Challenges in clinicogenetic correlations: one gene - many phenotypes

Background: Progress in genetics - particularly the advent of next-generation sequencing (NGS) - has enabled an unparalleled gene discovery and revealed unmatched complexity of genotype-phenotype correlations in movement disorders. Among other things, it has emerged that mutations in one and the same gene can cause multiple, often markedly different phenotypes. Consequently, movement disorder specialists have increasingly experienced challenges in clinicogenetic correlations. Objectives: To deconstruct biological phenomena and mechanistic bases of phenotypic heterogeneity in monogenic movement disorders and neurodegenerative diseases. To discuss the evolving role of movement disorder specialists in reshaping disease phenotypes in the NGS era. Methods: This scoping review details phenomena contributing to phenotypic heterogeneity and their underlying mechanisms. Results: Three phenomena contribute to phenotypic heterogeneity, namely incomplete penetrance, variable expressivity and pleiotropy. Their underlying mechanisms, which are often shared across phenomena and non-mutually exclusive, are not fully elucidated. They involve genetic factors (ie, different mutation types, dynamic mutations, somatic mosaicism, intragenic intra- and inter-allelic interactions, modifiers and epistatic genes, mitochondrial heteroplasmy), epigenetic factors (ie, genomic imprinting, X-chromosome inactivation, modulation of genetic and chromosomal defects), and environmental factors. Conclusion: Movement disorders is unique in its reliance on clinical judgment to accurately define disease phenotypes. This has been reaffirmed by the NGS revolution, which provides ever-growing sequencing data and fuels challenges in variant pathogenicity assertions for such clinically heterogeneous disorders. Deep phenotyping, with characterization and continual updating of "core" phenotypes, and comprehension of determinants of genotype-phenotype complex relationships are crucial for clinicogenetic correlations and have implications for the diagnosis, treatment and counseling

Genetic dystonia-ataxia syndromes: clinical spectrum, diagnostic approach and treatment options

Background: Dystonia and ataxia are manifestations of numerous disorders, and indeed, an ever-expanding spectrum of genes causing diseases that encompass dystonia and ataxia are discovered with the advances of genetic techniques. In recent years, a pathophysiological link between both clinical features and the role of the cerebellum in the genesis of dystonia, in some cases, has been proposed. In clinical practice, the genetic diagnosis of dystonia-ataxia syndromes is a major issue for genetic counseling, prognosis and, occasionally, specific treatment. Methods: For this pragmatic and educational review, we conducted a comprehensive and structured literature search in Pubmed, OMIM, and GeneReviews using the key words “dystonia” and “ataxia” to identify those genetic diseases that may combine dystonia with ataxia. Results: There are a plethora of genetic diseases causing dystonia and ataxia. We propose a series of clinico-radiological algorithms to guide their differential diagnosis depending on the age of onset, additional neurological or systemic features, and imaging findings. We suggest a sequential diagnostic approach to dystonia-ataxia syndromes. We briefly highlight the pathophysiological links between dystonia and ataxia and conclude with a review of specific treatment implications. Conclusions: The clinical approach presented in this review is intended to improve the diagnostic success of clinicians when faced with patients with dystonia-ataxia syndromes.Fil: Rossi, Malco. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Balint, Bettina. Institute of Neurology; Reino Unido. John Radcliffe Hospital; Reino Unido. University Hospital; AlemaniaFil: Millar Vernetti, Patricio. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Bhatia, Kailash P.. Institute of Neurology; Reino UnidoFil: Merello, Marcelo Jorge. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Psychiatric manifestations of ATP13A2 mutations

Background: Biallelic mutations in ATP13A2 were identified as the cause of Kufor-Rakeb disease, a pallido-pyramidal syndrome characterized by young-onset dystonia-parkinsonism with vertical supranuclear gaze palsy, spasticity, and cognitive decline. The phenotypic spectrum has broadened since, but predominantly psychiatric or behavioral manifestations have not been highlighted. Cases: Here we report the clinical, radiological, and genetic findings in 2 unrelated patients with ATP13A2 mutations. One patient had a prominent behavioral (autistic spectrum) presentation and the other a psychiatric (paranoid psychosis) presentation. Both had additional features, such as delayed milestones, ataxia, pyramidal signs, upgaze restriction, or impaired cognition to varying extent, but these were partly subtle or developed later in the disease course. Conclusion: Prominent behavioral or psychiatric features can be the first or most prominent manifestation of ATP13A2-related disease. They may be a diagnostic clue in patients with ataxia, spasticity, or parkinsonism and may require an interdisciplinary neurological and psychiatric treatment approach

Genetic dystonia-ataxia syndromes: clinical spectrum, diagnostic approach and treatment options

Background: Dystonia and ataxia are manifestations of numerous disorders, and indeed, an ever-expanding spectrum of genes causing diseases that encompass dystonia and ataxia are discovered with the advances of genetic techniques. In recent years, a pathophysiological link between both clinical features and the role of the cerebellum in the genesis of dystonia, in some cases, has been proposed. In clinical practice, the genetic diagnosis of dystonia-ataxia syndromes is a major issue for genetic counseling, prognosis and, occasionally, specific treatment. Methods: For this pragmatic and educational review, we conducted a comprehensive and structured literature search in Pubmed, OMIM, and GeneReviews using the key words “dystonia” and “ataxia” to identify those genetic diseases that may combine dystonia with ataxia. Results: There are a plethora of genetic diseases causing dystonia and ataxia. We propose a series of clinico-radiological algorithms to guide their differential diagnosis depending on the age of onset, additional neurological or systemic features, and imaging findings. We suggest a sequential diagnostic approach to dystonia-ataxia syndromes. We briefly highlight the pathophysiological links between dystonia and ataxia and conclude with a review of specific treatment implications. Conclusions: The clinical approach presented in this review is intended to improve the diagnostic success of clinicians when faced with patients with dystonia-ataxia syndromes.Fil: Rossi, Malco. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Balint, Bettina. Institute of Neurology; Reino Unido. John Radcliffe Hospital; Reino Unido. University Hospital; AlemaniaFil: Millar Vernetti, Patricio. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Bhatia, Kailash P.. Institute of Neurology; Reino UnidoFil: Merello, Marcelo Jorge. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

The spectrum of involuntary vocalizations in humans: A video atlas

In clinical practice, involuntary vocalizing behaviors are typically associated with Tourette syndrome and other tic disorders. However, they may also be encountered throughout the entire tenor of neuropsychiatry, movement disorders, and neurodevelopmental syndromes. Importantly, involuntary vocalizing behaviors may often constitute a predominant clinical sign, and, therefore, their early recognition and appropriate classification are necessary to guide diagnosis and treatment. Clinical literature and video-documented cases on the topic are surprisingly scarce. Here, we pooled data from 5 expert centers of movement disorders, with instructive video material to cover the entire range of involuntary vocalizations in humans. Medical literature was also reviewed to document the range of possible etiologies associated with the different types of vocalizing behaviors and to explore treatment options. We propose a phenomenological classification of involuntary vocalizations within different categorical domains, including (1) tics and tic-like vocalizations, (2) vocalizations as part of stereotypies, (3) vocalizations as part of dystonia or chorea, (4) continuous vocalizing behaviors such as groaning or grunting, (5) pathological laughter and crying, (6) vocalizations resembling physiological reflexes, and (7) other vocalizations, for example, those associated with exaggerated startle responses, as part of epilepsy and sleep-related phenomena. We provide comprehensive lists of their associated etiologies, including neurodevelopmental, neurodegenerative, neuroimmunological, and structural causes and clinical clues. We then expand on the pathophysiology of the different vocalizing behaviors and comment on available treatment options. Finally, we present an algorithmic approach that covers the wide range of involuntary vocalizations in humans, with the ultimate goal of improving diagnostic accuracy and guiding appropriate treatment

Validation of a self-completed Dystonia Non-Motor Symptoms Questionnaire

Objetive: To develop and validate a novel 14-item self-completed questionnaire (in English and German) enquiring about the presence of non-motor symptoms (NMS) during the past month in patients with craniocervical dystonia in an international multicenter study. Methods: The Dystonia Non-Motor Symptoms Questionnaire (DNMSQuest) covers seven domains including sleep, autonomic symptoms, fatigue, emotional well-being, stigma, activities of daily living, sensory symptoms. The feasibility and clinimetric attributes were analyzed. Results: Data from 194 patients with CD (65.6% female, mean age 58.96 ± 12.17 years, duration of disease 11.95 ± 9.40 years) and 102 age- and sex-matched healthy controls (66.7% female, mean age 55.67 ± 17.62 years) were collected from centres in Germany and the UK. The median total NMS score in CD patients was 5 (interquartile range 3-7), significantly higher than in healthy controls with 1 (interquartile range 0.75-2.25) (P < 0.001, Mann-Whitney U-test). Evidence for intercorrelation and convergent validity is shown by moderate to high correlations of total DNMSQuest score with motor symptom severity (TWSTRS: rs  = 0.61), clinical global impression (rs  = 0.40), and health-related quality of life measures: CDQ-24 (rs  = 0.74), EQ-5D index (rs  = -0.59), and scale (rs  = -0.49) (all P < 0.001). Data quality and acceptability was very satisfactory. Interpretation: The DNMSQuest, a patient self-completed questionnaire for NMS assessment in CD patients, appears robust, reproducible, and valid in clinical practice showing a tangible impact of NMS on quality of life in CD. As there is no specific, comprehensive, validated tool to assess the burden of NMS in dystonia, the DNMSQuest can bridge this gap and could easily be integrated into clinical practice.S

Development and clinimetric assessment of a nurse-administered screening tool for movement disorders in psychosis

Background: Movement disorders (MD) associated with exposure to antipsychotic drugs (AP). MD are common and stigmatising, but underdiagnosed. Methods: We developed a screening procedure for AP-MD for administration by mental health (MH) nurses. Item selection and content validity assessment were conducted by a panel of neurologists, psychiatrists and a MH nurse, who operationalised a 31-item screening procedure (ScanMove instrument). Inter-rater reliability was measured on ratings from ten MH nurses evaluating video-recordings of the procedure on 30 patients with psychosis. Criterion and concurrent validity were tested comparing the ScanMove instrument-based rating of thirteen MH nurses of 635 community patients from MH services to diagnostic judgement of a MD neurologist based on the ScanMove instrument and a reference procedure comprising a selection of commonly used rating scales. Results: Inter-reliability analysis showed no systematic difference between raters in their prediction of any AP-MD category. On criterion validity testing, the ScanMove instrument showed good sensitivity for parkinsonism (94%) and hyperkinesia (89%), but not for akathisia (38%), whereas specificity was low for parkinsonism and hyperkinesia, and moderate for akathisia. Mixed effect regression models showed low concurrent validity of quantitative scores obtained from the ScanMove instrument. Conclusions: The ScanMove instrument demonstrated good feasibility and inter-rater reliability, and acceptable sensitivity as MH nurse-administered screening tool for parkinsonism and hyperkinesia

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection