Paroxysmal Disorders Research Articles

Transient benign paroxysmal movement disorders in infancy.

Transient benign paroxysmal movement disorders in infancy encompass a group of disorders that appear during the neonatal period and in the first years of life, and that spontaneously disappear without leaving consequences. This article aimed to review the main transient benign paroxysmal movement disorders in infancy, focusing on recognition and diagnostic approach. Overall, it includes entities such as: jitteriness, benign neonatal sleep myoclonus, shuddering, benign myoclonus of early infancy, transient idiopathic dystonia in infancy, spasmus nutans, paroxysmal tonic upgaze of infancy, and benign paroxysmal torticollis. Transient benign paroxysmal movement disorders are non-epileptic paroxysmal episodes, and their diagnosis is eminently clinical. The correct recognition of these entities is crucial to avoid anxiety, unnecessary complementary exams, and treatments.

Genetic aspects of pain and its variability in the human population

The sensation of pain is common to both animals and human beings. Its threshold, intensity, tolerability, and characteristics are variable and depend on ethnicity, gender, stress exposure, co-existing mental disorders, such as depression or anxiety, social and economical background, as well as on genetic factors. It is estimated that about 5 and 20 percent of population suffer from acute and chronic pain, respectively, which results in the search for medical advice in healthcare facilities, and causes great expenses in health care budgets worldwide. Research aimed at identifying the causative agents of pain syndromes include single nucleotidepolymorphism (SNP), family history studies, twin siblings' genetic diversity studies, and recently, also a genome-wide association study (GWAS). Clinical syndromes of derangement of pain sensation are generally caused by single gene mutations (e.g. erythromelalgia and paroxysmal extreme pain disorder caused by mutations of SCN9A), but can also be associated with multiple gene mutations, as happens in migraine, fibromyalgia or hereditary sensory and autonomic neuropathies. Structural changes of proteins caused by gene mutations involve various cellular element, such as ion channels, receptors, scaffolding proteins, enzymes, transporting proteins, eventually leading to numerous clinical entities in which pain or its lack remain the leading symptoms. The sensation of pain is initiated by a stimulus, which activates the free nerve endings via chemical mediators, and the mechanical stimuli is then transmitted to the brain along the neurons and spinal tracts. Synaptic neurotransmitters and cell structures take part in this process and eventually affect the intensity of pain sensation.

Hyperekplexiа. Clinical observation

The differential diagnosis of paroxysmal conditions, as well as disorders of muscle tone (hypertension) in the neonatal period and in young children is quite complicated. Various states of the nervous system in newborns are transient and permanent, optimal and suboptimal, normal and pathological. Among them, we can mention non-epileptic paroxysmal states of early childhood. In some cases, non-epileptic paroxysmal states of early childhood is accompanied by motor disorders, manifested by an excessive increase in limb tone in newborns. This pathological condition of muscle tone in the English-language literature is referred to by the term stiffness baby (the syndrome of a rigid or fettered baby). Neonatal pathological muscle hypertonicity, unlike physiological hypertonicity of muscles of a newborn, is a rather rare condition. The article presents literature data and a description of the clinical observation of a patient with hyperekplexia. Hyperekplexia is a rare paroxysmal movement disorder in young children. The main clinical variants of the disease, methods of diagnosis and correction, the main mutations associated with this condition are considered. The article describes the own clinical observation of an early-age patient with hyperekplexia, its clinical picture, features of paroxysmal states and therapy, neuroimaging data, electroencephalographic phenomena recorded in the patient and genetic testing that confirmed the diagnosis of non-epileptic paroxysmal disorders. The child has a mutation in the ATAD1 gene associated with type 4 Hyperekplexia (618011).

Hemiplegic Migraine Associated With PRRT2 Variations: A Clinical and Genetic Study.

PRRT2 variants have been reported in a few cases of patients with hemiplegic migraine. To clarify the role of PRRT2 in familial hemiplegic migraine, we studied this gene in a large cohort of affected probands. PRRT2 was analyzed in 860 probands with hemiplegic migraine, and PRRT2 variations were identified in 30 probands. Genotyping of relatives identified a total of 49 persons with variations whose clinical manifestations were detailed. PRRT2 variations were found in 12 of 163 probands who previously tested negative for CACNA1A, ATP1A2, and SCN1A variations and in 18 of 697 consecutive probands screened simultaneously on the 4 genes. In this second group, pathogenic variants were found in 105 individuals, mostly in ATP1A2 (42%), followed by CACNA1A (26%), PRRT2 (17%), and SCN1A (15%). The PRRT2 variations included 7 distinct variants, 5 of which have already been described in persons with paroxysmal kinesigenic dyskinesia and 2 new variants. Eight probands had a deletion of the whole PRRT2 gene. Among the 49 patients with variations in PRRT2, 26 had pure hemiplegic migraine and 16 had hemiplegic migraine associated with another manifestation: epilepsy (8), learning disabilities (5), hypersomnia (4), or abnormal movement (3). Three patients had epilepsy without migraine: 2 had paroxysmal kinesigenic dyskinesia without migraine, and 1 was asymptomatic. PRRT2 should be regarded as the fourth autosomal dominant gene for hemiplegic migraine and screened in any affected patient, together with the 3 other main genes. Further studies are needed to understand how the same loss-of-function PRRT2 variations can lead to a wide range of neurologic phenotypes, including paroxysmal movement disorder, epilepsy, learning disabilities, sleep disorder, and hemiplegic migraine.

Episodic ataxia as a presenting symptom of anti-NMDAR encephalitis

Anti-NMDA receptor (anti-NMDAR) encephalitis presents commonly with cognitive and psychiatric symptoms, but also movement disorders are reported. Cerebellar ataxia has been described in young children, but it is uncommon in adults. Among paroxysmal movement disorders, dyskinesias are reported. Episodic ataxia is extremely rare and never reported as a presenting symptom.

Features and Course of Epilepsy in the Mountain Desert Regions of The Surkhandara Region

This article discusses the features of epilepsy in the mountainous desert areas of Surkhandarya region and how it occurs. Epilepsy is a chronic polyetiological neuropsychiatric disorder that often begins in childhood and adolescence and is characterized by paroxysmal disorders, personality changes in the emotional sphere. Therefore, the prevention of epilepsy begins in childhood, and the disease is not only a medical but also an important social problem. Knowing the clinic of epilepsy, especially to determine the extent of its onset, is necessary for general practitioners, as patients with epilepsy often consult these physicians when their initial symptoms appear. The article also describes what disease epilepsy is and the condition of the patient with it

Clinical features and related factors of freezing of gait in patients with Parkinson's disease.

BackgroundFreezing of gait (FOG) is a disabling paroxysmal gait disorder that prevents starting or resuming walking, which seriously negatively affects patients’ quality of life (QOL). The diagnosis and treatment of FOG remain a huge medical challenge. The purpose of this study was to explore the clinical characteristics and related factors of FOG in patients with Parkinson's disease (PD).MethodsThe motor and nonmotor symptoms of a total number of 77 PD patients were evaluated. Patients with or without FOG were defined as a score ≥1 in the new freezing of gait questionnaire (NFOG‐Q). A comparative study between patients with and without FOG was conducted.ResultsIn this investigation, the prevalence of FOG was 48%. The patients with FOG had longer disease duration, higher Hoehn‐Yahr stage (H‐Y stage), higher dose of dopaminergic agents, and higher nonmotor and motor symptom scores. A significant positive correlation was found between the NFOG‐Q score and the H‐Y stage, PIGD subscore, PDQ‐39, and the attention/memory in the nonmotor symptoms assessment scale (NMSS) subitem (r > 0.5, p < .05). The binary logistic regression analysis showed that the higher H‐Y stage, higher rigidity subscore and Unified Parkinson's Disease Rating Scale II (UPDRS II) score, and UPDRS III score were significantly correlated with the occurrence of FOG (p < .05). In the analysis of the frequency of FOG, the prevalence of FOG in H‐Y stage was higher in the middle and late stages, and the prevalence of FOG increased with the increase in PDQ‐39 scores.ConclusionThe severity of FOG was significantly positively correlated with the H‐Y stage, PIGD subscore, PDQ‐39 score, and attention/memory score. Based on our findings, we conclude that the clinical characteristics of rigidity can be used as a potential predictor of FOG.

Supraventricular tachycardia: modern methods of diagnosis and treatment (мethodical recommendations)

Methodical recommendations are devoted to one of the most pressing problems of cardiology – paroxysmal heart rhythm disorders in clinical practice. The recommendations consider the basic principles of determining supraventricular tachycardias (SVT) and their electrophysiological mechanisms. The clinic and features of ECG diagnostics of separate forms of tachycardias are stated. Emergency care and long-term therapy for SVT with narrow and wide QRS complexes are presented. Methods of treatment and algorithms for the management of patients with SVT in accordance with the updated in 2019 recommendations of the European Association of Cardiologists for the management of patients with SVT, antiarrhythmic drugs and their use, the principles of catheter treatment of tachycardia. Recommendations are addressed to cardiologists, therapists, doctors of functional diagnostics, general practitioners and family medicine, interns.

RHOBTB2 gene associated epilepsy and paroxysmal movement disorder: two cases report and literature review

BackgroundRHOBTB2 gene is associated with developmental and epileptic encephalopathy-64(DEE-64), which is characterized by epilepsy, developmental delay, microcephaly, unspecific facial dysmorphism, and paroxysmal movement disorders. Most previous studies showed that the phenotypes of RHOBTB2 gene include developmental and epileptic encephalopathy(DEE) and DEE with paroxysmal movement disorders. Only one study showed that patient with RHOBTB2 variant had paroxysmal movement disorders with no epilepsy.Case presentationsTwo cases with RHOBTB2 variants are presented here: Case one was diagnosed as DEE, he had recurrent afebrile focal status epilepticus and paroxysmal extrapyramidal symptoms in infancy. Interictal electroencephalogram (EEG) showed focal discharges. Brain magnetic resonance imaging (MRI) showed cortical dysplasia. Epilepsy of case one was refractory. Nevertheless, case two only showed paroxysmal movement disorders alone in adolescence. Video EEG showed focal discharges during an interictal dystonic episode and he brain MRI was normal.ConclusionThe phenotypes of RHOBTB2 gene include DEE, paroxysmal movement disorders, and DEE with paroxysmal movement disorders. RHOBTB2 can be one of the pathogenic genes of paroxysmal movement disorders.

Therapeutic Potential of Sodium Channel Blockers as a Targeted Therapy Approach in KCNA1-Associated Episodic Ataxia and a Comprehensive Review of the Literature.

Introduction: Among genetic paroxysmal movement disorders, variants in ion channel coding genes constitute a major subgroup. Loss-of-function (LOF) variants in KCNA1, the gene coding for KV1.1 channels, are associated with episodic ataxia type 1 (EA1), characterized by seconds to minutes-lasting attacks including gait incoordination, limb ataxia, truncal instability, dysarthria, nystagmus, tremor, and occasionally seizures, but also persistent neuromuscular symptoms like myokymia or neuromyotonia. Standard treatment has not yet been developed, and different treatment efforts need to be systematically evaluated.Objective and Methods: Personalized therapeutic regimens tailored to disease-causing pathophysiological mechanisms may offer the specificity required to overcome limitations in therapy. Toward this aim, we (i) reviewed all available clinical reports on treatment response and functional consequences of KCNA1 variants causing EA1, (ii) examined the potential effects on neuronal excitability of all variants using a single compartment conductance-based model and set out to assess the potential of two sodium channel blockers (SCBs: carbamazepine and riluzole) to restore the identified underlying pathophysiological effects of KV1.1 channels, and (iii) provide a comprehensive review of the literature considering all types of episodic ataxia.Results: Reviewing the treatment efforts of EA1 patients revealed moderate response to acetazolamide and exhibited the strength of SCBs, especially carbamazepine, in the treatment of EA1 patients. Biophysical dysfunction of KV1.1 channels is typically based on depolarizing shifts of steady-state activation, leading to an LOF of KCNA1 variant channels. Our model predicts a lowered rheobase and an increase of the firing rate on a neuronal level. The estimated concentration dependent effects of carbamazepine and riluzole could partially restore the altered gating properties of dysfunctional variant channels.Conclusion: These data strengthen the potential of SCBs to contribute to functional compensation of dysfunctional KV1.1 channels. We propose riluzole as a new drug repurposing candidate and highlight the role of personalized approaches to develop standard care for EA1 patients. These results could have implications for clinical practice in future and highlight the need for the development of individualized and targeted therapies for episodic ataxia and genetic paroxysmal disorders in general.

Cerebellar spreading depolarization mediates paroxysmal movement disorder.

Paroxysmal kinesigenic dyskinesia (PKD) is the most common paroxysmal dyskinesia, characterized by recurrent episodes of involuntary movements provoked by sudden changes in movement. Proline-rich transmembrane protein 2 (PRRT2) has been identified as the major causative gene for PKD. Here, we report that PRRT2 deficiency facilitates the induction of cerebellar spreading depolarization (SD) and inhibition of cerebellar SD prevents the occurrence of dyskinetic movements. Using Ca2+ imaging, we show that cerebellar SD depolarizes a large population of cerebellar granule cells and Purkinje cells in Prrt2-deficient mice. Electrophysiological recordings further reveal that cerebellar SD blocks Purkinje cell spiking and disturbs neuronal firing of the deep cerebellar nuclei (DCN). The resultant aberrant firing patterns in DCN are tightly, temporally coupled to dyskinetic episodes in Prrt2-deficient mice. Cumulatively, our findings uncover a pivotal role of cerebellar SD in paroxysmal dyskinesia, providing a potent target for treating PRRT2-related paroxysmal disorders.

Urban air pollution and emergency department visits related to central nervous system diseases, Toronto, Canada

BACKGROUND AND AIM: Ambient air pollution has been associated with various adverse neurological health outcomes. This work comprehensively examined possible associations between concentration of five major urban air pollutants, two air quality indexes, and emergency department (ED) visits. METHODS: The analysis was done by sex, age group, and season for ED visits for central and peripheral nervous system diseases, in the period April 1, 2004-Decembr 31, 2015 (4,292 days in total). The study was done in Toronto, a Canadian megacity, using a case-crossover design. Conditional Poisson regression was realized to construct statistical models. Our focus was on daily ED visits covering all diseases of the nervous system and identified by ICD-10 codes (G00-G99). RESULTS:In the study period, 140,511 ED visits for diseases of the nervous system among Toronto residents were recorded: 83,602 (59.5%) for women and 56,909 (40.5%) for men. We found that nearly 64% of the considered ED visits were related to the episodic and paroxysmal disorders (G40-G47), with the majority of those visits related to migraines (39%). Based on a number of positive consistent associations, largest effect on ED visits for G40-G47, especially G43 (migraines) was among women exposed to ambient CO, especially with either immediate effect (0 and 1 lag) or a week long effect (6 and 7 lag) were found. Relative risks (RR) with 95% confidence intervals were reported for a one interquartile range (IQR) increase, (IQR=0.1 ppm). Women exposed to CO had RR of 1.036 (1.007-1.065) on the same day (especially older women), and 1.019 (1.004-1.033), 1.024 (1.010-1.039), and 1.022 (1.007-1.036) for lags 1, 6, and 7 days, respectively. CONCLUSIONS:Our findings support the associations between onset of possible diseases of the central nervous system (particularly migraines) and concentration of ambient CO, even at relatively low levels, detected in Toronto. KEYWORDS: acute exposure, ambient carbon monoxide, case-crossover, conditional Poisson, migraine, female

Paroxysmal exercise-induced dyskinesia diagnosed using exercise test

Background Paroxysmal movement disorders are interesting forms of hyperkinetic movement disordersthat are perplexing to the neurologist and patients. The main features are transient dystonia or choreainvolving various body parts and lasting few seconds, minutes or hours depending on the subtype. Theparoxysmal exercise-induced dyskinesia is associated with a gene mutation of (NM_145239.2:c.649dupC)in proline-rich trans-membrane protein 2 (PRRT2). This is found in an average of 45% of cases. Familialcases have 85% penetrance.Case report We report a case of a 12-year old boy with intermittent episodes of abnormal movementswhich involved his face and / or limbs. These dyskinesias occur every few days without warning.Complete neurological examination was normal. Importantly, Magnetic Resonance Imaging head andElectroencephalography were normal in association with normal haemto-biochemistry profile. The familyrecorded a video for one episode of his abnormal movement. The doctor set a challenge of 20 meters racing.He excited the patient then started the race with the attendance of the parents and the nurse. Few secondsafter the end of the race the development of the abnormal movement was judged by the parents and nursewho all agreed on the provocation test.Conclusion Paroxysmal exercise-induced dyskinesia is the commonest primary episodic movementdisorder which has its negative effect on the quality of life. The diagnosis and management are mainlyclinical. It is of paramount importance to use simple tests (exercise test) and save the patient unnecessaryworries and side effects of medications.

Cortical thickness, gyrification and sulcal depth in trigeminal neuralgia

Neuroimaging studies have documented brain structural alterations induced by chronic pain, particularly in gray matter volume. However, the effects of trigeminal neuralgia (TN), a severe paroxysmal pain disorder, on cortical morphology are not yet known. In this study, we recruited 30 TN patients and 30 age-, and gender-matched healthy controls (HCs). Using Computational Anatomy Toolbox (CAT12), we calculated and compared group differences in cortical thickness, gyrification, and sulcal depth with two-sample t tests (p < 0.05, multiple comparison corrected). Relationships between altered cortical characteristics and pain intensity were investigated with correlation analysis. Compared to HCs, TN patients exhibited significantly decreased cortical thickness in the left inferior frontal, and left medial orbitofrontal cortex; decreased gyrification in the left superior frontal cortex; and decreased sulcal depth in the bilateral superior frontal (extending to anterior cingulate) cortex. In addition, we found significantly negative correlations between the mean cortical thickness in left medial orbitofrontal cortex and pain intensity, and between the mean gyrification in left superior frontal cortex and pain intensity. Chronic pain may be associated with abnormal cortical thickness, gyrification and sulcal depth in trigeminal neuralgia. These morphological changes might contribute to understand the underlying neurobiological mechanism of trigeminal neuralgia.

Paroxysmal Movement Disorders.

Paroxysmal movement disorders (PxMDs) are a clinical and genetically heterogeneous group of movement disorders characterized by episodic involuntary movements (dystonia, dyskinesia, chorea and/or ataxia). Historically, PxMDs were classified clinically (triggers and characteristics of the movements) and this directed single-gene testing. With the advent of next-generation sequencing (NGS), how we classify and investigate PxMDs has been transformed. Next-generation sequencing has enabled new gene discovery (RHOBTB2, TBC1D24), expansion of phenotypes in known PxMDs genes and a better understanding of disease mechanisms. However, PxMDs exhibit phenotypic pleiotropy and genetic heterogeneity, making it challenging to predict genotype based on the clinical phenotype. For example, paroxysmal kinesigenic dyskinesia is most commonly associated with variants in PRRT2 but also variants identified in PNKD, SCN8A, and SCL2A1. There are no radiological or biochemical biomarkers to differentiate genetic causes. Even with NGS, diagnosis rates are variable, ranging from 11 to 51% depending on the cohort studied and technology employed. Thus, a large proportion of patients remain undiagnosed compared to other neurological disorders such as epilepsy, highlighting the need for further genomic research in PxMDs. Whole-genome sequencing, deep-sequencing, copy number variant analysis, detection of deep-intronic variants, mosaicism and repeat expansions, will improve diagnostic rates. Identifying the underlying genetic cause has a significant impact on patient care, modification of treatment, long-term prognostication and genetic counseling. This paper provides an update on the genetics of PxMDs, description of PxMDs classified according to causative gene rather than clinical phenotype, highlighting key clinical features and providing an algorithm for genetic testing of PxMDs.

PRRT2 modulates presynaptic Ca2+ influx by interacting with P/Q-type channels.

SummaryLoss-of-function mutations in proline-rich transmembrane protein-2 (PRRT2) cause paroxysmal disorders associated with defective Ca2+ dependence of glutamatergic transmission. We find that either acute or constitutive PRRT2 deletion induces a significant decrease in the amplitude of evoked excitatory postsynaptic currents (eEPSCs) that is insensitive to extracellular Ca2+ and associated with a reduced contribution of P/Q-type Ca2+ channels to the EPSC amplitude. This synaptic phenotype parallels a decrease in somatic P/Q-type Ca2+ currents due to a decreased membrane targeting of the channel with unchanged total expression levels. Co-immunoprecipitation, pull-down assays, and proteomics reveal a specific and direct interaction of PRRT2 with P/Q-type Ca2+ channels. At presynaptic terminals lacking PRRT2, P/Q-type Ca2+ channels reduce their clustering at the active zone, with a corresponding decrease in the P/Q-dependent presynaptic Ca2+ signal. The data highlight the central role of PRRT2 in ensuring the physiological Ca2+ sensitivity of the release machinery at glutamatergic synapses.

PRRT2 Related Epilepsies: A Gene Review

AbstractPRRT2 encodes for proline-rich transmembrane protein 2 involved in synaptic vesicle fusion and presynaptic neurotransmitter release. Mutations in human PRRT2 have been related to paroxysmal kinesigenic dyskinesia (PKD), infantile convulsions with choreoathetosis, benign familial infantile epilepsies, and hemiplegic migraine. PRRT2 mutations cause neuronal hyperexcitability, which could be related to basal ganglia or cortical circuits dysfunction, leading to paroxysmal disorders. PRRT2 is expressed in the cerebral cortex, basal ganglia, and cerebellum. Approximately, 90% of pathogenic variants are inherited and 10% are de novo. Paroxysmal attacks in PKD are characterized by dystonia, choreoathetosis, and ballismus. In the benign familial infantile epilepsy (BFIE), seizures are usually focal with or without generalization, usually begin between 3 and 12 months of age and remit by 2 years of age. In 30% of cases of PRRT2-associated PKD, there is an association with BFIE, and this entity is referred to as PKD with infantile convulsions (PKD/IC). PRRT2 mutations are the cause of benign family childhood epilepsy and PKD/IC. On the other hand, PRRT2 mutations do not seem to correlate with other types of epilepsy. The increasing incidence of hemiplegic migraine in families with PRRT2-associated PKD or PKD/IC suggests a common disease pathway, and it is possible to assert that BFIE, paroxysmal kinesigenic dyskinesia, and PKD with IC belong to a continuous disease spectrum of PRRT2-associated diseases.

Irregular Case of Neuroacanthocytosis Presenting with Late Onset Attention Deficit Hyperactivity Disorder: A Case Report

Neuroacanthocytosis (NA) syndromes are characterized by various neurological abnormalities accompanied by abnormal red blood cells called acanthocytes. Neuroacanthocytosis syndromes may be divided into 4 main subgroups. These subgroups are named as; Core NA syndromes, Degenerative disorders where acanthocytosis is occasionally seen, Paroxysmal dyskinetic disorders and Disorders with reduced blood lipoproteins and acanthocytosis. This report focuses on a patient with Chorea-acanthocytosis who presented with motor signs in the 3rd decade of life. In the later course of disease, the patient developed attention deficit hyperactivity disorder and various tic disorders. We wanted to emphasize the importance of multidisciplinary care in the management of chorea-acanthocytosis.

Nonconvulsive Periodic Disorders

Key Points The overall prevalence in children of paroxysmal disorders that are not epileptic is high.Distinguishing them from seizures is important prognostically and to avoid unnecessary treatment that can entail significant side effects.A thorough history is typically the most potent diagnostic tool.In general, education and reassurance are the mainstays of management.

Alternating Hemiplegia of Childhood: Genotype-Phenotype Correlations in a Cohort of 39 Italian Patients.

Alternating hemiplegia of childhood is a rare neurological disease characterized by paroxysmal movement disorders and chronic neurological disturbances, with onset before 18 months of age. Mutations in the ATP1A3 gene have been identified in up to 80% of patients. Thirty-nine patients [20 females, 19 males, mean age 25.32 years (7.52–49.34)] have been recruited through the Italian Biobank and Clinical Registry for Alternating Hemiplegia of Childhood. Demographic data, genotype, paroxysmal movement disorders, chronic neurological features, and response to flunarizine have been analyzed. ATP1A3 gene mutations have been detected in 92.3% of patients. Patients have been divided into three groups—p.Asp801Asn mutation patients (26%), p.Glu815Lys cases (23%), and patients with other ATP1A3 mutations—and statistically compared. The Italian cohort has a higher percentage of ATP1A3 gene mutation than reported in literature (92.3%). Our data confirm a more severe phenotype in patients with p.Glu815Lys mutation, with an earlier age of onset of plegic (p = 0.02 in the correlation with other mutations) and tonic attacks. P.Glu815Lys patients most frequently present altered muscle tone, inability to walk (p = 0.01 comparing p.Glu815Lys and p.Asp801Asn mutations), epilepsy, and a more severe grade of dystonia (p < 0.05 comparing p.Glu815Lys and p.Asp801Asn mutations). They have moderate/severe intellectual disability and severe language impairment (p < 0.05). Interestingly, flunarizine seems to be more efficacious in patients with p.Glu815Lys mutation than p.Asp801Asn. In conclusion, our research suggests a genotype–phenotype correlation and provides information on this disorder's features, clinical course, and treatment.