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

Dynamic Analyses of Lymphoblast Membranes Exposed to Alpha Interferon Using Flow Cytometry and Fluorescence Recovery after Photobleaching

Interferons represent a major group of the biologic response modifiers which exert multipotent effects upon cell growth, cytodifferentiation and immune functions. Previous experimental studies with alpha interferon (IFN-) have suggested that modulation of transmembrane signaling could be a critical determinant in the bioregulatory diversity. To determine whether any initial changes at the plasma membrane would directly correlate with one or more actions of IFN-, we investigated cultures of Daudi lymphoblasts which are uniquely susceptible to growth inhibition. Complementary biophysical techniques were applied. In one approach, changes in plasma membrane ion flux were measured by flow cytometry, using a fluorescent dye indicator of membrane potential: Cells briefly exposed (5-10 min) to a DNA-recombinant IFN-2 (100 to 800 U/ml) manifested a consistent plasma membrane hyperpolarization (—60 to —90 mV) which could be blocked by ouabain. In a second approach, changes in diffusion coefficients of plasma membrane-associated macromolecules were determined by measuring the fluorescence redistribution after pulse photobleaching (FRAP): Individual plasma membrane proteins (sIgM, Leu 12 or Leu 16) were la-belled with FITC conjugated goat antibodies [F(ab\u27)2 or Fab\u27] or with phycoerythrin-B conjugated monoclonal mouse anti-bodies. Statistical comparisons of cells exposed to IFN-a2 for 10 to 30 min showed immediate 27 to 88 % increases in mean lateral diffusion rates. Mutant Daudi cells, cloned for resistance to growth inhibition showed no plasma membrane hyperpolarization with IFN-2 (up to 1000 U/ ml), and baseline lateral diffusion coefficients matched those ofIFN-2-treated, non-resistant cells. We conclude that biophysical status and responses of the plasma membrane must be closely linked to the molecular mechanisms of anti-proliferative signal transduction

Cluster growth in the dynamical Erdös-Rényi process with forest fires

We investigate the growth of clusters within the forest fire model of Ráth and Tóth [EJP, vol 14, paper no 45]. The model is a continuous-time Markov process, similar to the dynamical Erdős-Rényi random graph but with the addition of so-called fires. A vertex may catch fire at any moment and, when it does so, causes all edges within its connected cluster to burn, meaning that they instantaneously disappear. Each burned edge may later reappear. We give a precise description of the process CtCt of the size of the cluster of a tagged vertex, in the limit as the number of vertices in the model tends to infinity. We show that CtCt is an explosive branching process with a time-inhomogeneous offspring distribution and instantaneous return to 1 on each explosion. Additionally, we show that the characteristic curves used to analyse the Smoluchowski-type coagulation equations associated to the model have a probabilistic interpretation in terms of the process CtCt

Tremor in motor neuron disease may be central rather than peripheral in origin

BACKGROUND AND PURPOSE: Motor neuron disease (MND) refers to a spectrum of degenerative diseases affecting motor neurons. Recent clinical and post-mortem observations have revealed considerable variability in the phenotype. Rhythmic involuntary oscillations of the hands during action, resembling tremor, can occur in MND, but their pathophysiology has not yet been investigated. METHODS: A total of 120 consecutive patients with MND were screened for tremor. Twelve patients with action tremor and no other movement disorders were found. Ten took part in the study. Tremor was recorded bilaterally using surface electromyography (EMG) and triaxial accelerometer, with and without a variable weight load. Power spectra of rectified EMG and accelerometric signal were calculated. To investigate a possible cerebellar involvement, eyeblink classic conditioning was performed in five patients. RESULTS: Action tremor was present in about 10% of our population. All patients showed distal postural tremor of low amplitude and constant frequency, bilateral with a small degree of asymmetry. Two also showed simple kinetic tremor. A peak at the EMG and accelerometric recordings ranging from 4 to 12 Hz was found in all patients. Loading did not change peak frequency in either the electromyographic or accelerometric power spectra. Compared with healthy volunteers, patients had a smaller number of conditioned responses during eyeblink classic conditioning. CONCLUSIONS: Our data suggest that patients with MND can present with action tremor of a central origin, possibly due to a cerebellar dysfunction. This evidence supports the novel idea of MND as a multisystem neurodegenerative disease and that action tremor can be part of this condition

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

Michael Balint's word trail: The ‘Ocnophil’, the ‘Philobat’ and creative dyads

In this paper, I discuss how Michael Balint arrived at the concepts of ‘ocnophil’ and ‘philobat’, which refer to two kinds of object relations. I look at the correspondence between Balint and the classical scholar David Eichholz. The two crafted these words together in a passionate exchange of letters. By recognizing the importance of creative dyads in psychoanalysis, we gain more insight into the creation of psychoanalytic knowledge beyond the frame of individual authorship. I read the collaboration between Balint and Eichholz in its historical and theoretical context, particularly in relation to the Budapest School of psychoanalysis, where intellectual collaborations had an important place. The Budapest School was Michael Balint's first home, and it shaped his epistemic and psychoanalytic style. Balint constructed his psychoanalytic theories in a spirit of openness, maintaining a commitment to conversations between psychoanalysis and other disciplines