising new pathological hypotheses for RLS. An overview on therapeutic options and recent trials is given based on evidence-based management strategies for this common disorder. [ABSTRACT FROM AUTHOR]

Objective: Periodic limb movements in sleep (PLMS) are often associated with the restless legs syndrome (RLS). Although the dopaminergic system seems to be involved, the pathophysiology of PLMS and RLS is still obscure. The objective of this study is to explore whether a PLMS-like phenomenon can be observed in rodents in order to elucidate the underlying mechanisms. Methods: In a group of young and old rats (1.4–1.6 and 16.2–20.5 months, respectively), sleep–wake behavior was recorded and hindlimb movements were detected by means of a magneto-inductive device during two 12-h light periods. Furthermore, in the old rats, recordings were made after administration of the dopamine antagonist haloperidol (HAL) on three consecutive days. Periodic hindlimb movements (PHLM) during nonrapid eye movement sleep (NREM) were identified according to modified human criteria. Results: In the young animals, no PHLM were observed, whereas, 4 out of 10 old rats showed PHLM, two of them have more than 5 PHLM/h. Haloperidol affects neither the sleep pattern nor the number of PHLM. Interestingly, the percentage of old rats spontaneously displaying PHLM resembles the prevalence of PLMS in the elderly. Conclusions: Our study demonstrates for the first time that periodic hindlimb movements (PHLM) in sleep can occur spontaneously in rats. A clear effect of age on this phenomenon was seen, with only old animals displaying PHLM. To validate whether the observed PHLM constitute a good model for human PLMS or even RLS, their pharmacological properties need to be characterized in a large number of PHLM positive animals. [Copyright &y& Elsevier]

Introduction: RLS is a common movement disorders with a strong genetic component in its pathophysiology, but, up to now, no causative mutation has been reported.Methods: We re-evaluated the previously described RLS2 family by exome sequencing.Results: We identified fifteen variations in the 14q critical region. The c.485G > A transition of the TRAPPC6B gene segregates with the RLS2 haplotype, is absent in 200 local controls and is extremely rare in 12988 exomes from the Exome Variant Server (EVS). This variant alters a splicing site and hampers the normal transcript processing by promoting exon 3-skipping as demonstrated by minigene transfection and by patient transcripts.Conclusions: We identified a TRAPPC6B gene mutation associated to the RLS locus on chromosome 14. [ABSTRACT FROM AUTHOR]

Restless legs syndrome (RLS) is a common sleep-related movement disorder in populations of European descent and disease risk is strongly influenced by genetic factors. Common variants have been assessed extensively in several genome-wide association studies, but the contribution of rarer genetic variation has not been investigated at this scale. We therefore genotyped a case-control set of 9246 individuals for mainly rare and low frequency exonic variants using the Illumina ExomeChip. However, standard single variant and gene-level association tests were negative. This does not preclude a role of rare variants in RLS, but is likely due to the small sample size and the limited selection of rare genetic variation captured on the array. Therefore, exome or whole genome sequencing should be performed rather than increasing the sample size of ExomeChip studies in order to identify rare risk variants for RLS. [ABSTRACT FROM AUTHOR]

• Two subjects with novel TCF20 variants in whom dystonia was a leading phenotype. • Expand the spectrum of TCF20 neurodevelopmental disease to a dystonia-prominent. • To increase awareness of movement disorders contributing to developmental disorders. [ABSTRACT FROM AUTHOR]

Introduction: Although there has been increasing recognition of the occurrence of non-epileptic involuntary movements in developmental and epileptic encephalopathies (DEEs), the spectrum of dystonic presentations associated with these conditions remains poorly described. We sought to expand the catalogue of dystonia-predominant phenotypes in monogenic DEEs, building on the recently introduced concept of an epilepsy-movement disorder spectrum.Methods: Cases were identified from a whole-exome-sequenced cohort of 45 pediatric index patients with complex dystonia (67% sequenced as parent-child trios). Review of molecular findings in DEE-associated genes was performed. For five individuals with identified DEE-causing variants, detailed information about presenting phenotypic features and the natural history of disease was obtained.Results: De-novo pathogenic and likely pathogenic missense variants in GABRA1, GABBR2, GNAO1, and FOXG1 gave rise to infantile-onset persistent and paroxysmal dystonic manifestations, beginning in the limb or truncal musculature and progressing gradually to a generalized state. Coexisting, less prominent movement-disorder symptoms were observed and included myoclonic, ballistic, and stereotypic abnormal movements as well as choreoathetosis. Dystonia dominated over epileptic neurodevelopmental comorbidities in all four subjects and represented the primary indication for molecular genetic analysis. We also report the unusual case of an adult female patient with dystonia, tremor, and mild learning disability who was found to harbor a pathogenic frameshift variant in MECP2.Conclusions: Dystonia can be a leading clinical manifestation in different DEEs. A monogenic basis of disease should be considered on the association of dystonia and developmental delay-epilepsy presentations, justifying a molecular screening for variants in DEE-associated genes. [ABSTRACT FROM AUTHOR]

Early-onset generalized dystonia represents the severest form of dystonia, a hyperkinetic movement disorder defined by involuntary twisting postures. Although frequently transmitted as a single-gene trait, the molecular basis of dystonia remains largely obscure. By whole-exome sequencing a parent-offspring trio in an Austrian kindred affected by non-familial early-onset generalized dystonia, we identified a dominant de novo frameshift mutation, c.6406delC (p.Leu2136Serfs ∗ 17), in KMT2B , encoding a lysine-specific methyltransferase involved in transcriptional regulation via post-translational modification of histones. Whole-exome-sequencing-based exploration of a further 30 German-Austrian individuals with early-onset generalized dystonia uncovered another three deleterious mutations in KMT2B —one de novo nonsense mutation (c.1633C>T [p.Arg545 ∗ ]), one de novo essential splice-site mutation (c.7050−2A>G [p.Phe2321Serfs ∗ 93]), and one inherited nonsense mutation (c.2428C>T [p.Gln810 ∗ ]) co-segregating with dystonia in a three-generation kindred. Each of the four mutations was predicted to mediate a loss-of-function effect by introducing a premature termination codon. Suggestive of haploinsufficiency, we found significantly decreased total mRNA levels of KMT2B in mutant fibroblasts. The phenotype of individuals with KMT2B loss-of-function mutations was dominated by childhood lower-limb-onset generalized dystonia, and the family harboring c.2428C>T (p.Gln810 ∗ ) showed variable expressivity. In most cases, dystonic symptoms were accompanied by heterogeneous non-motor features. Independent support for pathogenicity of the mutations comes from the observation of high rates of dystonic presentations in KMT2B -involving microdeletion syndromes. Our findings thus establish generalized dystonia as the human phenotype associated with haploinsufficiency of KMT2B . Moreover, we provide evidence for a causative role of disordered histone modification, chromatin states, and transcriptional deregulation in dystonia pathogenesis. [ABSTRACT FROM AUTHOR]

A Task Force was established by the International Restless Legs Syndrome Study Group (IRLSSG) in conjunction with the European Restless Legs Syndrome Study Group (EURLSSG) and the RLS Foundation (RLS-F) to develop evidence-based and consensus-based recommendations for the prevention and treatment of long-term pharmacologic treatment of dopaminergic-induced augmentation in restless legs syndrome/Willis-Ekbom disease (RLS/WED). The Task Force made the following prevention and treatment recommendations: As a means to prevent augmentation, medications such as α2δ ligands may be considered for initial RLS/WED treatment; these drugs are effective and have little risk of augmentation. Alternatively, if dopaminergic drugs are elected as initial treatment, then the daily dose should be as low as possible and not exceed that recommended for RLS/WED treatment. However, the physician should be aware that even low dose dopaminergics can cause augmentation. Patients with low iron stores should be given appropriate iron supplementation. Daily treatment by either medication should start only when symptoms have a significant impact on quality of life in terms of frequency and severity; intermittent treatment might be considered in intermediate cases. Treatment of existing augmentation should be initiated, where possible, with the elimination/correction of extrinsic exacerbating factors (iron levels, antidepressants, antihistamines, etc.). In cases of mild augmentation, dopamine agonist therapy can be continued by dividing or advancing the dose, or increasing the dose if there are breakthrough night-time symptoms. Alternatively, the patient can be switched to an α2δ ligand or rotigotine. For severe augmentation the patient can be switched either to an α2δ ligand or rotigotine, noting that rotigotine may also produce augmentation at higher doses with long-term use. In more severe cases of augmentation an opioid may be considered, bypassing α2δ ligands and rotigotine. [ABSTRACT FROM AUTHOR]