Hereditary Movement Disorder Research Articles

Detection of Modified Histones from Oral Mucosa of a Patient with DYT-KMT2B Dystonia

Introduction: DYT-KMT2B is a rare childhood-onset, hereditary movement disorder typically characterized by lower-limb dystonia and subsequently spreads into the craniocervical and laryngeal muscles. Recently, KMT2B-encoding lysine (K)-specific histone methyltransferase 2B was identified as the causative gene for DYT-KMT2B, also known as DYT28. In addition to the fact that many physicians do not have sufficient experience or knowledge of hereditary dystonia, the clinical features of DYT-KMT2B overlap with those of other hereditary dystonia, and limited clinical biomarkers make the diagnosis difficult. Methods: Histone proteins were purified from the oral mucosa of patients with de novo KMT2B mutation causing premature stop codon, and then trimethylated fourth lysine residue of histone H3 (H3K4me3) which was catalyzed by KMT2B was analyzed by immunoblotting with specific antibody. We further analyzed the significance of H3K4me3 in patients with DYT-KMT2B using publicly available datasets. Results: H3K4me3 histone mark was markedly lower in the patient than in the control group. Additionally, a reanalysis of publicly available datasets concerning DNA methylation also demonstrated that KMT2B remained inactive in DYT-KMT2B. Discussion: Although only one case was studied due to the rarity of the disease, the reduction of H3K4me3 in the patient’s biological sample supports the dysfunction of KMT2B in DYT-KMT2B. Together with informatics approaches, our results suggest that KMT2B haploinsufficiency contributes to the DYT-KMT2B pathogenic process.

Nine Hereditary Movement Disorders First Described in Asia: Their History and Evolution.

Clinical case studies and reporting are important to the discovery of new disorders and the advancement of medical sciences. Both clinicians and basic scientists play equally important roles leading to treatment discoveries for both cures and symptoms. In the field of movement disorders, exceptional observation of patients from clinicians is imperative, not just for phenomenology but also for the variable occurrences of these disorders, along with other signs and symptoms, throughout the day and the disease course. The Movement Disorders in Asia Task Force (TF) was formed to help enhance and promote collaboration and research on movement disorders within the region. As a start, the TF has reviewed the original studies of the movement disorders that were preliminarily described in the region. These include nine disorders that were first described in Asia - Segawa disease, PARK-Parkin, X-linked dystonia-parkinsonism (XDP), dentatorubral-pallidoluysian atrophy (DRPLA), Woodhouse-Sakati syndrome, benign adult familial myoclonic epilepsy (BAFME), Kufor-Rakeb disease, tremulous dystonia associated with mutation of the calmodulin-binding transcription activator 2 (CAMTA2) gene, and paroxysmal kinesigenic dyskinesia (PKD). We hope that the information provided will honor the original researchers and help us learn and understand how earlier neurologists and basic scientists together discovered new disorders and made advances in the field, which impact us all to this day.

Generation of gene-corrected isogenic control cell lines from a DYT1 dystonia patient iPSC line carrying a heterozygous GAG mutation in TOR1A gene

Childhood-onset torsin dystonia (DYT1) is a rare hereditary movement disorder and usually caused by a heterozygous GAG deletion (c.907–909) in the TOR1A gene (ΔE, p.Glu303del). The neuronal functions of torsin proteins and the pathogenesis of ΔE mutation are not clear. Previously, we have generated a hiPSC line from DYT1 patient fibroblast cells. In this study, we genetically corrected GAG deletion and obtained two isogenic control lines. These hiPSC lines contain the wild-type TOR1A sequence, showed the normal stem cell morphology and karyotype, expressed pluripotency markers, and differentiated into three germ layers, providing a valuable resource in DYT1 research.

Balancing scientific interests and the rights of participants in designing a recall by genotype study

Recall by genotype (RbG) studies aim to better understand the phenotypes that correspond to genetic variants of interest, by recruiting carriers of such variants for further phenotyping. RbG approaches pose major ethical and legal challenges related to the disclosure of possibly unwanted genetic information. The Cooperative Health Research in South Tyrol (CHRIS) study is a longitudinal cohort study based in South Tyrol, Italy. Demand has grown for CHRIS study participants to be enrolled in RbG studies, thus making the design of a suitable ethical framework a pressing need. We here report upon the design of a pilot RbG study conducted with CHRIS study participants. By reviewing the literature and by consulting relevant stakeholders (CHRIS participants, clinical geneticists, ethics board, GPs), we identified key ethical issues in RbG approaches (e.g. complexity of the context, communication of genetic results, measures to further protect participants). The design of the pilot was based on a feasibility assessment, the selection of a suitable test case within the ProtectMove Research Unit on reduced penetrance of hereditary movement disorders, and the development of appropriate recruitment and communication strategies. An empirical study was embedded in the pilot study with the aim of understanding participants’ views on RbG. Our experience with the pilot study in CHRIS allowed us to contribute to the development of best practices and policies for RbG studies by drawing recommendations: addressing the possibility of RbG in the original consent, implementing tailored communication strategies, engaging stakeholders, designing embedded empirical studies, and sharing research experiences and methodology.

Phenotypic characterization of PIGN–associated paroxysmal dyskinesia in Soft-coated wheaten terriers and preliminary response to acetazolamide therapy

A hereditary movement disorder in Soft coated wheaten terriers (SCWT) has been associated with a mutation in PIGN which encodes an enzyme involved in synthesis of glycosylphosphatidylinositol (GPI). The objective of this study was to describe and classify the clinical phenotype and assess therapeutic response.Twenty-five SCWT and related dogs homozygous for PIGN:c.398C>T with paroxysmal dyskinesia were available for inclusion. Medical records and video recordings of 17 dogs were evaluated in a retrospective case series. Affected dogs had episodes of involuntary, hyperkinetic movements and dystonia. Median age of onset was 2.5 years. A typical episode consisted of rapid, irregular hyperflexion and extension of the pelvic limbs with some degree of truncal dystonia. A mild episode consisted of spontaneous flexion of one pelvic limb while walking which could resemble a lameness. Episodes lasted several minutes to several hours and occurred up to 10 times/day or more. They were not associated with exercise or fasting but were sometimes triggered by excitement or stress. Acetazolamide therapy improved nine of 11 dogs, in seven cases abolishing episodes. Five of 17 dogs treated with other agents had mild improvement with clonazepam (n = 2), levetiracetam (n = 1), or phenobarbital (n = 2). Paroxysmal dyskinesias must be differentiated from seizure disorders since they often respond to different therapies. The SCWT phenotype consisted predominantly of hyperkinesia, and can respond dramatically to acetazolamide. GPI anchors proteins to the cell surface including carbonic anhydrase IV which modulates synaptic pH in the brain. Altered activity of this enzyme may be the target of acetazolamide therapy.

Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS): The classical clinical manifestations, fundoscopic examination, and brain MRI findings

Background: Autosomal-recessive spastic ataxia of Charlevoix-Sagaenay (ARSACS) is a hereditary movement disorders characterized by classic triad including progressive early onset cerebella ataxia, lower limb spasticity with hyperreflexia, and peripheral polyneuropathy. It is typically caused by SACSIN gene mutation which leads to degeneration of the cerebellum and spinal cord.

Implantation of Osmotic Pumps and Induction of Stress to Establish a Symptomatic, Pharmacological Mouse Model for DYT/PARK-ATP1A3 Dystonia.

Genetically modified mouse models face limitations, especially when studying movement disorders, where most of the available transgenic rodent models do not present a motor phenotype resembling the clinical aspects of the human disease. Pharmacological mouse models allow for a more direct study of the pathomechanisms and their effect on the behavioral phenotype. Osmotic pumps connected to brain cannulas open up the possibility of creating pharmacological mouse models via local and chronic drug delivery. For the hereditary movement disorder of rapid-onset dystonia-parkinsonism, the loss-of-function mutation in the α3-subunit of the Na+/K+-ATPase can be simulated by a highly specific blockade via the glycoside ouabain. In order to locally block the α3-subunit in the basal ganglia and the cerebellum, which are the two brain structures believed to be heavily involved in the pathogenesis of rapid-onset dystonia-parkinsonism, a bilateral cannula is stereotaxically implanted into the striatum and an additional single cannula is introduced into the cerebellum. The cannulas are connected via vinyl tubing to two osmotic pumps, which are subcutaneously implanted on the back of the animals and allow for the chronic and precise delivery of ouabain. The pharmacological mouse model for rapid-onset dystonia-parkinsonism carries the additional advantage of recapitulating the clinical and pathological features of asymptomatic and symptomatic mutation carriers. Just like mutation carriers of rapid-onset dystonia parkinsonism, the ouabain-perfused mice develop dystonia-like movements only after additional exposure to stress. We demonstrate a mild stress paradigm and introduce two modified scoring systems for the assessment of a motor phenotype.

Decreased number of striatal cholinergic interneurons and motor deficits in dopamine receptor 2-expressing-cell-specific Dyt1 conditional knockout mice

DYT1 early-onset generalized torsion dystonia is a hereditary movement disorder characterized by abnormal postures and repeated movements. It is caused mainly by a heterozygous trinucleotide deletion in DYT1/TOR1A, coding for torsinA. The mutation may lead to a partial loss of torsinA function. Functional alterations of the basal ganglia circuits have been implicated in this disease. Striatal dopamine receptor 2 (D2R) levels are significantly decreased in DYT1 dystonia patients and in the animal models of DYT1 dystonia. D2R-expressing cells, such as the medium spiny neurons in the indirect pathway, striatal cholinergic interneurons, and dopaminergic neurons in the basal ganglia circuits, contribute to motor performance. However, the function of torsinA in these neurons and its contribution to the motor symptoms is not clear. Here, D2R-expressing-cell-specific Dyt1 conditional knockout (d2KO) mice were generated and in vivo effects of torsinA loss in the corresponding cells were examined. The Dyt1 d2KO mice showed significant reductions of striatal torsinA, acetylcholine metabolic enzymes, Tropomyosin receptor kinase A (TrkA), and cholinergic interneurons. The Dyt1 d2KO mice also showed significant reductions of striatal D2R dimers and tyrosine hydroxylase without significant alteration in striatal monoamine contents or the number of dopaminergic neurons in the substantia nigra. The Dyt1 d2KO male mice showed motor deficits in the accelerated rotarod and beam-walking tests without overt dystonic symptoms. Moreover, the Dyt1 d2KO male mice showed significant correlations between striatal monoamines and locomotion. The results suggest that torsinA in the D2R-expressing cells play a critical role in the development or survival of the striatal cholinergic interneurons, expression of striatal D2R mature form, and motor performance. Medical interventions to compensate for the loss of torsinA function in these neurons may affect the onset and symptoms of this disease.

Cortical circuit alterations precede motor impairments in Huntington\u2019s disease mice

Huntington’s disease (HD) is a devastating hereditary movement disorder, characterized by degeneration of neurons in the striatum and cortex. Studies in human patients and mouse HD models suggest that disturbances of neuronal function in the neocortex play an important role in disease onset and progression. However, the precise nature and time course of cortical alterations in HD have remained elusive. Here, we use chronic in vivo two-photon calcium imaging to longitudinally monitor the activity of identified single neurons in layer 2/3 of the primary motor cortex in awake, behaving R6/2 transgenic HD mice and wildtype littermates. R6/2 mice show age-dependent changes in cortical network function, with an increase in activity that affects a large fraction of cells and occurs rather abruptly within one week, preceeding the onset of motor defects. Furthermore, quantitative proteomics demonstrate a pronounced downregulation of synaptic proteins in the cortex, and histological analyses in R6/2 mice and human HD autopsy cases reveal a reduction in perisomatic inhibitory synaptic contacts on layer 2/3 pyramidal cells. Taken together, our study provides a time-resolved description of cortical network dysfunction in behaving HD mice and points to disturbed excitation/inhibition balance as an important pathomechanism in HD.

Will genotype drive treatment options?

Individual genetic variation can have a major impact on the clinical manifestation of a movement disorder and its response to treatment. Advances in gene discovery and increasing availability of diagnostic genetic testing have led to the identification of a growing number of patients with well-defined hereditary movement disorders. Establishing a genetic diagnosis may greatly impact patient counseling and shape therapeutic decisions. Further, assignment of a movement disorder to a specific genetic defect holds promise for the development of causal treatment approaches and individualized therapies, especially as the first gene-targeted approaches have recently entered clinical trials. However, important gaps remain, that is, genetic testing results are often inconclusive, gene-specific treatment options are still exceedingly rare, and designing clinical trials to demonstrate disease modification continues to pose a major challenge. © 2019 International Parkinson and Movement Disorder Society.

Dysregulation of the causative genes for hereditary parkinsonism in the midbrain in Parkinson's disease.

Many hereditary movement disorders with complex phenotypes without a locus symbol prefix for familial PD present as parkinsonism; however, the dysregulation of genes associated with these phenotypes in the SNpc of PD patients has not been systematically studied. Gene set enrichment analyses were performed using 10 previously published genome-wide expression datasets obtained by laser-captured microdissection of pigmented neurons in the SNpc. A custom-curated gene set for hereditary parkinsonism consisting of causative genes (n = 78) related to disorders with a parkinsonism phenotype, but not necessarily idiopathic or monogenic PD, was constructed from the Online Mendelian Inheritance in Man database. In 9 of the 10 gene expression data sets, gene set enrichment analysis showed that the disease-causing genes for hereditary parkinsonism were downregulated in the SNpc in PD patients compared to controls (nominal P values <0.05 in five studies). Among the 63 leading edge subset genes representing downregulated genes in PD, 79.4% were genes without a locus symbol prefix for familial PD. A meta-gene set enrichment analysis performed with a random-effect model showed an association between the gene set for hereditary parkinsonism and PD with a negative normalized enrichment score value (-1.40; 95% CI: -1.52∼-1.28; P < 6.2E-05). Disease-causing genes with a parkinsonism phenotype are downregulated in the SNpc in PD. Our study highlights the importance of genes associated with hereditary movement disorders with parkinsonism in understanding the pathogenesis of PD. © 2017 International Parkinson and Movement Disorder Society.

Applications of CRISPR/Cas9 for Gene Editing in Hereditary Movement Disorders.

Gene therapy is a potential therapeutic strategy for treating hereditary movement disorders, including hereditary ataxia, dystonia, Huntington’s disease, and Parkinson’s disease. Genome editing is a type of genetic engineering in which DNA is inserted, deleted or replaced in the genome using modified nucleases. Recently, clustered regularly interspaced short palindromic repeat/CRISPR associated protein 9 (CRISPR/Cas9) has been used as an essential tool in biotechnology. Cas9 is an RNA-guided DNA endonuclease enzyme that was originally associated with the adaptive immune system of Streptococcus pyogenes and is now being utilized as a genome editing tool to induce double strand breaks in DNA. CRISPR/Cas9 has advantages in terms of clinical applicability over other genome editing technologies such as zinc-finger nucleases and transcription activator-like effector nucleases because of easy in vivo delivery. Here, we review and discuss the applicability of CRISPR/Cas9 to preclinical studies or gene therapy in hereditary movement disorders.

Dopa-responsive dystonia or early-onset Parkinson disease – Genotype–phenotype correlation

ObjectiveDopa-responsive dystonia (DRD) is a rare form of hereditary movement disorder with onset in childhood, characterized by gait difficulties due to postural dystonia with marked improvement after low doses of levodopa. Mutations in the GCH1 gene are the most common cause of DRD, however, in some cases when the disease is associated with parkinsonism mutations in the PARK2 gene may be identified. The aim of this study was to analyze and compare genotype–phenotype correlation. Material/participantsFour families with inter- and intrafamilial variability of progressive gait dysfunction due to lower limb dystonia occurring in childhood or adolescence were included in the analysis. MethodsGeneral and neurological examination was performed for all affected family members and asymptomatic mutation carriers. The molecular analysis encompassed GCH1 and PARK2 genes. ResultsAll probands were clinically diagnosed with DRD. The molecular analysis revealed, however, that the dopa-responsive dystonia phenotype was caused by a mutation in the GCH1 gene in three families and in the PARK2 gene in one family. Obtained results allowed to establish the final diagnosis for all families as DYT5a or early-onset Parkinson disease (EO-PD). ConclusionsReported cases confirm that the DRD phenotype may have heterogeneous genetic background and may be caused by point mutations or rearrangements in the GCH1 gene as well as in the PARK2 gene. Differential diagnosis and genetic tests covering the analysis of genes causative for DRD and EO-PD should be obligatory in both disorders diagnostics as DRD, mainly adolescent onset dystonia, may be associated with parkinsonism.

Dystonia and Paroxysmal Dyskinesias: Under-Recognized Movement Disorders in Domestic Animals? A Comparison with Human Dystonia/Paroxysmal Dyskinesias.

Dystonia is defined as a neurological syndrome characterized by involuntary sustained or intermittent muscle contractions causing twisting, often repetitive movements, and postures. Paroxysmal dyskinesias are episodic movement disorders encompassing dystonia, chorea, athetosis, and ballism in conscious individuals. Several decades of research have enhanced the understanding of the etiology of human dystonia and dyskinesias that are associated with dystonia, but the pathophysiology remains largely unknown. The spontaneous occurrence of hereditary dystonia and paroxysmal dyskinesia is well documented in rodents used as animal models in basic dystonia research. Several hyperkinetic movement disorders, described in dogs, horses and cattle, show similarities to these human movement disorders. Although dystonia is regarded as the third most common movement disorder in humans, it is often misdiagnosed because of the heterogeneity of etiology and clinical presentation. Since these conditions are poorly known in veterinary practice, their prevalence may be underestimated in veterinary medicine. In order to attract attention to these movement disorders, i.e., dystonia and paroxysmal dyskinesias associated with dystonia, and to enhance interest in translational research, this review gives a brief overview of the current literature regarding dystonia/paroxysmal dyskinesia in humans and summarizes similar hereditary movement disorders reported in domestic animals.

PP15.15 – 2688: NBIA Alliance – The impact of the international NBIA patient advocacy on NBIA research and vice versa

Objective Neurodegeneration with Brain Iron Accumulation (NBIA) is a group of very rare and mostly hereditary neurological movement disorders characterized by high iron levels in the basal ganglia and a progressive degeneration of the nervous system. Currently, there is no cure or proven therapy for any of the NBIA forms. Given the lack of treatment options, the international consortium TIRCON (Treat–Iron–Related–Childhood–Onset–Neurodegeneration), funded by the EU under FP7, is dedicated to the investigation of NBIA. 13 partners from eight countries are conducting a clinical therapy study and set up a patient registry/biobank in order to improve the infrastructure for NBIA research and care. We present the latest development, goals, recent and upcoming activities of the NBIA lay advocacy, thus demonstrating the rising impact of the growing NBIA Alliance and its member groups in interrelationship to the TIRCON consortium and to further NBIA research groups. Methods The lay advocacy groups, NBIA Disorders Association (NBIADA, USA) and Hoffnungsbaum e.V. (HoBa, Germany), are full partners in TIRCON. Based upon their experience in such collaborative projects, NBIADA and HoBa have been promoting the creation of further patient groups worldwide. The NBIA Alliance, launched under the patronage of TIRCON in 2012, is the only international umbrella association for NBIA lay advocacy groups. Currently, eight NBIA patient organizations are involved in the Alliance. The groups share the common goals of helping families cope with NBIA disorders, promoting improved health care in NBIA, and supporting research to find more effective treatments for these disorders. Results Current efforts include developing a strategic plan to support these common goals and expand the Alliance to other countries. Conclusion We will underline the mutual empowerment of the NBIA patients' movement and the NBIA research and care community.

Neurophysiology in Huntington's disease: an update.

Huntington's disease (HD) is a hereditary movement disorder with dementia and behavioral difficulties caused by a mutation in the HTT gene. Age-at-onset, clinical phenotype and disease evolution vary and are not explained by the mutation alone. Electrophysiological techniques, like transcranial magnetic stimulation and electroencephalography, have advanced our understanding of the pathophysiology but have not revealed any consistent abnormalities suitable as biomarkers. The most promising candidate may be somatosensory or visual evoked potentials, which repeatedly had reduced amplitudes in manifest HD. To test their potential, large cohorts of clinically homogeneous patients need to be studied with electrophysiological in conjunction with neuroimaging techniques to delineate neural network function in relation to micro- and macro-structural brain changes.

Non‐invasive detection of neurochemical changes prior to overt pathology in a mouse model of spinocerebellar ataxia type 1

Spinocerebellar ataxia type 1 (SCA1) is a hereditary, progressive and fatal movement disorder that primarily affects the cerebellum. Non-invasive imaging markers to detect early disease in SCA1 will facilitate testing and implementation of potential therapies. We have previously demonstrated the sensitivity of neurochemical levels measured by (1) H magnetic resonance spectroscopy (MRS) to progressive neurodegeneration using a transgenic mouse model of SCA1. In order to investigate very early neurochemical changes related to neurodegeneration, here we utilized a knock-in mouse model, the Sca1(154Q/2Q) line, which displays milder cerebellar pathology than the transgenic model. We measured cerebellar neurochemical profiles of Sca1(154Q/2Q) mice and wild-type littermates using 9.4T MRS at ages 6, 12, 24, and 39weeks and assessed the cerebellar pathology of a subset of the mice at each time point. The Sca1(154Q/2Q) mice displayed very mild cerebellar pathology even at 39weeks, however, were distinguished from wild types by MRS starting at 6weeks. Taurine and total choline levels were significantly lower at all ages and glutamine and total creatine levels were higher starting at 12weeks in Sca1(154Q/2Q) mice than controls, demonstrating the sensitivity of neurochemical levels to neurodegeneration related changes in the absence of overt pathology. We measured cerebellar neurochemical alterations in a knock-in mouse model of spinocerebellar ataxia type 1, a hereditary movement disorder, using ultra-high field magnetic resonance spectroscopy (MRS). Very early neurochemical alterations were detectable prior to overt pathology in the volume-of-interest for MRS. Alterations were indicative of osmolytic changes and of disturbances in membrane phospholipid and energy metabolism.

A Novel Mutation in Exon 6 of the Epsilon-Sarcoglycan Gene in Myoclonus Dystonia Syndrome

Abstract Myoclonus-dystonia syndrome (MDS) is a rare hereditary movement disorder characterized by the early onset of myoclonus in the first or second decade of life. The first locus for MDS was mapped to chromosome 7q21 and identified as the epsilon-sarcoglycan (SGCE) gene, and numerous mutations were subsequently identified. We here present the first reported Turkish MDS patient identified with a novel mutation in exon 6 of the SGCE gene, which resulted in truncation of the protein before the transmembrane domain, presumably causing the loss of function either by mislocalization of the protein away from the plasma membrane or through nonsense-mediated decay.

Dimerization of the DYT6 dystonia protein, THAP1, requires residues within the coiled‐coil domain

Thanatos-associated [THAP] domain-containing apoptosis-associated protein 1 (THAP1) is a DNA-binding protein that has been recently associated with DYT6 dystonia, a hereditary movement disorder involving sustained, involuntary muscle contractions. A large number of dystonia-related mutations have been identified in THAP1 in diverse patient populations worldwide. Previous reports have suggested that THAP1 oligomerizes with itself via a C-terminal coiled-coil domain, raising the possibility that DYT6 mutations in this region might affect this interaction. In this study, we examined the ability of wild-type THAP1 to bind itself and the effects on this interaction of the following disease mutations: C54Y, F81L, ΔF132, T142A, I149T, Q154fs180X, and A166T. The results confirmed that wild-type THAP1 associated with itself and most of the DYT6 mutants tested, except for the Q154fs180X variant, which loses most of the coiled-coil domain because of a frameshift at position 154. However, deletion of C-terminal residues after position 166 produced a truncated variant of THAP1 that was able to bind the wild-type protein. The interaction of THAP1 with itself therefore required residues within a 13-amino acid region (aa 154-166) of the coiled-coil domain. Further inspection of this sequence revealed elements highly consistent with previous descriptions of leucine zippers, which serve as dimerization domains in other transcription factor families. Based on this similarity, a structural model was generated to predict how hydrophobic residues in this region may mediate dimerization. These observations offer additional insight into the role of the coiled-coil domain in THAP1, which may facilitate future analyses of DYT6 mutations in this region.

DEVELOPMENT OF MESIAL TEMPORAL LOBE EPILEPSY IN CHOREA-ACANTHOCYTOSIS

Chorea-acanthocytosis (ChAc) is a hereditary movement disorder that is caused by recessive mutations in the VPS13A gene on chromosome 9q21, encoding for chorein.1 Epilepsy is currently not considered a core clinical feature of ChAc, although approximately 40% of patients are affected by seizures. We report on 3 patients with mesial temporal lobe epilepsy as the first, predominant clinical indication, and in 2 of the patients so far the sole clinical symptom of the disease. For the first time in this context, a pathologic process in the medial temporal lobes, leading to hippocampal atrophy, is unequivocally documented. ### Case histories. Patient 1 was a 14-year-old boy when, after repeat epigastric sensations, a first seemingly generalized tonic-clonic seizure led to hospital admission. Several weeks prior, he had started to complain about repetitive deja vu. Repeat EEG studies most frequently showed normal 10/second alpha-, but also paroxysmal generalized theta-, right hemispheric delta-, and right temporo-occipital spike- and sharp-wave activity. Until the present, 4 years after the initial onset, 2 more tonic-clonic seizures have occurred, and, with variable frequencies, the patient continues to report rising epigastric sensations, deja vu, and amnesic auras. Medical treatment currently consists of the administration of topiramate (300 mg/day). Patient 2, the older brother of patient 1, had a first complex partial seizure at 23 years of age. His history was unremarkable; no febrile seizures had been reported. Lately, however, he has also reported repeat episodes of deja vu. EEG findings ranged from normal 9/second alpha- to intermittent and continuous spike- and sharp-wave activity over both frontotemporal regions. Apart from rare epigastric auras, the patient is presently (i.e., 8 months after his first epileptic seizure) seizure-free under levetiracetam (2,500 mg/day). Patient 3 is a 39-year-old man …