Paroxysmal Disorders Research Articles

Paroxysmal Genetic Movement Disorders and Epilepsy.

Paroxysmal movement disorders include paroxysmal kinesigenic dyskinesia, paroxysmal non-kinesigenic dyskinesia, paroxysmal exercise-induced dyskinesia, and episodic ataxias. In recent years, there has been renewed interest and recognition of these disorders and their intersection with epilepsy, at the molecular and pathophysiological levels. In this review, we discuss how these distinct phenotypes were constructed from a historical perspective and discuss how they are currently coalescing into established genetic etiologies with extensive pleiotropy, emphasizing clinical phenotyping important for diagnosis and for interpreting results from genetic testing. We discuss insights on the pathophysiology of select disorders and describe shared mechanisms that overlap treatment principles in some of these disorders. In the near future, it is likely that a growing number of genes will be described associating movement disorders and epilepsy, in parallel with improved understanding of disease mechanisms leading to more effective treatments.

Years of Life Lost Due to Premature Death and Their Trends in People With Selected Neurological Disorders in Shanghai, China, 1995–2018: A Population-Based Study

Background: Neurological disorders are the leading cause of long-term disability and the second leading cause of death in the world. We aimed to characterize the long-term trends in mortality and disease burden of selected neurological disorders and quantitatively analyze the contributions of demographic and non-demographic factors on the mortality of selected neurological disorders in Shanghai, China, 1995–2018.Methods: Mortality data were derived from the Vital Statistics System of Pudong New Area, Shanghai, China, during 1995–2018. Temporal trends for the mortality rates and burden of selected neurological disorders were analyzed by Joinpoint Regression Program. Years of life lost (YLL) was used to analyze the burden of disease. The increasing mortality rates related to demographic and non-demographic factors were estimated by the decomposition method.Results: A total of 4432 deaths from selected neurological disorders occurred during 1995–2018, accounting for 0.98% of total deaths. The crude mortality rates (CMR) and age-standardized mortality rates (ASMRW) of neurological disorders were 7.14/105 person–years and 4.08/105 person–years, respectively. Extrapyramidal and movement disorders, other degenerative diseases of the nervous system, and episodic and paroxysmal disorders were the three leading causes of mortality and YLL of selected neurological disorders. The CMR, ASMRW, and rate of YLL for deaths from selected neurological disorders showed significantly increasing trends in males, females, and the total population during 1995–2018 (all P < 0.001). The contribution rates of increased values of CMR related to demographic factors were more evident than non-demographic factors.Conclusion: The mortality rate and rate of YLL for death from selected neurological disorders increased significantly during 1995–2018 in Pudong New Area, Shanghai. The demographic factors, particularly aging, might be related to an increase in the mortality of neurological disorders. More effective prevention strategies are needed to prevent the aging-related death and burden from neurological disorders in the future.

From Genotype to Phenotype: Expanding the Clinical Spectrum of CACNA1A Variants in the Era of Next Generation Sequencing.

Ion channel dysfunction is a key pathological substrate of episodic neurological disorders. A classical gene associated to paroxysmal movement disorders is CACNA1A, which codes for the pore-forming subunit of the neuronal calcium channel P/Q. Non-polyglutamine CACNA1A variants underlie familial hemiplegic ataxia type 1 (FHM1) and episodic ataxia type 2 (EA2). Classical paroxysmal manifestations of FHM1 are migraine attacks preceded by motor aura consisting of hemiparesis, aphasia, and disturbances of consciousness until coma. Patients with EA2 suffer of recurrent episodes of vertigo, unbalance, diplopia, and vomiting. Beyond these typical presentations, several reports highlighted manifold clinical features associated with P/Q channelopathies, from chronic progressive cerebellar ataxia to epilepsy and psychiatric disturbances. These manifestations may often outlast the burden of classical episodic symptoms leading to pitfalls in the diagnostic work-up. Lately, the spreading of next generation sequencing techniques linked de novo CACNA1A variants to an even broader phenotypic spectrum including early developmental delay, autism spectrum disorders, epileptic encephalopathy, and early onset paroxysmal dystonia. The age-dependency represents a striking new aspect of these phenotypes und highlights a pivotal role for P/Q channels in the development of the central nervous system in a defined time window. While several reviews addressed the clinical presentation and treatment of FHM1 and EA2, an overview of the newly described age-dependent manifestations is lacking. In this Mini-Review we present a clinical update, delineate genotype-phenotype correlations as well as summarize evidence on the pathophysiological mechanisms underlying the expanded phenotype associated with CACNA1A variants.

Features of Cognitive Impairments in Patients with Comorbid Recurrent Affective and Panic Disorders

Objectives. To identify targets for medication and psychotherapy in the treatment of patients with comorbid recurrent affective and panic disorders based on results from studies of cognitive functions. Materials and methods. A set of pathopsychological methods (Schulte tables, correction test, 120-word test, cube drawing test, Binet and Berstein tests) was used. Cognitive status was studied in 60 patients with signs of recurrent affective (depressive) and panic disorders. ICD-10 diagnoses for the 27 patients making up the study group (SG) were recurrent affective disorder with mild and moderate depressive episodes (RAD, F33.0, F33.1) in combination with panic disorder (PD, F41.0). The control group (CG) included 33 patients with recurrent affective disorder (RAR, F33.0, F33.1) without panic disorder. Results and conclusions. All patients showed changes in the cognitive domain. Cognitive disorders in patients of the SG were more severe than those in patients of the CG. Cognitive functions in SG patients were characterized by being “left-hemisphere” impairments, in the form of paroxysmal emotional disorders with a predominance of fear and anxiety and dysfunction in the operation of a number of neuropsychological factors: successiveness, spatiality, inertia-mobility, for which the mediobasal and subcortical parts of the brain are responsible. Studies of cognitive impairments in remission provided evidence of some level of improvement in the cognitive domain in SG and CG patients, though there were no significant differences between the groups (p > 0.05). Targets for medication and psychotherapy in SG patients were attention, audioverbal memory, and components of thought (logical and spatial). The authors believe that use of neuropsychological correction of cognitive impairments is appropriate in patients of this group.

The effectiveness of therapy correction in children with paroxysmal disorders of consciousness based on the results of video electroencephalographic monitoring

Background. An important condition for adequate drug therapy is the early differential diagnosis of paroxysmal conditions in children, the estab lishment or clarification of their epileptic or non-epileptic nature.Objective: to demonstrate the necessity, effectiveness and safety of the correction therapy in children with paroxysmal disorders of consciousness according to results of complex investigation, including video-electroencephalographic monitoring.Materials and methods. A comprehensive examination with the inclusion of video-electroencephalographic monitoring was carried out in 527 pa tients referred by neurologists to clarify the nature of paroxysmal consciousness disorder, clarify the form of epilepsy, and select an adequate treatment.Results. Based on the results obtained during the comprehensive examination of children with video-electroencephalographic monitoring, in all the examined children the diagnosed was corrected. According to the results of the survey, it was found that 210 children had non-epileptic paroxysms. In the overwhelming majority of cases, the treatment was changed.Conclusions. The presented results of treatment of children with epileptic and non-epileptic paroxysms after correction of treatment indicate the need for careful analysis of all data (clinical and anamnestic, electroencephalographic, laboratory) for correct diagnosis, identification of causes of resistance and reasonable selection of therapy in each patient.

Demographic and clinical phenotypic differences between people with dissociative seizures and those with other psychiatric disorders.

A large amount of literature surrounds the differences between dissociative neurological symptom disorder with non-epileptic seizures (DNSD-S) and epilepsy. To explore the research gap on phenotypic differences between DNSD-S and other psychiatric disorders. We conducted a case-control study of 1860 patients (620 patients with DNSD-S and 1240 controls with other psychiatric disorders) seen at the South London and Maudsley Hospital NHS Trust between 2007 and 2019. Compared with the controls, the patients with DNSD-S were more likely to be female (76 v. 47%, P < 0.001), of White ethnicity (77 v. 60%, P < 0.001), married (34 v. 14%, P < 0.001) and living in areas of lower socioeconomic status (-3.79, 95% CI -2.62 to -4.96, P < 0.001). Two peaks for age at diagnosis were observed for DNSD-S: the early 20s and late 40s. After 31 years of age, men's chance of being diagnosed with DNSD-S increased from 19 to 28% (P = 0.009). People with DNSD-S presented more commonly with a history of a neurological episodic or paroxysmal disorder (OR = 12, 95% CI 7.82-20.26), another dissociative disorder (OR = 10, 95% CI 1.64- 65.95) or unclassified signs or symptoms (OR = 4, 95% CI 2.61-6.43). Neither anxiety, depression nor other somatoform disorders predicted subsequent diagnosis of DNSD-S, and controls had a larger proportion of preceding psychiatric diagnoses than patients with DNSD-S (65 v. 49%, P < 0.001). This is the first study comparing demographic and phenotypic correlates of patients with DNSD-S against a large cohort of psychiatric patients. These data will inform development and drive service needs in psychiatry for people with DNSD-S.

Generation of an induced pluripotent stem cell line (ZZUi022-A) from a paroxysmal kinesigenic dyskinesia individual carrying the PRRT2 gene mutation.

Paroxysmal kinesigenic dyskinesia (PKD), the most common type of paroxysmal movement disorders, is caused by mutations in PRRT2 gene. We identified an unreported PRRT2 c. 535 C>T (p. Q 1 7 9 *) pathogenic mutation in a Chinese Han family with PKD and generated an induced pluripotent stem cell (iPSC) line from a patient in the family by reprogramming fibroblasts with sendai virus. The iPSC line was characterized for genetic uniqueness, genomic integrity, pluripotency, and differentiation ability. This iPSC line will be a powerful tool to to study the molecular mechanisms underlying PKD.

Unveiling the comparative efficacy and tolerability of comprehensive treatments for migraine: A protocol of systematic review and Bayesian network meta-analysis.

Background:Migraine is a chronic paroxysmal incapacitating neurological disorder, which endangers the health of human worldwide ranking as the third most prevalent medical condition. There are no comprehensive estimates of treatments for migraine. We will conduct this systematic review and Bayesian network meta-analysis (NMA) to synthesis quantitative and comparative evidence on the efficacy and tolerability of all the known pharmacological and non-pharmacological interventions for migraine.Method:We will perform the systematic electronic search of the literature utilizing MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Cumulative Index to Nursing & Allied Health (CINAHL), and PsycINFO. We will only include randomized controlled trials (RCTs) of high quality which appraise the efficacy or safety of any potential pharmacological or non-pharmacological interventions in the treatment of patients with migraine. The traditional pairwise meta-analyses will be performed to anticipate the heterogeneities and publication bias and the NMA will be conducted within a Bayesian hierarchical model framework to obtain estimates for all valuable treatments for migraine. The entire heterogeneity will be quantified by Q statistic and I2 index. Other analyses included sensitivity analyses, meta-regression, and subgroup analyses will also be conducted. The whole process will be conducted using in R-3.6.0 software.Results:This study will obtain the efficacy and tolerability of all potential treatments for migraine, aiming at providing consolidated evidence to help make the best choice of interventions. The results will be published in a peer-reviewed journal.Discussion:This Bayesian network meta-analysis may be the first attempt to quantitatively synthesize the efficacy and tolerability of all potential treatments for migraine. And this method can ensure us to fully utilize both the direct and indirect evidence as well as gain the comparative estimates displayed in the derived hierarchies. Besides, we have registered this protocol on the international prospective register of systematic review (PROSPERO) (CRD42020157278).

Increased responsiveness at the cerebellar input stage in the PRRT2 knockout model of paroxysmal kinesigenic dyskinesia

PRoline-Rich Transmembrane protein-2 (PRRT2) is a recently described neuron-specific type-2 integral membrane protein with a large cytosolic N-terminal domain that distributes in presynaptic and axonal domains where it interacts with several presynaptic proteins and voltage-gated Na+ channels. Several PRRT2 mutations are the main cause of a wide and heterogeneous spectrum of paroxysmal disorders with a loss-of-function pathomechanism. The highest expression levels of PRRT2 in brain occurs in cerebellar granule cells (GCs) and cerebellar dysfunctions participate in the dyskinetic phenotype of PRRT2 knockout (KO) mice. We have investigated the effects of PRRT2 deficiency on the intrinsic excitability of GCs and the input-output relationships at the mossy fiber-GC synapses. We show that PRRT2 KO primary GCs display increased expression of Na+ channels, increased amplitude of Na+ currents and increased length of the axon initial segment, leading to an overall enhancement of intrinsic excitability. In acute PRRT2 KO cerebellar slices, GCs were more prone to action potential discharge in response to mossy fiber activation and exhibited an enhancement of transient and persistent Na+ currents, in the absence of changes at the mossy fiber-GC synapses. The results support a key role of PRRT2 expressed in GCs in the physiological regulation of the excitatory input to the cerebellum and are consistent with a major role of a cerebellar dysfunction in the pathogenesis of the PRRT2-linked paroxysmal pathologies.

The European Reference Network for Rare Neurological Diseases.

While rare diseases (RDs) are by definition of low prevalence, the total number of patients suffering from an RD is high, and the majority of them have neurologic manifestations, involving central, peripheral nerve, and muscle. In 2017, 24 European Reference Networks (ERNs), each focusing on a specific group of rare or low-prevalence complex diseases, were formed to improve the care for patients with an RD. One major aim is to have “the knowledge travel instead of the patient,” which has been put into practice by the implementation of the Clinical Patient Management System (CPMS) that enables clinicians to perform pan-European virtual consultations. The European Reference Network for Rare Neurological Diseases (ERN-RND) provides an infrastructure for knowledge sharing and care coordination for patients affected by a rare neurological disease (RND) involving the most common central nervous system pathological conditions. It covers the following disease groups: (i) Cerebellar Ataxias and Hereditary Spastic Paraplegias; (ii) Huntington's disease and Other Choreas; (iii) Frontotemporal dementia; (iv) Dystonia, (non-epileptic) paroxysmal disorders, and Neurodegeneration with Brain Iron Accumulation; (v) Leukoencephalopathies; and (vi) Atypical Parkinsonian Syndromes. At the moment, it unites 32 expert centers and 10 affiliated partners in 21 European countries, as well as patient representatives, but will soon cover nearly all countries of the European Union as a result of the ongoing expansion process. Disease expert groups developed and consented on diagnostic flowcharts and disease scales to assess the different aspects of RNDs. ERN-RND has started to discuss diagnostically unclear patients in the CPMS, is one of four ERNs that serve as foundation of Solve-RD, and has established an RND training and education program. The network will facilitate trial readiness through the establishment of an ERN-RND registry with a minimal data of all patients seen at the ERN-RND centers, thus providing a unique overview of existing genotype-based cohorts. The overall aim of the ERNs is to improve access for patients with RDs to quality diagnosis, care, and treatment. Based on this objective, ERNs are monitored by the European Commission on a regular basis to provide transparency and reassurance to the RD community and the general public.

Medical disorders in a Danish cohort of children with attention-deficit hyperactivity disorder.

Studies have identified a higher prevalence of co-existing psychiatric and medical disorders in children with ADHD. There is a shortage of longitudinal studies providing an overview of potential medical disorders in children with ADHD. The objective of this study was to provide a broad overview of lifetime prevalence and relative risk of medical disorders in a nationwide Danish cohort of children with and without ADHD during the first 12years of life. A population-based prospective follow-back cohort study used data from Danish national health registries to identify a cohort of all children born in Denmark between 1995 and 2002. The children were followed from birth until 12years of age in two national registries. Children with ADHD had a significantly higher prevalence of recorded diagnoses across all included chapters of medical disorders in the ICD-10, except for neoplasms, where the association with ADHD was non-significant. The highest relative risk was observed for the chapter concerning diseases of the nervous system, with episodic and paroxysmal disorders being the most frequently registered underlying category. The findings indicate that children with ADHD have an increased risk of a broad range of medical disorders compared to the general population during the first 12years of life, except for neoplasms.

Early pacemaker insertion after aortic valve replacement with Edwards Intuity sutureless valve versus standard bioprosthesis

In patients undergoing aortic valve replacement the occurrence of postoperative conduction disorders is a serious adverse event, which may prolong the duration of hospitalisation and require insertion of a pacemaker. To evaluate the rate of pacemaker insertion after implantation of an Intuity sutureless aortic valve compared to standard surgical bioprosthesis. This retrospective, monocentric study included patients who underwent aortic valve replacement with an Intuity sutureless aortic valve or a standard bioprosthetic valve between June 4, 2014 and June 27, 2016. The main assessment criterion was the rate of postoperative pacemaker insertion. Secondary assessment criteria included the rate of de novo conduction disorders, the rate of atrial arrhythmia or paroxysmal conduction disorders, mortality and duration of hospitalisation. Ninety-three patients received an Intuity sutureless aortic valve (median age: 76 [71,80] years) and 176 were implanted with a standard biological aortic valve (median age: 73 [68,79] years; P = 0.007). The rate of postoperative pacemaker insertion, after adjustment, was 22.5% in the Intuity group and 5.7% in the standard aortic valve group (OR = 5.5 [95% CI: 1.37–34.54]; P = 0.036). The main indications for postoperative pacemaker insertion were complete atrioventricular block and de novo left bundle branch block (LBBB) with slowing of the infra-hisian conduction velocity. The rate of postoperative de novo bundle branch block was higher in patients implanted with an Intuity valve (OR = 6.25 [2.01–24.74]; P = 0.042). Higher rates of pacemaker insertion and de novo bundle branch block were observed in patients implanted with an Intuity sutureless bioprosthesis compared to those who received a standard surgical aortic valve.

Sleep Exacerbations and Facial Twitching: Diagnostic Clues for ADCY5-Related Dyskinesias

Abstract Background Mutations in the adenylate cyclase 5 (ADCY5) gene are associated with childhood-onset paroxysmal dyskinesia. Methods We report a new video-documented case of pediatric ADCY5-related dyskinesia with de novo ADCY5 mutation. Results A boy born to nonconsanguineous parents after an uneventful pregnancy had developmental delay and hypotonia. At the age of 7 months, he presented with paroxysmal jerky–choreic–dystonic involuntary movements in wakefulness involving limbs, trunk, and face, exacerbated by emotional stimuli. These episodes gradually worsened in duration and frequency: at the age of 2.5 years, they occurred up to six times per day, and appeared also during sleep in prolonged bouts; the boy also had basal choreoathetoid–dystonic movements, hyperactivity, paraparetic–ataxic gait, generalized hypotonia with brisk tendon reflexes, drooling, and language delay with intellectual disability. Brain magnetic resonance imaging, electroencephalogram, electromyogram, eye review, metabolic investigations, oligoclonal bands, and autoantibodies were normal. Extensive genetic testing had not let to a diagnosis, until a heterozygous de novo mutation c.1252C &gt; T (p.Arg418Trp) was identified in the ADCY5 gene. Clonazepam had partial effectiveness. The boy walked at the age of 3.5 years. At the age of 5 years, the paroxysmal movement disorder has slightly improved. Conclusion ADCY5 mutations should be considered among the differential diagnoses of early-onset paroxysmal choreic–athetosic–myoclonic–dystonic movement disorder involving limbs, trunk, and face, in patients with global neurological impairment with hypotonia and developmental delay. Facial dyskinesias and exacerbation by drowsiness/sleep and emotional stimuli are important clues that may allow a timely recognition of the disorder and avoidance of unnecessary diagnostic investigations.

Principles and Practice of Child Neurology in Infancy, Second Edition Edited by Colin, KennedyLondon: Mac Keith Press, 2020. £65.00 (Softback), pp 552. ISBN: 9781911612001

The first edition of this practical guide was published in 2012 and became the basis of a teaching series for the European Pediatric Neurology Society. Principles and Practice of Child Neurology in Infancy may not have seeped into the consciousness of North America yet, but that is likely to change with the second edition. It is a thoughtfully constructed title and fills an important niche in pediatric neurology. There are 29 multi-authored chapters organized into two main sections: the first being a general approach and the second devoted to clinical topics. The general approach section covers a wide breadth, including inter-professional working, evidence-based medicine, neonatal and infant neurological examinations, vaccination, imaging, neurophysiology, biochemical testing, genetic testing, drug treatments, and nonpharmacological approaches. The clinical topics begin with birth asphyxia and acute newborn infant encephalopathy, and then cover areas pertinent to neonates (vs infants). There is a neonatal seizure chapter and later a post-neonatal seizure chapter, as well as a separate discussion of non-epileptic paroxysmal disorders in infancy. There are individual chapters on microcephaly (including congenital infections) and macrocephaly (including hydrocephalus and brain tumors). Chapters more focused on the post-neonatal period include the hypotonic infant, infant sleep and behavior, cerebral palsy, movement disorders, and developmental regression. Each chapter begins with highlighted, boxed sections covering ‘Key messages’, ‘Common errors’, and ‘When to worry’, and ends with key references followed by resources. This consistent structure sets a user-friendly tone and provides immediacy to what the clinician (novice and seasoned) really needs to know. The first chapter, authored by Colin Kennedy (editor of the book), implores us to use terms with precision and exercise our responsibility to encourage standard care and discourage unproven, potentially harmful measures. The chapter on inter-professional care covers childhood (and parental) depression and living with a disability, so pertinent in this domain of pediatric medicine. Andrew Lux’s tour-de-force in epidemiology is essential reading for anyone writing, or reviewing, in the peer-reviewed literature. The chapter on promoting child development develops into a superb discussion of neurodiversity and the right to ‘live happily ever after’, drawing from sources such as the United Nations and the World Health Organization. The chapters on the neonatal examination, infant developmental and neurological evaluations, and vaccination/disease prevention are well done and deserve a wide audience of pediatricians and neurodevelopmental specialists. The discussions on classical diagnostic tests (imaging, electroencephalography, laboratory medicine) are lucid introductions with advanced information as well. The genetic testing portion is timely and paramount, and perhaps could even include the standard terminology of gene variants in a future rendition. The discussion on drug treatments has comprehensive and practical information on vitamin treatments in neonates. The chapter on nonpharmacological treatment – a topic often unseen in standard child neurology literature – is a balanced and welcome addition. The second section of the book, as noted above, covers the major clinical topics of neonatal/infantile neurology. Each chapter is rich in clinical detail plus some surprises, e.g. a primer on herniation syndromes in the chapter on acute neurological illness with fever. While there are some inconsistencies (e.g. references range from none to 30+), each chapter maintains the same organizational pattern of ‘Key messages’, ‘Common errors’, and ‘When to worry’. What could be better? Mac Keith Press, publisher of Principles and Practice of Child Neurology in Infancy, now also offers an online interactive course based on the volume’s contents. This carefully edited book, spanning the neonatal and infantile periods, is sure to enter the pantheon of authoritative works in pediatric neurology and become an educational treasure for the foreseeable future.

Paroxysmal tachycardia

The article highlights the issues of paroxysmal heart rhythm disorders, which are one of the most pressing problems of modern cardiology. Modern information on classification, course and prognosis, as well as the algorithm of differential diagnosis of these conditions are provided. The factors that cause the development of paroxysmal tachycardia, which must be taken into account when making a diagnosis, are described in detail.

Neuromodulatory approach in paroxysmal neurological disorders

Neuromodulatory approach in paroxysmal neurological disorders

Imepitoin for treatment of idiopathic head tremor syndrome in dogs: A randomized, blinded, placebo-controlled study.

BackgroundIdiopathic head tremor syndrome is a paroxysmal movement disorder of unknown etiology. Spontaneous remission may occur, but owners may request treatment in severely affected dogs with continued episodes. Controlled studies of the disease are not available.Hypothesis/ObjectivesA drug with gamma amino butyric acid‐ergic and anxiolytic effects will decrease head tremor episodes.AnimalsTwenty‐four dogs with severe nonremitting head tremor and presumptive clinical diagnosis of idiopathic head tremor syndrome.MethodsProspective, blinded, placebo‐controlled clinical trial to compare imepitoin with placebo in dogs with frequent episodes of idiopathic head tremor. Evaluation of efficacy used the quotient T2/T1 that represented prolongation of the head tremor‐free period compared to a 3‐month baseline. A dog was considered a responder if tremors subsided or if the head tremor‐free period was 3× longer than the longest period during baseline (T2/T1 ≥ 3). Sample size calculations considered a large effect of imepitoin on T2/T1 (Cohen's d = 0.8).ResultsThere were no responders in the placebo group (0/12). In the imepitoin group, the responder rate was 17% (2/12; P = .18) with T2/T1 3.8 and 4.0. Mean T2/T1 was 1.0 ± 1.4 in the imepitoin and 0.4 ± 0.4 in the placebo group (P = .37).Conclusion and Clinical ImportanceImepitoin did not result in a significant overall benefit. Future studies should focus on treatment of subgroups with a common pathophysiology and similar comorbidities.

The Phenotypic Spectrum of PRRT2-Associated Paroxysmal Neurologic Disorders in Childhood.

Pathogenic variants in PRRT2, encoding the proline-rich transmembrane protein 2, have been associated with an evolving spectrum of paroxysmal neurologic disorders. Based on a cohort of children with PRRT2-related infantile epilepsy, this study aimed at delineating the broad clinical spectrum of PRRT2-associated phenotypes in these children and their relatives. Only a few recent larger cohort studies are on record and findings from single reports were not confirmed so far. We collected detailed genetic and phenotypic data of 40 previously unreported patients from 36 families. All patients had benign infantile epilepsy and harbored pathogenic variants in PRRT2 (core cohort). Clinical data of 62 family members were included, comprising a cohort of 102 individuals (extended cohort) with PRRT2-associated neurological disease. Additional phenotypes in the cohort of patients with benign sporadic and familial infantile epilepsy consist of movement disorders with paroxysmal kinesigenic dyskinesia in six patients, infantile-onset movement disorders in 2 of 40 individuals, and episodic ataxia after mild head trauma in one girl with bi-allelic variants in PRRT2. The same girl displayed a focal cortical dysplasia upon brain imaging. Familial hemiplegic migraine and migraine with aura were reported in nine families. A single individual developed epilepsy with continuous spikes and waves during sleep. In addition to known variants, we report the novel variant c.843G>T, p.(Trp281Cys) that co-segregated with benign infantile epilepsy and migraine in one family. Our study highlights the variability of clinical presentations of patients harboring pathogenic PRRT2 variants and expands the associated phenotypic spectrum.

Homology-guided identification of a conserved motif linking the antiviral functions of IFITM3 to its oligomeric state.

The interferon-inducible transmembrane (IFITM) proteins belong to the Dispanin/CD225 family and inhibit diverse virus infections. IFITM3 reduces membrane fusion between cells and virions through a poorly characterized mechanism. Mutation of proline-rich transmembrane protein 2 (PRRT2), a regulator of neurotransmitter release, at glycine-305 was previously linked to paroxysmal neurological disorders in humans. Here, we show that glycine-305 and the homologous site in IFITM3, glycine-95, drive protein oligomerization from within a GxxxG motif. Mutation of glycine-95 (and to a lesser extent, glycine-91) disrupted IFITM3 oligomerization and reduced its antiviral activity against Influenza A virus. An oligomerization-defective variant was used to reveal that IFITM3 promotes membrane rigidity in a glycine-95-dependent and amphipathic helix-dependent manner. Furthermore, a compound which counteracts virus inhibition by IFITM3, Amphotericin B, prevented the IFITM3-mediated rigidification of membranes. Overall, these data suggest that IFITM3 oligomers inhibit virus-cell fusion by promoting membrane rigidity.

Re-Establishing Solid Food Consumption in a Person With Traumatic Brain Injury and Extended Food Avoidance/Restriction Using a Multicomponent Behavioral Intervention

We describe and report the results of a multicomponent behavioral intervention for re-establishing solid food consumption in a 26-year-old woman with prolonged food avoidance and restriction which developed following a traumatic brain injury. The intervention was evaluated by direct measurement of daily meal consumption over a period of several months, including an extended follow-up, and resulted in successful resumption of oral feeding. A complicating paroxysmal movement disorder resolved during treatment as well and resolution of the presenting problem led to significant quality of life improvements. We discuss the relationship of the presenting symptoms to avoidant/restrictive food intake disorder and to food rejection behavior seen when substantial damage has occurred to the parietal lobe. The case illustrates the value of assessment-based, individualized intervention design and an integrated neurobehavioral case conceptualization.