Longstanding Paroxysmal Dyskinesia in GLUT1 Deficiency Syndrome

View Supplementary Video 1

GLUT1 deficiency syndrome (GLUT1DS), a rare autosomal dominant condition, is typically suspected in cases of severe neurologic symptoms in infants, including seizures, developmental delay, and movement disorders. ¹ , ² Adult presentations with milder and variable phenotypes are increasingly recognized, including paroxysmal dyskinesia, seizures, and cognitive impairment. We describe the case of a young adult man with paroxysmal dyskinesia as the presenting feature of GLUT1DS.

Case Report

A 24‐year‐old man presented to our department for clinical evaluation with a long‐standing history of abnormal movements. By the age of 5 months, he had experienced 4 episodes of sudden limb stiffening, opisthotonic posturing, and eye rolling that lasted for <10 minutes. At the time, workup was unremarkable (including a normal electroencephalogram [EEG] between episodes), and in the presence of an otherwise normal development, the infrequent episodes were attributed to Sandifer syndrome. However, at 4 years of age, he began to experience events beginning with a minutes‐long premonitory sensation in the legs, followed by uncoordinated gait and involuntary leg movements, opisthotonic posturing, and upper limb involvement developing over the course of several minutes and continuing for ~1 hour. These episodes were infrequent (~3 times per year), until his late teenage years when they began to occur 1 to 2 times per month and escalated to twice weekly in his early 20s. Interestingly, attendance at church services was his most consistent trigger (2–3 times per week). Occasionally, his episodes were provoked by repetitive movements such as bicycling, chewing gum, or swimming. Of note, exercise alone was insufficient to provoke an event, and he had no difficulties playing football in high school. Other triggers noted included sleep deprivation, fasting, and caffeine.

Two types of episodes were reported. On some occasions, stiffening of a certain body part, typically his legs, occurred over 5 to 10 minutes. This preceded the gradual onset of “jerking” movements of the same body part, which lasted for 1 to 2 hours without loss of consciousness. Resolution of the event also occurred gradually within several minutes, and he was prone to recurrent events until he rested for several hours. The second type of episode involved movements of his head, neck, and face of similar duration. Either type of event could be aborted with diazepam within 15 minutes of administration. Between episodes, he reported no symptoms or involuntary movements, but noted the presence of migrainous headaches since adolescence. His family history was notable for a great uncle with similar episodic movements, as well as 2 cousins (his great uncle's granddaughters) who were reported to often exhibit bizarre behaviors, but had no specific neurologic diagnosis.

He had several clinical evaluations, including multiple unremarkable EEGs, computed tomography (CT) head, and magnetic resonance (MR) brain imaging studies. A diagnosis of functional neurologic disorder had been previously suspected until he was diagnosed with paroxysmal dystonic choreoathetosis. Examination at age 23 in our facility revealed unremarkable neurologic exam including cognitive assessment.

Genetic testing for paroxysmal dyskinesia (NextGen sequencing of SLC2A1, PNKD, and PRRT2 genes) revealed a known pathogenic missense mutation in the SLC2A1 gene (c.884C > T; p.Thr295Met; reference GRCH37) that has been reported in GLUT1DS. ³ He experienced symptomatic improvement of his movements on a ketogenic diet, however, his headaches have been unaffected by dietary intervention.

Discussion

This case highlights unique problems inherent in the diagnosis of GLUT1DS. Paroxysmal dyskinesia are classified based on their triggers: exercise‐induced (PED), kinesigenic (PKD), and non‐kinesigenic (PNKD). Many genetic abnormalities have been linked to these phenotypes, and as has been noted in other genetic movement disorders, there is significant clinical heterogeneity within as well as overlap between genetic entities. A full enumeration of the genes implicated and their most common phenotypic correlates can be found in a recent review by Erro and Bhatia. ⁴

Our patient's case was notable for many reasons. First, his phenotype does not immediately appear consistent with classic infantile onset GLUT1 deficiency syndrome. De novo mutations account for 90% of GLUT1DS cases. Classically, these de novo mutations cause the infantile onset of a panoply of symptoms including intellectual disability, epilepsy, microcephaly, spasticity, ataxia, dystonia, and rapid irregular eye movements. ¹ , ² A less severe phenotype occurs in ~10% of cases with an inherited mutation and can manifest as late as early adulthood. In this less severe phenotype, affected individuals often experience paroxysmal dyskinesia, typically exercise‐induced, and usually also suffer from epilepsy as well as intellectual disability. ⁵ , ⁶ , ⁷ , ⁸ Although our patient presented first symptoms in infancy, he had never had a seizure and remained cognitively normal that is a milder phenotype than either group commonly manifests. Second, his movements were consistent with those typically noted in the less severe form of GLUT1DS, lower extremity predominant choreatic/ballistic/dystonic events. However, because the phenotype is rare, it can be misinterpreted as a functional movement disorder. Third, church attendance, that seemed to trigger his dyskinesia, is also an intriguing phenomenon. Although he denied fasting or heightened emotions linked to church attendance, we suspected that there may have been such triggers originally, and subsequently, the expectation that an event would occur became the primary trigger. Fourth, the fact that caffeine triggered his events as well as the long duration of the events are features more typical of non‐kinesigenic dyskinesia, but not commonly associated with GLUT1DS. Finally, he found diazepam to be helpful as an abortive treatment. This, as well as barbiturates and other benzodiazepines, have been demonstrated to inhibit GLUT1 function in vitro and possibly aggravate epilepsy in vivo. ⁹ , ¹⁰ We wonder if this suggests a dysregulation of glucose in this phenotype as opposed to exclusively a deficiency of glucose intracellularly.

Hypoglycorrhachia or erythrocyte glucose uptake assay has historically been used in the diagnosis; however, genetic diagnosis is increasingly favored during initial workup when GLUT1DS is suspected. ¹ , ¹¹ Despite increased recognition in the literature, this treatable condition is still under‐recognized in clinical practice. Early diagnosis is imperative, because the syndrome is amenable to treatment with a ketogenic diet but is typically otherwise pharmaco‐resistant. ⁶ , ⁸ , ¹² This diagnosis must be considered by neurologists when evaluating patients with childhood‐onset paroxysmal involuntary movements.

Author Roles

(1) Research Project: A. Conception; (2) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.

J.J.C.: 2A

M.D.: 1A, 2B

Disclosures

Ethical Compliance Statement

An institutional review board (IRB) was not required for a case report. The patient provided both written and verbal consent for video submission as well as written case report submission. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest

Neither author has any conflicts of interest. No specific funding was received for this work.

Financial Disclosures for Previous 12 Months

Neither author has any disclosures to report.

Supporting information

Video S1 This is a home video taken by the patient's mother during each type of episode. The first type of event captured occurs while the patient is lying on his back and is in no significant distress. He is able to use his hands freely to reposition himself and gesture. However, his legs and pelvis are moving with arrhythmic, large‐amplitude, non‐stereotyped movements that appear dystonic/choreatic. Some movements are very brief and appear myoclonic/ballistic, some are more sustained and result in varied abnormal postures alternately with flexion and extension positions of his feet, knees, and hips. During the second type of event involving his head, he is seated in no distress and watching television with a meal tray in front of him and is chewing his meal. He has arrhythmic large amplitude jerking and twisting motions of his neck with intermittent eyebrow raising. Throughout this episode, he is interactive with the videographer.