Rare and Treatable Cause of Early-Onset Refractory Absence Seizures.

Glut-1 transporter deficiency syndrome (GLUT1-DS) is a rare disorder caused by the mutation in SLC2A1 gene, which results in impaired glucose transport into the brain. It has a broad spectrum of phenotypic presentation ranging from cognitive decline, microcephaly, and refractory seizures to complex movement disorder. Recognition of this disorder is necessary as it is refractory to antiepileptic drugs (AEDs) and responds significantly to ketogenic diet. We report a case of 7-year-old girl who presented with paroxysmal eye movements in infancy with early-onset absence epilepsy (EOAE), which worsened in early morning and on fasting and was found to be refractory to four AEDs. She had mild developmental delay and subtle ataxia. Cerebrospinal fluid showed hypoglycorrhachia, and molecular analysis identified deletion in exon 4 of SLC2A1 gene (p.leu169del), thus confirming GLUT1-DS. She had a near-complete seizure control on ketogenic diet. Thus, GLUT1-DS should be suspected in all cases of refractory generalized seizures specially EOAE, especially if it worsens on fasting, is associated with development delay, positive family history, or paroxysmal movement disorder.

INTRODUCTION

Glut-1 transporter deficiency syndrome (GLUT1-DS) is a rare treatable disorder caused by the mutation in SLC2A1 gene, which interferes with glucose transport across blood–brain barrier. Less than 300 cases have been reported worldwide. Its spectrum ranges from classical infantile epileptic encephalopathy to atypical forms such as paroxysmal dystonia, alternating hemiplegia, and migraine. It should be considered in the differential diagnosis of any form of intractable epilepsy,[1] especially early-onset absence seizures in which 12% patients may have this disorder.[2] Cerebrospinal fluid (CSF) hypoglycorrhachia and detection of SLC2A1 mutation can establish diagnosis. Early recognition is important as these seizures are usually refractory to antiepileptic drugs (AEDs), and initiation of ketogenic diet (KD) can control seizures significantly and improve neurological outcome.

CASE HISTORY

A 7-year-old girl born of nonconsanguineous marriage presented with absence seizures since 2 years of age, associated with head drop and occasional falls with a frequency of 100–200 times daily, which worsened on fasting and in early morning. She also had paroxysmal eye movements in the form of upward nystagmoid jerks lasting for a few seconds since 7 months of age. Birth history was insignificant, and no positive family history was observed. She had mild global developmental delay and poor scholastic performance. She had microcephaly (45 cm), mild lower limb spasticity, and subtle cerebellar signs. Her seizures were precipitated on hyperventilation. She was initially treated with valproate without significant relief, and gradually valproate, lamotrigine, nitrazepam, and phenobarbitone were added but she continued to have seizures. Electroencephalogram (EEG) showed runs of 3–4 Hz generalized spike and wave discharges lasting for 4–10 s [Figure 1]. Magnetic resonance imaging of brain was normal. For considering the diagnosis of refractory early-onset absence epilepsy (EOAE), pre and 1 and 2 h postprandial EEG were performed, which showed significant postprandial decrease in seizures and epileptiform discharges. CSF showed hypoglycorrhachia (CSF glucose, 28 mg%; CSF/serum glucose ratio of 0.39). GLUT1-DS diagnosis was confirmed by identifying deletion in exon 4 of SLC2A1 gene (p.leu169del). KD was started and valproate, phenobarbitone, and nitrazepam were gradually tapered and stopped. She had marked improvement in seizure frequency; only occasional seizures were reported. She started going back to school. We plan to start the modified Atkins diet once she reaches adulthood.

Figure 1

EEG showing 3–4 Hz generalized spike and waves discharges lasting for 7–8 s

DISCUSSION

GLUT1-DS is a rare and underrecognized disorder caused by the mutation in SLC2A1 gene, which interferes with glucose transport. Most mutations are de novo, and familial cases have autosomal-dominant inheritance.

GLUT1-DS is a broad-spectrum disorder, and classifying the disease phenotype as “classical” or “nonclassical” has limited clinical utility. Recent phenotypic classification includes three categories: (1) classic, complex phenotype with intellectual disability in combination with epilepsy or a movement disorder, (2) “epilepsy-dominant” phenotype, with epilepsy as main symptom, sometimes in combination with a paroxysmal movement disorder such as paroxysmal exertion-induced dystonia (PED), but without intellectual disability, and (3) “movement disorder–dominant” phenotype characterized by an isolated movement disorder (mostly PED) without intellectual disability and without epilepsy.[3]

In classic GLUT1-DS, seizures begin between 1 and 6 months of age and may present with subtle myoclonic limb jerks with alternating staring and eye-rolling, horizontal roving eye movements, unresponsiveness, and head bobbing. EEG may show multifocal spike discharges.[456] Apneic episodes and abnormal episodic eye movements indistinguishable from opsoclonus may precede the onset of seizures.[4] Our patient had similar opsoclonus-like eye movements in infancy and later on developed EOAE at 2 years of age.

In a review of 87 patients, 90% had epilepsy with a mean age of 8 months at onset. The different types of seizures were generalized tonic–clonic (53%), absence (49%), complex partial (37%), myoclonic (27%), drop (26%), tonic (12%), simple partial (3%), and spasms (3%).[5]

With brain maturation, the seizures become synchronized and manifest as generalized events associated with 3–4 Hz spike and wave discharges.[4] EOAE is a rare type of generalized epilepsy with onset before 4 years of age. GLUT1-DS has been reported in 10%–12% of EOAE.[2] Refractory absence seizures are seen in 50% cases especially in EOAE.

Most frequent movement disorders are gait disturbances such as ataxia with/without spasticity (89%), dystonia (86%), chorea (75%), cerebellar tremor (70%), paroxysmal events (28%), dyspraxia (21%), and myoclonus (16%).[5] This can fluctuate during stressors such as fasting, infection, prolonged exercise, and anxiety.

Our patient had EOAE refractory to multiple AEDs and characteristic aggravation on fasting.

Acquired microcephaly is seen frequently.[4]

Speech and language impairment are observed in all affected individuals. Dysarthria and disfluency are common.[4]

GLUT1-DS should be suspected in children of any age presenting with a single or a combination of the following features[1]:

Any form of intractable epilepsy particularly EOAE

Global developmental delay, particularly in speech

Complex movement disorders

Paroxysmal events triggered by exercise, exertion, or fasting

Family history of movement disorder and/or seizures

DIAGNOSIS

Initial step is lumbar puncture after 4–6 h of fast. Hypoglycorrhachia is a major characteristic in GLUT1-DS (<60 mg/dL in all cases, <40 mg/dL in >90% cases, 41–52 mg/dL in approximately 10% cases). CSF to blood glucose ratio should be <0.45. CSF lactate concentration is low and usually <11.7 mg/dL (5.4–13.5 mg/dL).[4]

Rarely in mild variants of GLUT1-DS, EOAE, and PED, absent hypoglycorrhachia has been reported.[1]

Hence, molecular analysis of the SLC2A1 gene has become the gold standard for diagnosis. A total of 70%–80% of patients carry SLC2A1 mutations.[7] In SLC2A1-negative patients, the diagnosis of GLUT1-DS can be considered affirmative if definite hypoglycorrhachia is present.

Erythrocyte glucose uptake assay can be performed in such cases. Uptake is reduced in all patients with 35-74 percent reduction in uptake in assays.[8]

EEG recordings in fasting and postprandial state can be helpful. If fasting EEG is abnormal, a postprandial EEG (1 and 2 h) might show improvement as was seen in our patient.

Our patient had epilepsy-dominant phenotype with refractory EOAE. CSF hypoglycorrhachia with positive SLC2A1 mutation confirmed the diagnosis of GLUT1-DS.

Brain fluorodeoxyglucose PET findings are distinctive with diffuse hypometabolism of the cerebral cortex and regional hypometabolism of the cerebellum and thalamus with relatively preserved basal ganglia metabolism.[9]

The mainstay of treatment is KD, which provides an alternative fuel for brain metabolism. It is well tolerated and highly effective in controlling seizures and improving gait disturbance, but its impact on developmental delay appears less prominent.[4] However, newer studies show cognition improvement in children and improved alertness in adults. Introduction of KD in the first years of life guarantees a better cognitive outcome. The modified Atkins diet has been used successfully.[10]

AEDs are ineffective or offer limited improvement. Phenobarbital, valproate, acetazolamide, topiramate, and zonisamide are relatively contraindicated as adjunctive treatment in children on KD.

Our patient had remarkable seizure control on KD. She is currently only on lamotrigine and has only occasional seizures in 6 months. Thus, early recognition of GLUT1-DS is important for early initiation of KD, which controls seizures and also improves neurological outcome in these patients.

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Conflicts of interest

There are no conflicts of interest.