Paroxysmal Exercise-induced Dyskinesia Research Articles

Atypical Paroxysmal Kinesigenic Dyskinesia with Paroxysmal Exercise-induced Dyskinesia

Paroxysmal kinesigenic dyskinesia (PKD) is a diagnostic term for transient, involuntary abnormal movements triggered by sudden motions. The treatment for PKD differs from other paroxysmal dyskinesias, as it notably responds well to sodium channel blockers. We report a case of atypical PKD, coupled with paroxysmal exercise-induced dyskinesia (PED). Both PKD and PED in this patient showed a good response to oxcarbazepine. This case could be clinical evidence that paroxysmal dyskinesias could potentially be regarded as a spectrum disorder with overlapping features.

Genetic Links to Episodic Movement Disorders: Current Insights.

Episodic or paroxysmal movement disorders (PxMD) are conditions, which occur episodically, are transient, usually have normal interictal periods, and are characterized by hyperkinetic disorders, including ataxia, chorea, dystonia, and ballism. Broadly, these comprise paroxysmal dyskinesias (paroxysmal kinesigenic and non-kinesigenic dyskinesia [PKD/PNKD], paroxysmal exercise-induced dyskinesias [PED]) and episodic ataxias (EA) types 1-9. Classification of paroxysmal dyskinesias has traditionally been clinical. However, with advancement in genetics and the discovery of the molecular basis of several of these disorders, it is becoming clear that phenotypic pleiotropy exists, that is, the same variant may give rise to a variety of phenotypes, and the classical understanding of these disorders requires a new paradigm. Based on molecular pathogenesis, paroxysmal disorders are now categorized as synaptopathies, transportopathies, channelopathies, second-messenger related disorders, mitochondrial or others. A genetic paradigm also has an advantage of identifying potentially treatable disorders, such as glucose transporter 1 deficiency syndromes, which necessitates a ketogenic diet, and ADCY5-related disorders, which may respond to caffeine. Clues for a primary etiology include age at onset below 18 years, presence of family history and fixed triggers and attack duration. Paroxysmal movement disorder is a network disorder, with both the basal ganglia and the cerebellum implicated in pathogenesis. Abnormalities in the striatal cAMP turnover pathway may also be contributory. Although next-generation sequencing has restructured the approach to paroxysmal movement disorders, the genetic underpinnings of several entities remain undiscovered. As more genes and variants continue to be reported, these will lead to enhanced understanding of pathophysiological mechanisms and precise treatment.

Pearls & Oy-sters: Paroxysmal Exercise-Induced Dyskinesias Due to Pyruvate Dehydrogenase Deficiency.

Paroxysmal exercise-induced movement disorders may be caused by energy metabolism disorders, such as Glut 1 deficiency, pyruvate dehydrogenase deficiency, or mitochondrial respiratory chain disorders. A 4-year-old boy with a history of febrile seizures presented with paroxysmal dystonia, triggered by exercise, or occurring at rest. Additional investigations demonstrated pallidal hyperintensities on brain MRI and low CSF glucose. Pyruvate and lactate were elevated. The clinical presentation combined with neuroimaging abnormalities and biochemical profile (the lactate/pyruvate ratio) were clues to pyruvate dehydrogenase deficiency, a treatable metabolic disorder with neurologic presentations.

Glut1 deficiency syndrome throughout life: clinical phenotypes, intelligence, life achievements and quality of life in familial cases

BackgroundGlut1 deficiency syndrome (Glut1-DS) is a rare metabolic encephalopathy. Familial forms are poorly investigated, and no previous studies have explored aspects of Glut1-DS over the course of life: clinical pictures, intelligence, life achievements, and quality of life in adulthood.Clinical, biochemical and genetic data in a cohort of familial Glut1-DS cases were collected from medical records. Intelligence was assessed using Raven’s Standard Progressive Matrices and Raven’s Colored Progressive Matrices in adults and children, respectively. An ad hoc interview focusing on life achievements and the World Health Organization Quality of Life Questionnaire were administered to adult subjects.ResultsThe clinical picture in adults was characterized by paroxysmal exercise-induced dyskinesia (PED) (80%), fatigue (60%), low intelligence (60%), epilepsy (50%), and migraine (50%). However, 20% of the adults had higher-than-average intelligence. Quality of Life (QoL) seemed unrelated to the presence of PED or fatigue in adulthood. An association of potential clinical relevance, albeit not statistically significant, was found between intelligence and QoL. The phenotype of familial Glut1-DS in children was characterized by epilepsy (83.3%), intellectual disability (50%), and PED (33%).ConclusionThe phenotype of familial Glut1-DS shows age-related differences: epilepsy predominates in childhood; PED and fatigue, followed by epilepsy and migraine, characterize the condition in adulthood. Some adults with familial Glut1-DS may lead regular and fulfilling lives, enjoying the same QoL as unaffected individuals. The disorder tends to worsen from generation to generation, with new and more severe symptoms arising within the same family. Epigenetic studies might be useful to assess the phenotypic variability in Glut1-DS.

Screening of the TMEM151A Gene in Patients With Paroxysmal Kinesigenic Dyskinesia and Other Movement Disorders.

BackgroundParoxysmal kinesigenic dyskinesia (PKD) is a rare neurological disorder characterized by recurrent involuntary movements usually triggered by sudden movements. Mutations in the TMEM151A gene were found to be the causative factor of PKD in recent studies. It has also been revealed that loss-of-function is the mechanism by which TMEM151A mutations cause PKD.MethodsTo investigate the genetic basis of PKD and broaden the clinical spectrum of the TMEM151A mutations, we recruited 181 patients of Chinese origin with movement disorders (MDs), including 39 PRRT2-negative PKD, 3 paroxysmal exercise-induced dyskinesia (PED), 2 paroxysmal non-kinesigenic dyskinesia (PNKD), 127 isolated dystonia, 8 choreas, and 2 myoclonus-dystonia syndromes. Whole-exome sequencing was applied to identify their possible disease-causing mutations. Then, Sanger sequencing was performed for validation and co-segregation analysis. Genetic analysis was also performed on additional family members of patients with TMEM151A mutations. Clinical manifestations of all PKD cases with mutations in TMEM151A reported, so far, were reviewed.ResultsTwo novel variants of the TMEM151A gene (NM_153266.4, NP_694998.1), c.627_643dup (p.A215Gfs*53) and c.627delG (p.L210Wfs*52), were identified in 2 patients with PKD by whole-exome sequencing and further Sanger sequencing. Both variants were inherited by the patients from their respective mothers. No mutation of the TMEM151A gene was found in the other type of movement disorders. In reviewing the clinical presentation of TMEM151A-related PKD, no statistically significant difference in the age of onset, family history, duration of attacks, laterality, and phenotype was found between genders. More male patients received treatment and had a good response. A higher proportion of female patients did not receive any treatment, possibly because they had a milder condition of the disease.ConclusionsThis study further validated the role of TMEM151A in PKD. Future studies on protein function will be needed to ascertain the pathogenesis of TMEM151A in PKD.

Shedding light on the phenotypic\u2013genotypic correlation of rare treatable and potentially treatable pediatric movement disorders

BackgroundAdvances in genetic science have led to the identification of many rare treatable pediatric movements disorders (MDs). We explored the phenotypic–genotypic spectrum of pediatric patients presenting with MDs. By this, we aimed at raising awareness about such rare disorders, especially in our region. Over the past 3 years, we reviewed the demographic data, clinical profile, molecular genetics and other diagnostic workups of pediatric patients presenting with MDs.ResultsTwelve patients were identified; however, only six patients were genetically confirmed. The phenomenology of MDs ranged from paroxysmal kinesigenic choreoathetosis (1 patient), exercise-induced dyskinesia (2 patients), ataxia (2 patients) and dystonia (2 patients). Whole-exome sequencing in addition to the functional studies for some patients revealed a specific genetic diagnosis being responsible for their MDs. The genetic diagnosis of our patients included infantile convulsions and paroxysmal choreoathetosis syndrome and episodic ataxia due to “pathogenic homozygous mutation of PRRT2 gene,” glucose transporter type 1 deficiency-exercise induced dyskinesia due to “De Novo pathogenic heterozygous missense mutation of exon 4 of SLC2A1 gene,” aromatic L amino acid decarboxylase deficiency due to “pathogenic homozygous mutation of the DDC gene,” myopathy with extrapyramidal signs due to “likely pathogenic homozygous mutations of the MICU1 gene,” mitochondrial trifunctional protein deficiency due to “homozygous variant of uncertain significance (VUS) of HADHB gene” and glutaric aciduria II with serine deficiency due to “homozygous VUS for both ETFDH and PHGDH genes.” After receiving the treatment as per recognized treatment protocols, two patients showed complete resolution of symptoms and the rest showed variable responses.ConclusionIdentifying the genetic etiology of our patients guided us to provide either disease-specific treatment or redirected our management plan. Hence, highlighting the value of molecular genetic analysis to avoid the diagnostic odyssey and identify treatable MDs.

A Patient with Glucose Transporter Type 1 Deficiency Syndrome

Glucose transporter type 1 deficiency syndrome (GLUT-1 DS) is an inborn error of metabolism that results in defective glucose transport and consequently a reduced supply of glucose to the brain. Here, we describe a patient with a molecularly proven GLUT-1 mutation who presented with severe paroxysmal choreoathetosis. Different regional changes involving bilateral mesial temporal lobes were revealed using positron-emission tomography (PET). Several cases of GLUT-1 DS have been studied from the point of view of hyperkinetic movement disorders rather than epilepsy and ataxia. It is usual for these patients to first present with dystonia, choreoathetosis, parkinsonism, and paroxysmal exercise-induced dyskinesia, including dystonic, choreoathetotic, and ballistic movements. F18-fluorodeoxyglucose PET revealed hypometabolism in bilateral mesial temporal lobes along with the cerebellar cortex, confirming an impaired glucose metabolism effect on the area responsible for the extrapyramidal movement disorders.

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.

Varied phenotypic spectrum presenting of paroxysmal exercise-induced dyskinesia: a Turkish family with SLC2A1 mutation.

Paroxysmal exercise-induced dyskinesia (PED) is characterized by repeated episodes of involuntary movement disorders that are typically caused by prolonged walking or running and mostly caused by SLC2A1 gene mutations. Phenotypes vary from focal dystonia, ataxia, tremor, and complex non-kinesigenic movements to other movement disorders in patients with SLC2A1 mutation. Also, SLC2A1 mutations carriers may present with also other phenotypes such as epileptic seizure and migraine. We report five patients with various phenotypic spectrums of PED in a Turkish family. Whole exome sequencing revealed a likely pathogenic synonymous variant p.Ser324Ser (c.972G > A) in the SLC2A1 gene (ENST00000426263.3) and the variant segregated in all affected family members. Also, other than PED, the phenotypical spectrum of affected individuals in this family includes epilepsy, mental retardation, and weakness. We concluded that family members with the same SLC2A1 gene mutation may show very heterogenous phenotypes. Clinicians should be aware of wide variety of symptoms of the patients with PED. We also emphasized that even if a mutation in the coding sequence does not make an amino acid change, it may cause the disease.

The case of paroxysmal kinesigenic dyskinesia: a long way from a symptom to the diagnosis

Paroxysmal kinesigenic dyskinesia belongs to the group of primary dyskinesias, which also includes paroxysmal non-kinesigenic dyskinesia and exercise-induced paroxysmal dyskinesia. Due to the rarity of this disease group, as well as to the existence of a wide spectrum of disorders associated with transient movement abnormalities, the diagnosis is often difficult. A thorough analysis of clinical presentation, objective registration of paroxysmal events (video-electroencephalography monitoring) is helpful in the diagnosis. The most common causes of paroxysmal kinesigenic dyskinesia are mutations in the PRRT2 gene, while paroxysmal non-kinesigenic dyskinesia is caused by the MR1 gene mutations.The paper describes a clinical case of a 13 year old patient with acute, movement-associated, shortterm dystonic, choreic and ballistic hyperkinesis attacks. The patient had been treated with the diagnosis of epilepsy, tics, and dystonia for a long time without any effect. During diagnostic workup, a mutation in the PRRT2 gene intron was identified by a new generation sequencing of gene panel. Despite of this mutation has not been previously described, taking into account the type of Informed consent statement hyperkinesis attacks, association of their onset to movements, as well as the data of instrumental assessments, the diagnosis of paroxysmal kinesi-genic dyskinesia was made. Treatment with carbamazepine was successful with complete control over hyperkinesis.The diagnosis of paroxysmal dyskinesias remains based on the analysis of clinical picture and the trigger type. Molecular genetic diagnostics, with consideration of the most frequent causal mutations related to these conditions, can minimize both time and financial costs.

Genetics of Paroxysmal Dyskinesia: Novel Variants Corroborate the Role of KCNA1 in Paroxysmal Dyskinesia and Highlight the Diverse Phenotypic Spectrum of KCNA1- and SLC2A1-Related Disorders.

Paroxysmal dyskinesias (PxD) are rare movement disorders with characteristic episodes of involuntary mixed hyperkinetic movements. Scientific efforts and technical advances in molecular genetics have led to the discovery of a variety of genes associated with PxD; however, clinical and genetic information of rarely affected genes or infrequent variants is often limited. In our case series, we present two individuals with PxD including one with classical paroxysmal kinesigenic dyskinesia, who carry new likely pathogenic de novo variants in KCNA1 (p.Gly396Val and p.Gly396Arg). The gene has only recently been discovered to be causative for familial paroxysmal kinesigenic dyskinesia. We also provide genetic evidence for pathogenicity of two newly identified disease-causing variants in SLC2A1 (p.Met96Thr and p.Leu231Pro) leading to paroxysmal exercise-induced dyskinesia. Since clinical information of carriers of variants in known disease-causing genes is often scarce, we encourage to share clinical data of individuals with rare or novel (likely) pathogenic variants to improve disease understanding.

Pediatric Paroxysmal Exercise-Induced Neurological Symptoms: Clinical Spectrum and Diagnostic Algorithm.

Paroxysmal exercise-induced neurological symptoms (PENS) encompass a wide spectrum of clinical phenomena commonly presenting during childhood and characteristically elicited by physical exercise. Interestingly, few shared pathogenetic mechanisms have been identified beyond the well-known entity of paroxysmal exercise-induced dyskinesia, PENS could be part of more complex phenotypes including neuromuscular, neurodegenerative, and neurometabolic disease, epilepsies, and psychogenetic disorders. The wide and partially overlapping phenotypes and the genetic heterogeneity make the differential diagnosis frequently difficult and delayed; however, since some of these disorders may be treatable, a prompt diagnosis is mandatory. Therefore, an accurate characterization of these symptoms is pivotal for orienting more targeted biochemical, radiological, neurophysiological, and genetic investigations and finally treatment. In this article, we review the clinical, genetic, pathophysiologic, and therapeutic landscape of paroxysmal exercise induced neurological symptoms, focusing on phenomenology and differential diagnosis.

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.

Mitochondrial PCK2 Missense Variant in Shetland Sheepdogs with Paroxysmal Exercise-Induced Dyskinesia (PED).

Four female Shetland Sheepdogs with hypertonic paroxysmal dyskinesia, mainly triggered by exercise and stress, were investigated in a retrospective multi-center investigation aiming to characterize the clinical phenotype and its underlying molecular etiology. Three dogs were closely related and their pedigree suggested autosomal dominant inheritance. Laboratory diagnostic findings included mild lactic acidosis and lactaturia, mild intermittent serum creatine kinase (CK) elevation and hypoglycemia. Electrophysiological tests and magnetic resonance imaging of the brain were unremarkable. A muscle/nerve biopsy revealed a mild type II fiber predominant muscle atrophy. While treatment with phenobarbital, diazepam or levetiracetam did not alter the clinical course, treatment with a gluten-free, home-made fresh meat diet in three dogs or a tryptophan-rich, gluten-free, seafood-based diet, stress-reduction, and acetazolamide or zonisamide in the fourth dog correlated with a partial reduction in, or even a complete absence of, dystonic episodes. The genomes of two cases were sequenced and compared to 654 control genomes. The analysis revealed a case-specific missense variant, c.1658G>A or p.Arg553Gln, in the PCK2 gene encoding the mitochondrial phosphoenolpyruvate carboxykinase 2. Sanger sequencing confirmed that all four cases carried the mutant allele in a heterozygous state. The mutant allele was not found in 117 Shetland Sheepdog controls and more than 500 additionally genotyped dogs from various other breeds. The p.Arg553Gln substitution affects a highly conserved residue in close proximity to the GTP-binding site of PCK2. Taken together, we describe a new form of paroxysmal exercise-induced dyskinesia (PED) in dogs. The genetic findings suggest that PCK2:p.Arg553Gln should be further investigated as putative candidate causal variant.

Paroxysmal Exercise-Induced Dyskinesia in Siblings due to ECHS1 Gene Mutation - First Indian Case Report.

Paroxysmal Exercise-Induced Dyskinesia in Siblings due to ECHS1 Gene Mutation - First Indian Case Report.

053 GLUT-1 deficiency presenting as dopa-responsive dystonia: an atypical phenotype of a rare disease

IntroductionThe SLC2A1 gene encodes the glucose transporter GLUT1, responsible for normal glucose transport across the blood-brain barrier. Mutations in this gene have classically been associated with an epileptic encephalopathy referred to as GLUT-1 Deficiency Syndrome, which typically presents with early-onset refractory epilepsy, developmental delay and complex movement disorders.1 2 More recently, SLC2A1 variants have been identified in patients with paroxysmal exercise-induced dyskinesia (PED), with or without a history of epilepsy.3 4 Response to medication is typically poor; however, both seizures and dyskinesia may improve following implementation of a ketogenic diet.5 A single case of levodopa responsiveness has previously been described in a subject with SLC2A1 mutation and PED.5Methods and resultsWe describe a 47-year-old female with mild intellectual disability since childhood but no history of epilepsy, who developed episodic dystonia affecting the lower limbs in her early 20’s. A clinical diagnosis of dopa-responsive dystonia was made following a marked, sustained response to levodopa. There was no significant family history. In her 40’s she developed breakthrough dystonia with exertion and choreiform movements affecting the fingers and face. A subsequent dystonia panel identified a heterozygous variant c.[1199G>T];[=] (p.Arg400Leu) in the SLC2A1 gene. Cerebrospinal fluid glucose concentration was low (2.0 mmol/L). She declined a trial of a ketogenic diet.SLC2A1 variants are associated with PED; however, response to levodopa has not been widely reported.ConclusionIt is becoming increasingly evident that the phenotypic presentations of GLUT1 deficiency are diverse, and SLC2A1 testing should be considered in a broader range of patients.ReferencesWang, D, Kranz-Eble P, De Vivo DK. Mutational analysis of GLUT1 (SLC2A1) in Glut-1 Deficiency Syndrome. Human Mutation 2001;16:224–231.Klepper J, Leiendecker B. GLUT1 deficiency syndrome – 2007 update. Developmental Medicine & Child Neurology 2007;49:707–716.Schneider SA, Paisan-Ruiz C, Garcia-Gorostiaga I, Quinn NP, Weber YG, et al. GLUT1 gene mutations cause sporadic paroxysmal exercise-induced dyskinesias. Mov Disord 2009;24(11):1684–1696.Suls A, Dedeken P, Goffin K, Van Esch H, Dupont P. Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, endoding the glucose transporter GLUT1. Brain 2008;131:1831–1844.Baschieri F, Batla A, Erro R, Ganos C, Cordivari C, Bhatia KP. Paroxysmal exercise-induced dystonia due to GLUT-1 mutation can be responsive to levodopa: a case report. J Neurol 2014;261:615–616.

The expanding spectrum of paroxysmal movement disorders: update from clinical features to therapeutics.

This review will discuss the expanding clinical spectrum of paroxysmal movement disorders and therapeutic options in light of emerging genotypic heterogeneity in these conditions. Paroxysmal movement disorders comprise a heterogeneous group of rare neurological conditions characterized by intermittent episodes of abnormal movement associated with various triggers. As the clinical and genotypic spectrum of these disorders evolves, so also has the range of therapeutic options. Triheptanoin has recently been shown to be a very promising alternative to the ketogenic diet in paroxysmal exercise-induced dyskinesia. Four-aminopyridine is now considered first-line symptomatic therapy for episodic ataxia type-2, with pre-clinical findings indicating cerebellar neuroprotection. In light of the newly emerging therapies, careful clinical phenotyping is needed to ensure diagnostic precision and timely initiation of appropriate therapies.

Paroxysmal Dyskinesia in Children: from Genes to the Clinic.

Background and PurposeParoxysmal dyskinesia is a genetically and clinically heterogeneous movement disorder. Recent studies have shown that it exhibits both phenotype and genotype overlap with other paroxysmal disorders as well as clinical heterogeneity. We investigated the clinical and genetic characteristics of paroxysmal dyskinesia in children.MethodsFifty-five patients (16 from 14 families and 39 sporadic cases) were enrolled. We classified them into three phenotypes: paroxysmal kinesigenic dyskinesia (PKD), paroxysmal nonkinesigenic dyskinesia (PNKD), and paroxysmal exercise-induced dyskinesia (PED). We sequenced PRRT2, SLC2A1, and MR-1 in these patients and reviewed their medical records.ResultsForty patients were categorized as PKD, 14 as PNKD, and 1 as PED. Thirty-eight (69.1%) patients were male, and their age at onset was 8.80±4.53 years (mean±SD). Dystonia was the most common symptom (38 patients, 69.1%). Pathogenic variants were identified in 20 patients (36.4%): 18 with PRRT2 and 2 with SLC2A1. All of the patients with PRRT2 mutations presented with PKD alone. The 2 patients carrying SLC2A1 mutations presented as PNKD and PED, and one of them was treated effectively with a ketogenic diet. Six mutations in PRRT2 (including 2 novel variants) were identified in 9 of the 13 tested families (69.2%) and in 8 patients of the 25 tested sporadic cases (32.0%). There were no significant differences in clinical features or drug response between the PRRT2-positive and PRRT2-negative PKD groups.ConclusionsThis study has summarized the clinical and genetic heterogeneity of paroxysmal dyskinesia in children. We suggest that pediatric paroxysmal dyskinesia should not be diagnosed using clinical features alone, but by combining them with broader genetic testing.

GLUT1-deficiency syndrome: Report of a four-generation Norwegian family with a mild phenotype.

Glucose transporter type 1 deficiency syndrome (GLUT1-DS) is a rare metabolic encephalopathy with a wide variation of clinical phenotypes. Familial variants are often milder than de novo cases, and may therefore remain undiagnosed. The aim of this study was to characterize the clinical course of GLUT1-DS in a four-generation Norwegian family where the oldest generations had never received any treatment. Through interviews and clinical investigations, we characterized a family of 26 members, where 11 members had symptoms strongly suggesting GLUT1-DS. All members were offered genetic testing of the SLC2A1 gene. Affected members were offered treatment with ketogenic diet, and the effect of the treatment was registered. We sequenced the SLC2A1 gene in 13 members, and found that 10, all with symptoms, had the c.823G>A (p.Ala275Thr) variant. All affected members had experienced early-onset epilepsy, paroxysmal exercise-induced dyskinesias, and most had mild learning disability. Moreover, some had symptoms and signs of a distal neuropathy in addition to reduced sense of orientation and excessive daytime sleep. Their load of symptoms had decreased over the years, although that they never had received any treatment. Nevertheless, those who started dietary treatment all experienced an improved quality of life. We report a four-generation family with GLUT1-DS where the disease has a mild course, even when untreated. In addition to classical GLUT1-DS features, we also describe symptoms which have never been reported in GLUT1-DS previously. As such, this family extends the phenotypic spectrum of GLUT1-DS and underlines the importance of diagnosing also relatively mildly affected patients, even in adult life, as they also seem to benefit from dietary treatment.

Atypical Manifestations in Glut1 Deficiency Syndrome

Glucose transporter type 1 deficiency syndrome is a genetically determined, treatable, neurologic disorder that is caused by an insufficient transport of glucose into the brain. It is caused by a mutation in the SCL2A1 gene, which is so far the only known to be associated with this condition. Glucose transporter type 1 deficiency syndrome consists of a wide clinical spectrum that usually presents with cognitive impairment, epilepsy, paroxysmal exercise-induced dyskinesia, acquired microcephaly, hemolytic anemia, gait disturbance, and dyspraxia in different combinations. However, there are other clinical manifestations that we consider equally peculiar but that have so far been poorly described in literature. In this review, supported by a video contribution, we will accurately describe this type of clinical manifestation such as oculogyric crises, weakness, paroxysmal kinesigenic and nonkinesigenic dyskinesia in order to provide an additional instrument for a correct, rapid diagnosis.