-
Epilepsia Aug 2023The progressive myoclonus epilepsies (PMEs) are a heterogeneous group of neurodegenerative disorders, typically presenting in late childhood. An etiologic diagnosis is...
The progressive myoclonus epilepsies (PMEs) are a heterogeneous group of neurodegenerative disorders, typically presenting in late childhood. An etiologic diagnosis is achieved in about 80% of patients with PME, and genome-wide molecular studies on remaining, well-selected, undiagnosed cases can further dissect the underlying genetic heterogeneity. Through whole-exome sequencing (WES), we identified pathogenic truncating variants in the IRF2BPL gene in two, unrelated patients presenting with PME. IRF2BPL belongs to the transcriptional regulators family and it is expressed in multiple human tissues, including the brain. Recently missense and nonsense mutations in IRF2BPL were found in patients presenting with developmental delay and epileptic encephalopathy, ataxia, and movement disorders, but none with clear PME. We identified 13 other patients in the literature with myoclonic seizures and IRF2BPL variants. There was no clear genotype-phenotype correlation. With the description of these cases, the IRF2BPL gene should be considered in the list of genes to be tested in the presence of PME, in addition to patients with neurodevelopmental or movement disorders.
Topics: Humans; Child; Myoclonic Epilepsies, Progressive; Seizures; Epilepsies, Myoclonic; Genotype; Movement Disorders; Carrier Proteins; Nuclear Proteins
PubMed: 36810721
DOI: 10.1111/epi.17557 -
Orthopadie (Heidelberg, Germany) Aug 2023Rheumatic diseases in childhood and adolescence like juvenile idiopathic arthritis can cause movement disorders due to pain, swelling and limited range of motion. This... (Review)
Review
Rheumatic diseases in childhood and adolescence like juvenile idiopathic arthritis can cause movement disorders due to pain, swelling and limited range of motion. This article describes different possibilities and results of movement analysis for rheumatic diseases. The influence of JIA on specific movements in individual joints and complex movements such as gait is examined. The results of gait analyses show a great influence of the disease on spatiotemporal parameters such as gait speed, cadence and stride length, on joint angles during walking and on torques and forces. Furthermore, the importance of gait analysis for estimating the efficacy of interventions like intra-articular steroids is described. This article provides a summary of current studies on the effects of rheumatic diseases on movement disorders in children and adolescents, as well as an outlook on the increasing importance of movement analysis for therapy monitoring and optimisation.
Topics: Humans; Child; Adolescent; Rheumatology; Gait; Walking; Rheumatic Diseases; Movement Disorders
PubMed: 37391675
DOI: 10.1007/s00132-023-04406-1 -
European Journal of Neurology Oct 2023Most episodic ataxias (EA) are autosomal dominantly inherited and characterized by recurrent attacks of ataxia and other paroxysmal and non-paroxysmal features. EA is... (Review)
Review
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.
Topics: Humans; Ataxia; Movement Disorders; Genotype; Phenotype
PubMed: 37422902
DOI: 10.1111/ene.15969 -
Movement Disorders : Official Journal... Dec 2023Parkin RBR E3 ubiquitin-protein ligase (PRKN) mutations are the most common cause of young onset and autosomal recessive Parkinson's disease (PD). PRKN is located in...
BACKGROUND
Parkin RBR E3 ubiquitin-protein ligase (PRKN) mutations are the most common cause of young onset and autosomal recessive Parkinson's disease (PD). PRKN is located in FRA6E, which is one of the common fragile sites in the human genome, making this region prone to structural variants. However, complex structural variants such as inversions of PRKN are seldom reported, suggesting that there are potentially unrevealed complex pathogenic PRKN structural variants.
OBJECTIVES
To identify complex structural variants in PRKN using long-read sequencing.
METHODS
We investigated the genetic cause of monozygotic twins presenting with a young onset dystonia-parkinsonism using targeted sequencing, whole exome sequencing, multiple ligation probe amplification, and long-read sequencing. We assessed the presence and frequency of complex inversions overlapping PRKN using whole-genome sequencing data of Accelerating Medicines Partnership Parkinson's disease (AMP-PD) and United Kingdom (UK)-Biobank datasets.
RESULTS
Multiple ligation probe amplification identified a heterozygous exon three deletion in PRKN and long-read sequencing identified a large novel inversion spanning over 7 Mb, including a large part of the coding DNA sequence of PRKN. We could diagnose the affected subjects as compound heterozygous carriers of PRKN. We analyzed whole genome sequencing data of 43,538 participants of the UK-Biobank and 4941 participants of the AMP-PD datasets. Nine inversions in the UK-Biobank and two in AMP PD were identified and were considered potentially damaging and likely to affect PRKN expression.
CONCLUSIONS
This is the first report describing a large 7 Mb inversion involving breakpoints outside of PRKN. This study highlights the importance of using long-read sequencing for structural variant analysis in unresolved young-onset PD cases. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
Topics: Humans; Heterozygote; Mutation; Parkinson Disease; Parkinsonian Disorders; Ubiquitin-Protein Ligases
PubMed: 37926948
DOI: 10.1002/mds.29610 -
The Journal of Clinical Psychiatry Aug 2023Schizophrenia is a chronic and debilitating mental health condition that significantly impacts quality of life and can shorten patients' lifetime by decades. It is...
Schizophrenia is a chronic and debilitating mental health condition that significantly impacts quality of life and can shorten patients' lifetime by decades. It is characterized by symptoms including hallucinations and delusions, apathy, and cognitive impairment, and people with schizophrenia also experience many somatic comorbidities, such as metabolic disturbances, infectious diseases, cardiovascular issues, and respiratory illnesses. For decades, treatment for schizophrenia has focused on antipsychotics (APs) that reduce excess dopamine signaling to the associative striatum, which also blocks dopamine signaling in the dorsal striatum, creating movement disorders. Second-generation APs have a lower propensity to cause drug-induced movement disorders than first-generation APs. Nonetheless, only 1 out of 3 patients respond to any of the available APs; moreover, negative and cognitive symptoms tend to persist, while side effects and long-term risks can contribute to poor outcomes. However, there are new understandings in how to reduce dopamine release both presynaptically and selectively in circuits governing psychotic symptoms. These mechanisms offer a different treatment approach for patients with schizophrenia.
Topics: Humans; Schizophrenia; Dopamine; Quality of Life; Psychotic Disorders; Movement Disorders; Antipsychotic Agents
PubMed: 37555680
DOI: 10.4088/JCP.sunscz3001sho -
Movement Disorders : Official Journal... Oct 2023Several lysosomal genes are associated with Parkinson's disease (PD), yet the association between PD and ARSA remains unclear. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Several lysosomal genes are associated with Parkinson's disease (PD), yet the association between PD and ARSA remains unclear.
OBJECTIVES
To study rare ARSA variants in PD.
METHODS
To study rare ARSA variants (minor allele frequency < 0.01) in PD, we performed burden analyses in six independent cohorts with 5801 PD patients and 20,475 controls, followed by a meta-analysis.
RESULTS
We found evidence for associations between functional ARSA variants and PD in four cohorts (P ≤ 0.05 in each) and in the meta-analysis (P = 0.042). We also found an association between loss-of-function variants and PD in the United Kingdom Biobank cohort (P = 0.005) and in the meta-analysis (P = 0.049). These results should be interpreted with caution as no association survived multiple comparisons correction. Additionally, we describe two families with potential co-segregation of ARSA p.E382K and PD.
CONCLUSIONS
Rare functional and loss-of-function ARSA variants may be associated with PD. Further replications in large case-control/familial cohorts are required. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Humans; Gene Frequency; Parkinson Disease; United Kingdom; Cerebroside-Sulfatase
PubMed: 37381728
DOI: 10.1002/mds.29521 -
Gait & Posture Sep 2023Single and motor or cognitive dual-gait analysis is often used in clinical settings to evaluate older adults affected by neurological and movement disorders or with a...
BACKGROUND
Single and motor or cognitive dual-gait analysis is often used in clinical settings to evaluate older adults affected by neurological and movement disorders or with a stroke history. Gait features are frequently investigated using Machine Learning (ML) with significant results that can help clinicians in diagnosis and rehabilitation. The present study aims to classify patients with stroke, neurological and movement disorders using ML to analyze gait characteristics and to understand the importance of the single and dual-task features among Korean older adults.
METHODS
A cohort of 122 non-hospitalized Korean older adult participated in a single and a cognitive dual-task gait performance analysis. The extracted temporal and spatial features, together with clinical data, were used as input for the binary classification using tree-based ML algorithms. A repeated-stratified 10-fold cross-validation was performed to better evaluate multiple classification metrics with a final feature importance analysis.
RESULTS AND SIGNIFICANCE
The best accuracy - maximum >90 % - for gait and neurological disorders classification was obtained with Random Forest. In the stroke classification a 91.7 % of maximum accuracy was reached, with a significant recall of 92 %. The feature importance analysis showed a substantial balance between single and dual-task, while clinical data did not show elevated importance. The current findings indicate that a cognitive dual-task gait performance is highly recommendable together with a single-task in the analysis of older population, particularly for patients with a history of stroke. The results could be useful to medical professionals in treating and diagnosing motor and neurological disorders, and to improve rehabilitation strategies for stroke patients. Furthermore, the results confirm the proficiency of the tree-based ML algorithms in biomedical data analysis. Finally, in the future, this research could be replicated with a non-Asian population dataset to deepen the understanding of gait differences between Asian-Korean population and other ethnicities.
Topics: Humans; Aged; Cognition; Gait; Stroke; Movement Disorders; Republic of Korea; Stroke Rehabilitation
PubMed: 37515891
DOI: 10.1016/j.gaitpost.2023.07.282 -
Social Neuroscience Dec 2023Numerous lines of research indicate that our social brain involves a network of cortical and subcortical brain regions that are responsible for sensing and controlling... (Review)
Review
Numerous lines of research indicate that our social brain involves a network of cortical and subcortical brain regions that are responsible for sensing and controlling body movements. However, it remains unclear whether movement disorders have a systematic impact on social cognition. To address this question, we conducted a systematic review examining the influence of hyperkinetic movement disorders (including Huntington disease, Tourette syndrome, dystonia, and essential tremor) on social cognition. Following the PRISMA guidelines and registering the protocol in the PROSPERO database (CRD42022327459), we analyzed 50 published studies focusing on theory of mind (ToM), social perception, and empathy. The results from these studies provide evidence of impairments in ToM and social perception in all hyperkinetic movement disorders, particularly during the recognition of negative emotions. Additionally, individuals with Huntington's Disease and Tourette syndrome exhibit empathy disorders. These findings support the functional role of subcortical structures (such as the basal ganglia and cerebellum), which are primarily responsible for movement disorders, in deficits related to social cognition.
Topics: Humans; Social Cognition; Hyperkinesis; Tourette Syndrome; Social Perception; Movement Disorders; Theory of Mind; Cognition; Emotions
PubMed: 37580305
DOI: 10.1080/17470919.2023.2248687 -
Movement Disorders : Official Journal... Dec 2023Early-onset Parkinson's disease (EOPD) commonly recognizes a genetic basis; thus, patients with EOPD are often addressed to diagnostic testing based on next-generation...
BACKGROUND AND OBJECTIVE
Early-onset Parkinson's disease (EOPD) commonly recognizes a genetic basis; thus, patients with EOPD are often addressed to diagnostic testing based on next-generation sequencing (NGS) of PD-associated multigene panels. However, NGS interpretation can be challenging in a diagnostic setting, and few studies have addressed this issue so far.
METHODS
We retrospectively collected data from 648 patients with PD with age at onset younger than 55 years who underwent NGS of a minimal shared panel of 15 PD-related genes, as well as PD-multiplex ligation-dependent probe amplification in eight Italian diagnostic laboratories. Data included a minimal clinical dataset, the complete list of variants included in the diagnostic report, and final interpretation (positive/negative/inconclusive). Patients were further stratified based on age at onset ≤40 years (very EOPD, n = 157). All variants were reclassified according to the latest American College of Medical Genetics and Genomics criteria. For classification purposes, PD-associated GBA1 variants were considered diagnostic.
RESULTS
In 186 of 648 (29%) patients, the diagnostic report listed at least one variant, and the outcome was considered diagnostic (positive) in 105 (16%). After reanalysis, diagnosis changed in 18 of 186 (10%) patients, with 5 shifting from inconclusive to positive and 13 former positive being reclassified as inconclusive. A definite diagnosis was eventually reached in 97 (15%) patients, of whom the majority carried GBA1 variants or, less frequently, biallelic PRKN variants. In 89 (14%) cases, the genetic report was inconclusive.
CONCLUSIONS
This study attempts to harmonize reporting of PD genetic testing across several diagnostic labs and highlights current difficulties in interpreting genetic variants emerging from NGS-multigene panels, with relevant implications for counseling. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Humans; Middle Aged; Adult; Parkinson Disease; Retrospective Studies; Mutation; Genetic Testing; Age of Onset
PubMed: 37750340
DOI: 10.1002/mds.29617 -
Tremor and Other Hyperkinetic Movements... 2023Movement disorders, particularly chorea, are uncommon in inborn errors of metabolism, but their identification is essential for improved clinical outcomes. In this... (Review)
Review
BACKGROUND
Movement disorders, particularly chorea, are uncommon in inborn errors of metabolism, but their identification is essential for improved clinical outcomes. In this context, comprehensive descriptions of movement disorders are limited and primarily derived from single cases or small patient series, highlighting the need for increased awareness and additional research in this field.
METHODS
A systematic review was conducted using the MEDLINE database and GeneReviews. The search included studies on inborn errors of metabolism associated with chorea, athetosis, or ballismus. The review adhered to PRISMA guidelines.
RESULTS
The systematic review analyzed 76 studies out of 2350 records, encompassing the period from 1964 to 2022. Chorea was observed in 90.1% of the 173 patients, followed by athetosis in 5.7%. Various inborn errors of metabolism showed an association with chorea, with trace elements and metals being the most frequent. Cognitive and developmental abnormalities were common in the cohort. Frequent neurological features included seizures, dysarthria, and optic atrophy, whereas non-neurological features included, among others, facial dysmorphia and failure to thrive. Neuroimaging and biochemical testing played crucial roles in aiding diagnosis, revealing abnormal findings in 34.1% and 47.9% of patients, respectively. However, symptomatic treatment efficacy for movement disorders was limited.
DISCUSSION
This study emphasizes the complexities of chorea in inborn errors of metabolism. A systematic approach with red flags, biochemical testing, and neuroimaging is required for diagnosis. Collaboration between neurologists, geneticists, and metabolic specialists is crucial for improving early detection and individualized treatment. Utilizing genetic testing technologies and potential therapeutic avenues can aid in the improvement of patient outcomes.
Topics: Humans; Chorea; Athetosis; Metabolism, Inborn Errors; Movement Disorders; Dyskinesias
PubMed: 37810989
DOI: 10.5334/tohm.801