Short Communication

Refractory Absence Epilepsy and Glut1 Deficiency Syndrome: A New Case Report and Literature Review Francesca Ragona1 Sara Matricardi1,2 Simona Binelli4 Tiziana Granata1

Barbara Castellotti3

1 Department of Pediatric Neuroscience, Foundation I.R.C.C.S.

Neurological Institute C. Besta, Milan, Italy 2 Department of Pediatrics, University of Chieti, Chieti, Italy 3 Clinical Neurophysiology and Epilepsy Center, Foundation I.R.C.C.S. Neurological Institute C. Besta, Milan, Italy 4 Unit of Genetics of Neurodegenerative and Metabolic Diseases, Foundation I.R.C.C.S. Neurological Institute C. Besta, Milan, Italy

Mara Patrini1

Elena Freri1

Address for correspondence Tiziana Granata, MD, Pediatric Neuroscience, Foundation I.R.C.C.S. Neurological Institute C. Besta, Milan, Italy Via celoria 11, 20133 Milan, Italy (e-mail: [email protected]).

Neuropediatrics 2014;45:328–332.

Abstract

Keywords

► Glut1 deficiency syndrome ► absence epilepsy ► electroencephalogram ► SLC2A1 ► refractory seizures ► children

We report a 12-year-old female patient with a mild phenotype of glucose transporter type 1 deficiency syndrome (Glut1D). The clinical picture was characterized by refractory absence epilepsy, migraine, and learning disabilities. Absence seizures appeared at the age of 4 years, and electroencephalogram (EEG) showed irregular discharges of diffuse epileptic abnormalities. During the follow-up, seizures became drug resistant, cognitive evaluation revealed learning difficulties, and the patient complained migraine episodes. The evidence of seizure worsening before meals and the drug resistance suggested a Glut1D. Molecular analysis of SLC2A1 gene showed the presence of a pathogenic de novo mutation of the gene in heterozygosity (p.Ala275Thr, c.823G > A). Our case and the review of literature data on patients with Glut1D and absences provide a combination of clinical and EEG keys that should prompt the genetic analysis. The Glut1D should be suspected when absence seizures are associated with at least one among: irregular ictal EEG discharges, mild mental retardation, migraine, microcephaly, drug resistance, and worsening during fasting. An early diagnosis allows to establish one of the available ketogenic regimens which could modify the natural history of this treatable condition.

Introduction Glucose transporter type 1 deficiency syndrome (Glut1D) is a metabolic disorder caused by impaired glucose transport across the blood–brain barrier and into brain cells, due to mutations or deletions of SLC2A1 gene encoding the Glut1 transporter. First described in patients with early onset epileptic encephalopathy and acquired microcephaly,1 the spectrum of the clinical phenotype has progressively wid-

received December 27, 2013 accepted after revision March 29, 2014 published online June 3, 2014

ened to include patients with early-onset epilepsy, severe developmental delay, complex movement disorders, and acquired microcephaly but also patients with paroxysmal exertion-induced dyskinesia (PED), and patients with epilepsy and normal or nearly normal mental abilities.2,3 The epileptic phenotype, beyond the classical severe early onset epileptic encephalopathy, varies widely, including: focal epilepsy, myoclonic astatic epilepsy, benign myoclonic

© 2014 Georg Thieme Verlag KG Stuttgart · New York

DOI http://dx.doi.org/ 10.1055/s-0034-1378130. ISSN 0174-304X.

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epilepsy, and idiopathic generalized epilepsies (IGE).4,5 Among the mild epileptic phenotype, absence epilepsy has been frequently reported.4,6 We report a patient with de novo SLC2A1 mutation associated with refractory absence seizures and borderline cognitive functioning, and analyze the epileptic characteristics, as well as the peculiar clinical and neurophysiologic features. Furthermore, we review literature data on the association between absence epilepsy and Glut1D and discuss indication to genetic analysis in children with absence seizures.

Case Report A 12-year-old female patient was first observed at the age of 6 years for the assessment of absence seizures, which started at the age of 4 years. The patient is the first of two females born to unrelated parents. The family history reported migraine in her mother, grandmother, and younger sister; her father experienced five tonic clonic seizures during recurrent tonsillitis in the third decade of life, neither electroencephalogram (EEG) was performed nor was antiepileptic treatment given. Pregnancy, delivery, and neonatal period were uneventful. Psychomotor and language development were normal. The patient experienced two febrile generalized seizures with body temperature lower than 38°C at the age of 2 and 11 months, respectively. Unprovoked seizures started at the age of 4 years and were characterized by brief episodes of unresponsiveness and eyelid myoclonic jerks. The seizures recurred sporadically and were interpreted as psychogenic phenomena. Starting from the age of 5 years, absence seizures increased in frequency and recurred many times per day, they were sporadically associated with unexplained episodes of falling, which spontaneously disappeared. At the same age, the girl started to complain headache that fulfilled the criteria for migraine without aura. At our first observation, at the age of 6 years, neurological examination was normal and cognitive abilities, assessed by Wechsler Intelligence Scale for Children—third edition (WISCIII), were in the normal range for age (total IQ [TIQ] 106, verbal [VIQ] 104, performance [PIQ] 105). The EEG recordings showed normal background activity and sleep organization. While awake, the EEG revealed several discharges of irregular diffuse spike and waves, in most cases associated with staring and myoclonic eyelid jerks; the seizures occurred at rest and were enhanced during hyperventilation (►Fig. 1a). Diffuse, short, apparently interictal, and brief epileptic discharges persisted during slow sleep. The girl was given Valproate, which was only partially effective and induced abdominal pain, weight gain, and drowsiness; 4 months later, the treatment was switched to Ethosuximide. During the short period of bitherapy, the girl was seizure free and EEG normalized. Sporadic absences and diffuse epileptic discharges recurred soon after valproate withdrawal, however, given the very low seizure frequency no antiepileptic drug was added until the age of 10 years. At this age, seizures increased in frequency, and the ambulatory video EEG monitoring docu-

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mented that seizures and interictal discharges were particularly frequent soon after awakening (►Fig. 1b). Lamotrigine was added-on, but it was only partially successful. Cognitive evaluation performed by means of WISC-III scale during the follow-up demonstrated mild cognitive decline (8 years: TIQ: 95, VIQ: 99, PIQ: 92; 10 years: TIQ: 84, VIQ: 93, PIQ: 77). At the age of 12 years, the neuropsychological evaluation confirmed a borderline cognitive functioning (TIQ: 84, VIQ: 88, and PIQ: 83) and revealed attention deficit, impairment in executive functions, in visuospatial and verbal memory. The persistence of seizures and the IQ decline led us to reconsider the clinical picture: during the clinical conversation, the parents underscored that seizures consistently worsened before meals. These data suggested to carry out the molecular analysis of SLC2A1 gene which revealed the presence of a heterozygous mutation in SLC2A1 gene (c.823G > A), resulting in p.Ala275Thr substitution in Glut1 protein. This missense variant (rs121909740) is reported as having a pathogenic role in Ensamble database (www.ensamble.org), with a SIFT score ¼ 0.02 (http://sift.jcvi.org/), and a PolyPhen score ¼ 0.941 (http://genetics.bwh.harvard.edu/pph2/). Molecular testing, performed in her parents and sister, showed in SLC2A1 gene the absence of the mutation. The subsequent research of this variant in 300 control alleles by direct sequence analysis ruled out the possibility that this variant is a rare polymorphism, and confirmed the pathogenic role of this de novo mutation. Furthermore, the MLPA analysis failed to find deletions or duplications in the 10 exons of the SLC2A1 gene. Given these molecular findings, the invasive procedure of lumbar puncture was avoided. The ketogenic diet was proposed but refused by the girl and her parents.

Discussion We report the case of a young girl with childhood onset absence seizures and an initial diagnosis of IGE. Glut1D was detected 6 years after seizure onset because of drug resistance and awareness that absence seizures worsened before meals. The association between absence seizures and Glut1D is a long and still endless story (►Table 1). Since the first description of this syndrome, it appeared that one of the most common EEG pattern was that of generalized discharges, associated with “absences.” Boles et al in 1999 described two patients with early onset atypical absence seizures associated with runs of brief generalized, irregular discharges.7 In two series of patients with SLC2A1 mutation, drug resistant absence seizures have been reported to occur in half of the cases, namely in 10 of 20 patients in the series of Leary et al,8 and in 7 of 15 patients in the series of Klepper et al.3 Both the authors underscored that absence seizures had an early onset (less than 5 years) in most patients. Following these reports, several authors performed Glut1 molecular analysis in the cohorts of patients with early onset absence epilepsy (EOAE) with inconsistent results. In a series of 34 children with EOAE, the mutational screening revealed Glut1 deficiency in 4 cases9; a similar proportion was found by the same researchers in a recent study performed on 55 new cases.10 Putting together the results of the Neuropediatrics

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Absence Epilepsy and Glut1D

Absence Epilepsy and Glut1D

Ragona et al.

Fig. 1 (a) Electroencephalogram (EEG) recording at the age of 6 years: brief absence seizure associated with a diffuse, irregular, high amplitude spike, and wave discharges at 2.5 Hz. (b) EEG recording at the age of 10 years: occurrence of several interictal discharges of diffuse spike, and waves soon after awakening.

two studies, the authors conclude that approximately 12% of patients with EOAE are potentially carriers of Glut1D and strongly recommend the mutational analysis in all children with this epileptic syndrome.10,11 A collaborative Italian study, by contrast, failed to find SLC2A1 mutations in a series of 84 patients with onset of absences within the first 3 years of life.12 The discrepancies between the two series may be related to the different diagnostic criteria. The Australian series included patients aged less than 4 years, with absence seizures as the predominant, not necessarily unique, seizure type, and with generalized spike-waves > 2.5 Hz. The Italian series included only patients younger than 3 years but who otherwise fulfilled the criteria for childhood absence epilepsy: absence seizures as the only seizure type, EEG discharges of generalized, symmetric, regular, 3 to 4 Hz spike-waves on a normal background activity, and normal development and neurological examination at onset. An early age at onset (ranging between 2 months and 5 years) appear to be almost the rule in the sporadic cases, whereas a wider range of onset is observed in familial cases. The review of individual cases and of the few series of patients reveals that “pure” absence epilepsy is an extremely rare phenotype of Glut1D.13,14 Absence seizures are in most cases associated with other Neuropediatrics

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seizure types (namely, myoclonic, tonic-clonic and more rarely focal or tonic seizures), diffuse epileptic discharges may be irregular in shape and frequency, and neurological symptoms are often associated. Neurological symptoms vary in type and severity, and include mental retardation of varying degree, hypotonia, microcephaly, ataxia, migraine, and movement disorders, particularly PED (►Table 1). The co-occurrence of migraine and absences, observed in our patient, was reported in one sporadic patient carrying a mutation of SLC2A1 gene (c.274C > T), resulting in p. R91W,15 as well as in two twins carrying a mutation (c.493G > A), leading to a p.Val165Ile substitution in Glut1 protein.16 In our patient, however, the positive family history for migraine has probably a major or concurrent role. Epileptic phenotypes mimicking IGE with absences are more frequently reported in familial cases.2,4,11,16 Absence seizures may be the predominant seizure type, and may respond to antiepileptic drugs.5 PED, albeit frequently reported, may appear as late as young adulthood and may be the only symptom beside seizures. These data suggest that Glut1 analysis is worth doing in families with seizures featuring IGE, either isolated or associated with PED or mental retardation, either drug sensitive or resistant.

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1 family: 4 cases

1 family: 2 twins

2 families: 10 cases

1 family: 9 cases

Weber et al 2

Urbizu et al 16

Mullen et al 4

Striano et al 5

Neuropediatrics

10 cases

7 cases

1 case

4 cases

1 case

2 cases

3 cases

7 cases

Leary et al 8

Klepper et al3

Roulet-Perez et al 13

Suls et al11

Schneider et al 15

Byrne et al 14

Anand et al6

Arsov et al 10