ABSTRACT
This review explores the role of the antisaccadic task in understanding inhibitory mechanisms in basal ganglia disorders. It conducts a comparative analysis of saccadic profiles in conditions such as Parkinson's disease, Tourette syndrome, obsessive-compulsive disorder, Huntington's disease, and dystonia, revealing distinct patterns and proposing mechanisms for impaired performance. The primary focus is on two inhibitory mechanisms: global, pre-emptive inhibition responsible for suppressing prepotent responses, and slower, selective response inhibition. The antisaccadic task demonstrates practicality in clinical applications, aiding in differential diagnoses, treatment monitoring and reflecting gait control. To further enhance its differential diagnostic value, future directions should address issues such as the standardization of eye-tracking protocol and the integration of eye-tracking data with other disease indicators in a comprehensive dataset.
Subject(s)
Basal Ganglia Diseases , Saccades , Humans , Saccades/physiology , Basal Ganglia Diseases/physiopathology , Neuropsychological Tests , Parkinson Disease/physiopathology , Parkinson Disease/psychology , Obsessive-Compulsive Disorder/physiopathology , Obsessive-Compulsive Disorder/diagnosis , Tourette Syndrome/physiopathology , Huntington Disease/physiopathology , Huntington Disease/psychology , Inhibition, PsychologicalABSTRACT
Pathogenic variants in LRRK2 are one of the most common genetic risk factors for Parkinson's disease (PD). Recently, the lesser-known p.L1795F variant was proposed as a strong genetic risk factor for PD, however, further families are currently lacking in literature. A multicentre young onset and familial PD cohort (n = 220) from 9 movement disorder centres across Central Europe within the CEGEMOD consortium was screened for rare LRRK2 variants using whole exome sequencing data. We identified 4 PD cases with heterozygous p.L1795F variant. All 4 cases were characterised by akinetic-rigid PD phenotype with early onset of severe motor fluctuations, 2 receiving LCIG therapy and 2 implanted with STN DBS; all 4 cases showed unsatisfactory effect of advanced therapies on motor fluctuations. Our data also suggest that p.L1795F may represent the most common currently known pathogenic LRRK2 variant in Central Europe compared to the more studied p.G2019S, being present in 1.81% of PD cases within the Central European cohort and 3.23% of familial PD cases. Together with the ongoing clinical trials for LRRK2 inhibitors, this finding emphasises the urgent need for more ethnic diversity in PD genetic research.
Subject(s)
Dystonia , Mitochondrial Diseases , Humans , Mitochondrial Diseases/genetics , Mitochondrial Diseases/diagnosis , Dystonia/genetics , Dystonia/diagnosis , Male , Female , Adult , Movement Disorders/genetics , Movement Disorders/diagnosis , Movement Disorders/physiopathology , Middle Aged , Mutation , AdolescentABSTRACT
Background: Spinocerebellar ataxia 21 (SCA21) is a rare neurological disorder caused by heterozygous variants in TMEM240. A growing, yet still limited number of reports suggested that hyperkinetic movements should be considered a defining component of the disease. Case Series: We describe two newly identified families harboring the recurrent pathogenic TMEM240 p.Pro170Leu variant. Both index patients and the mother of the first proband developed movement disorders, manifesting as myoclonic dystonia and action-induced dystonia without co-occurring ataxia in one case, and pancerebellar syndrome complicated by action-induced dystonia in the other. We reviewed the literature on TMEM240 variants linked to hyperkinetic disorders, comparing our cases to described phenotypes. Discussion: Adding to prior preliminary observations, our series highlights the relevance of hyperkinetic movements as clinically meaningful features of SCA21. TMEM240 mutation should be included in the differential diagnosis of myoclonic dystonia and ataxia-dystonia syndromes.
Subject(s)
Dystonia , Dystonic Disorders , Myoclonus , Spinocerebellar Degenerations , Humans , Dystonia/diagnosis , Dystonia/genetics , Myoclonus/diagnosis , Myoclonus/genetics , Hyperkinesis , Ataxia , Rare Diseases , Syndrome , Membrane ProteinsABSTRACT
PURPOSE: ATP2B2 encodes the variant-constrained plasma-membrane calcium-transporting ATPase-2, expressed in sensory ear cells and specialized neurons. ATP2B2/Atp2b2 variants were previously linked to isolated hearing loss in patients and neurodevelopmental deficits with ataxia in mice. We aimed to establish the association between ATP2B2 and human neurological disorders. METHODS: Multinational case recruitment, scrutiny of trio-based genomics data, in silico analyses, and functional variant characterization were performed. RESULTS: We assembled 7 individuals harboring rare, predicted deleterious heterozygous ATP2B2 variants. The alleles comprised 5 missense substitutions that affected evolutionarily conserved sites and 2 frameshift variants in the penultimate exon. For 6 variants, a de novo status was confirmed. Unlike described patients with hearing loss, the individuals displayed a spectrum of neurological abnormalities, ranging from ataxia with dystonic features to complex neurodevelopmental manifestations with intellectual disability, autism, and seizures. Two cases with recurrent amino-acid variation showed distinctive overlap with cerebellar atrophy-associated ataxia and epilepsy. In cell-based studies, all variants caused significant alterations in cytosolic calcium handling with both loss- and gain-of-function effects. CONCLUSION: Presentations in our series recapitulate key phenotypic aspects of Atp2b2-mouse models and underline the importance of precise calcium regulation for neurodevelopment and cerebellar function. Our study documents a role for ATP2B2 variants in causing heterogeneous neurodevelopmental and movement-disorder syndromes.
Subject(s)
Cerebellar Ataxia , Dystonia , Hearing Loss , Intellectual Disability , Neurodevelopmental Disorders , Animals , Humans , Mice , Behavioral Symptoms , Calcium , Cerebellar Ataxia/genetics , Dystonia/genetics , Intellectual Disability/genetics , Neurodevelopmental Disorders/genetics , Phenotype , Plasma Membrane Calcium-Transporting ATPases , Seizures/geneticsABSTRACT
Purpose: De novo variants in CUL3 (Cullin-3 ubiquitin ligase) have been strongly associated with neurodevelopmental disorders (NDDs), but no large case series have been reported so far. Here we aimed to collect sporadic cases carrying rare variants in CUL3, describe the genotype-phenotype correlation, and investigate the underlying pathogenic mechanism. Methods: Genetic data and detailed clinical records were collected via multi-center collaboration. Dysmorphic facial features were analyzed using GestaltMatcher. Variant effects on CUL3 protein stability were assessed using patient-derived T-cells. Results: We assembled a cohort of 35 individuals with heterozygous CUL3 variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features. Of these, 33 have loss-of-function (LoF) and two have missense variants. CUL3 LoF variants in patients may affect protein stability leading to perturbations in protein homeostasis, as evidenced by decreased ubiquitin-protein conjugates in vitro . Specifically, we show that cyclin E1 (CCNE1) and 4E-BP1 (EIF4EBP1), two prominent substrates of CUL3, fail to be targeted for proteasomal degradation in patient-derived cells. Conclusion: Our study further refines the clinical and mutational spectrum of CUL3 -associated NDDs, expands the spectrum of cullin RING E3 ligase-associated neuropsychiatric disorders, and suggests haploinsufficiency via LoF variants is the predominant pathogenic mechanism.
Subject(s)
Attention Deficit Disorder with Hyperactivity , Epilepsy , Female , Humans , Hyperkinesis/genetics , Epilepsy/geneticsABSTRACT
Niemann-Pick type C (NPC) is a rare but treatable lysosomal disorder with heterogeneous clinical presentations including cognitive impairment, movement disorders and vertical gaze palsy. We illustrate five cases of genetically confirmed NPC and highlight backward leaning during gait as a relevant clinical sign and a useful diagnostic clue.
Subject(s)
Niemann-Pick Disease, Type C , Gait , Humans , Niemann-Pick Disease, Type C/complications , Niemann-Pick Disease, Type C/diagnosisABSTRACT
Skin manifestations are well-recognized non-motor symptoms of Parkinson's disease (PD) and other hypokinetic and hyperkinetic movement disorders. Skin conditions are usually well visible during routine clinical examination and their recognition may play a major role in diagnostic work-up. In this educational review we: (1) briefly outline skin conditions related to Parkinson's disease, including therapy-related skin complications and their management; (2) discuss the role of skin biopsies in early diagnosis of PD and differential diagnosis of parkinsonian syndromes; and focus more on areas which have not been reviewed in the literature before, including (3) skin conditions related to atypical parkinsonism, and (4) skin conditions related to hyperkinetic movement disorders. In case of rare hyperkinetic movement disorders, specific dermatological manifestations, like presence of angiokeratomas, telangiectasias, Mongolian spots, lipomas, ichthyosis, progeroid skin changes and others may point to a very specific group of disorders and help guide further investigations.
ABSTRACT
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.
Subject(s)
Dystonia , Dystonic Disorders , Parkinsonian Disorders , Ataxia/genetics , Dystonia/diagnosis , Dystonia/genetics , Dystonic Disorders/diagnosis , Dystonic Disorders/genetics , Exome , Humans , Mutation , Parkinsonian Disorders/genetics , PhenotypeABSTRACT
BACKGROUND: ADCY5-related dyskinesia is characterized by early-onset movement disorders. There is currently no validated treatment, but anecdotal clinical reports and biological hypotheses suggest efficacy of caffeine. OBJECTIVE: The aim is to obtain further insight into the efficacy and safety of caffeine in patients with ADCY5-related dyskinesia. METHODS: A retrospective study was conducted worldwide in 30 patients with a proven ADCY5 mutation who had tried or were taking caffeine for dyskinesia. Disease characteristics and treatment responses were assessed through a questionnaire. RESULTS: Caffeine was overall well tolerated, even in children, and 87% of patients reported a clear improvement. Caffeine reduced the frequency and duration of paroxysmal movement disorders but also improved baseline movement disorders and some other motor and nonmotor features, with consistent quality-of-life improvement. Three patients reported worsening. CONCLUSION: Our findings suggest that caffeine should be considered as a first-line therapeutic option in ADCY5-related dyskinesia. © 2022 International Parkinson and Movement Disorder Society.
Subject(s)
Dyskinesias , Movement Disorders , Adenylyl Cyclases/genetics , Caffeine/therapeutic use , Child , Dyskinesias/etiology , Dyskinesias/genetics , Humans , Movement Disorders/genetics , Retrospective StudiesABSTRACT
SLC41A1 (A1) SNPs rs11240569 and rs823156 are associated with altered risk for Parkinson's disease (PD), predominantly in Asian populations, and rs708727 has been linked to Alzheimer's disease (AD). In this study, we have examined a potential association of the three aforementioned SNPs and of rs9438393, rs56152218, and rs61822602 (all three lying in the A1 promoter region) with PD in the Slovak population. Out of the six tested SNPs, we have identified only rs708727 as being associated with an increased risk for PD onset in Slovaks. The minor allele (A) in rs708727 is associated with PD in dominant and completely over-dominant genetic models (ORD = 1.36 (1.05-1.77), p = 0.02, and ORCOD = 1.34 (1.04-1.72), p = 0.02). Furthermore, the genotypic triplet GG(rs708727) + AG(rs823156) + CC(rs61822602) might be clinically relevant despite showing a medium (h ≥ 0.5) size difference (h = 0.522) between the PD and the control populations. RandomForest modeling has identified the power of the tested SNPs for discriminating between PD-patients and the controls to be essentially zero. The identified association of rs708727 with PD in the Slovak population leads us to hypothesize that this A1 polymorphism, which is involved in the epigenetic regulation of the expression of the AD-linked gene PM20D1, is also involved in the pathoetiology of PD (or universally in neurodegeneration) through the same or similar mechanism as in AD.
Subject(s)
Alzheimer Disease/genetics , Cation Transport Proteins/genetics , Parkinson Disease/genetics , Polymorphism, Single Nucleotide , Sequence Analysis, DNA/methods , Adult , Aged , Aged, 80 and over , Case-Control Studies , Epigenesis, Genetic , Female , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Machine Learning , Male , Middle Aged , SlovakiaABSTRACT
Dystonia is a prevalent, heterogeneous movement disorder characterized by involuntarily abnormal postures. Biomarkers of dystonia are notoriously lacking. Here, a biomarker is reported for histone lysine methyltransferase (KMT2B)-deficient dystonia, a leading subtype among the individually rare monogenic dystonias. It was derived by applying a support vector machine to an episignature of 113 DNA CpG sites, which, in blood cells, showed significant epigenome-wide association with KMT2B deficiency and at least 1× log-fold change of methylation. This classifier was accurate both when tested on the general population and on samples with various other deficiencies of the epigenetic machinery, thus allowing for definitive evaluation of variants of uncertain significance and identifying patients who may profit from deep brain stimulation, a highly successful treatment in KMT2B-deficient dystonia. Methylation was increased in KMT2B deficiency at all 113 CpG sites. The coefficients of variation of the normalized methylation levels at these sites also perfectly classified the samples with KMT2B-deficient dystonia. Moreover, the mean of the normalized methylation levels correlated well with the age at onset of dystonia (P = 0.003)-being lower in samples with late or incomplete penetrance-thus serving as a predictor of disease onset and severity. Similarly, it may also function in monitoring the recently envisioned treatment of KMT2B deficiency by inhibition of DNA methylation.
Subject(s)
Dystonia , Dystonic Disorders , Biomarkers , DNA Methylation/genetics , Dystonia/genetics , Dystonia/therapy , Dystonic Disorders/genetics , Dystonic Disorders/therapy , Histone-Lysine N-Methyltransferase/genetics , Humans , MutationABSTRACT
Progressive supranuclear palsy (PSP) is a progressive atypical parkinsonian syndrome characterised by postural instability, supranuclear ophthalmoplegia, dysarthria, dysphagia, executive dysfunction and other features. This clinical presentation represents the classic PSP-Richardson syndrome (PSP-RS). However, several other clinical subtypes have been recognised, including PSP-parkinsonism (PSP-P), probably the second most common PSP variant. Unlike PSP-RS, PSP-P often presents with an asymmetric onset, tremor and a moderate initial response to levodopa, especially during the first years of the disease, thus resembling Parkinson's disease (PD). It runs a more favourable course, but over time, PSP-P may evolve clinically into PSP-RS. Therefore, it may seem that PSP-P stands clinically between PD and PSP. There are several peculiarities that can distinguish PSP-P from these entities. As there is lack of systematic reviews on PSP-P in the literature, we decided to summarise all the necessary data about the epidemiology, clinical picture, neuroimaging, genetics and other aspects of this PSP variant in order to provide complete information for the reader.
Subject(s)
Parkinson Disease , Parkinsonian Disorders , Supranuclear Palsy, Progressive , Humans , Levodopa , Parkinson Disease/complications , Parkinson Disease/diagnosis , Parkinson Disease/epidemiology , Supranuclear Palsy, Progressive/diagnosis , Supranuclear Palsy, Progressive/epidemiology , Systematic Reviews as TopicABSTRACT
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.
Subject(s)
Brain Diseases/genetics , Dystonia/genetics , Epileptic Syndromes/genetics , Neurodevelopmental Disorders/genetics , Adolescent , Brain Diseases/complications , Child , Child, Preschool , Epileptic Syndromes/complications , Female , Forkhead Transcription Factors/genetics , GTP-Binding Protein alpha Subunits, Gi-Go/genetics , Humans , Male , Methyl-CpG-Binding Protein 2/genetics , Nerve Tissue Proteins/genetics , Neurodevelopmental Disorders/complications , Phenotype , Receptors, GABA-A/genetics , Receptors, GABA-B/geneticsABSTRACT
BACKGROUND: Despite the established value of genomic testing strategies, practice guidelines for their use do not exist in many indications. OBJECTIVES: We sought to validate a recently introduced scoring algorithm for dystonia, predicting the diagnostic utility of whole-exome sequencing (WES) based on individual phenotypic aspects (age-at-onset, body distribution, presenting comorbidity). METHODS: We prospectively enrolled a set of 209 dystonia-affected families and obtained summary scores (0-5 points) according to the algorithm. Singleton (N = 146), duo (N = 11), and trio (N = 52) WES data were generated to identify genetic diagnoses. RESULTS: Diagnostic yield was highest (51%) among individuals with a summary score of 5, corresponding to a manifestation of early-onset segmental or generalized dystonia with coexisting non-movement disorder-related neurological symptoms. Sensitivity and specificity at the previously suggested threshold for implementation of WES (3 points) was 96% and 52%, with area under the curve of 0.81. CONCLUSIONS: The algorithm is a useful predictive tool and could be integrated into dystonia routine diagnostic protocols. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.
Subject(s)
Dystonia , Dystonic Disorders , Parkinson Disease , Algorithms , Dystonia/diagnosis , Dystonia/genetics , Dystonic Disorders/genetics , Genetic Testing , HumansABSTRACT
INTRODUCTION: Next-generation sequencing is now used on a routine basis for molecular testing but studies on copy-number variant (CNV) detection from next-generation sequencing data are underrepresented. Utilizing an existing whole-exome sequencing (WES) dataset, we sought to investigate the contribution of rare CNVs to the genetic causality of dystonia. METHODS: The CNV read-depth analysis tool ExomeDepth was applied to the exome sequences of 953 unrelated patients with dystonia (600 with isolated dystonia and 353 with combined dystonia; 33% with additional neurological involvement). We prioritized rare CNVs that affected known disease genes and/or were known to be associated with defined microdeletion/microduplication syndromes. Pathogenicity assessment of CNVs was based on recently published standards of the American College of Medical Genetics and Genomics and the Clinical Genome Resource. RESULTS: We identified pathogenic or likely pathogenic CNVs in 14 of 953 patients (1.5%). Of the 14 different CNVs, 12 were deletions and 2 were duplications, ranging in predicted size from 124bp to 17 Mb. Within the deletion intervals, BRPF1, CHD8, DJ1, EFTUD2, FGF14, GCH1, PANK2, SGCE, UBE3A, VPS16, WARS2, and WDR45 were determined as the most clinically relevant genes. The duplications involved chromosomal regions 6q21-q22 and 15q11-q13. CNV analysis increased the diagnostic yield in the total cohort from 18.4% to 19.8%, as compared to the assessment of single-nucleotide variants and small insertions and deletions alone. CONCLUSIONS: WES-based CNV analysis in dystonia is feasible, increases the diagnostic yield, and should be combined with the assessment of single-nucleotide variants and small insertions and deletions.