Introduction

Glucose transporter type 1 (GLUT1) deficiency syndrome (GLUT1 DS) (OMIM 606777) is a disorder of brain energy metabolism caused by insufficient transport of glucose from the blood to the brain. The first patients were reported by De Vivo et al. in 1991 (hence the disorder is also referred to as De Vivo syndrome). The original patients presented with an early infantile-onset developmental encephalopathy associated with seizures, acquired microcephaly, low cerebrospinal fluid (CSF) glucose and lactate concentrations, and a decreased uptake of glucose by isolated erythrocytes in vitro [1]. This clinical presentation represents the most frequent manifestation of the condition (80–90%) and is generally referred to as the “classic phenotype” [2]. Additionally, a small proportion of patients with GLUT1 DS (10–20%) demonstrate milder clinical presentations such as benign epilepsy phenotypes, and non-epileptic phenotypes manifesting with paroxysmal and/or chronic movement disorders. These less common presentations generally are referred to as the “non-classic phenotypes” [2]. Altogether, it is apparent that GLUT1 DS may present with a wide spectrum of clinical phenotypes, each with discrete and overlapping symptoms [2–4]. Additionally, a key clinical feature of GLUT1 DS is the propensity of the neurological manifestations, mainly the motor symptoms, to worsen in the context of fasting (early morning upon awakening and before eating), exercise or environmental stress such as intercurrent illnesses, infections, anxiety, or ketogenic diet noncompliance. Furthermore, long-term follow-up of GLUT1 DS patients has helped to define the natural history and to delineate additional key features such as the presence of characteristic episodes of eye–head movements during infancy, and the evolution of the dominant clinical manifestations (seizures and movement disorders) with age and development [5–9].

Epidemiology

GLUT1 DS shows no obvious sex or racial predilection [9]. The epidemiological data are not congruent at this point. However, there is general agreement that GLUT1 DS is a rare disease. The estimated prevalence is 1 in 90,000 in Australia [10], 1 in 83,000 in Denmark [11], and 1 in 160,000 in Norway [12]. The prevalence estimate in Scotland using more rigorous techniques is 1 in 24,000 [13] suggesting that under-reporting is a problem when estimating the prevalence of a rare disease. Based on reports that SLC2A1 mutations account for several forms of idiopathic epilepsy, and based on the recognition of an expanding GLUT1 DS phenotype spectrum, it has been suggested that there may be approximately 11,000 individuals afflicted with the disorder in the USA [14]. Studies analyzing the frequency of GLUT1 DS in various forms of epilepsy have shown that GLUT1 DS is responsible for 10–12% of absence epilepsy syndromes, 0.7–1% of idiopathic generalized epilepsies, 0–5% of myoclonic astatic epilepsy, 0.6% of pediatric refractory epilepsies, and 2.7% of unselected epilepsies with intellectual disability and/or various movement disorders [11, 12, 15–18].

GLUT1 DS Pathophysiology

GLUT1 DS results from haploinsufficiency due to inactivating mutations in the SLC2A1 gene and resulting decrease of the gene product, the GLUT1 protein. A wide spectrum of heterozygous mutations have been identified with the majority of cases representing de novo dominant mutations (about 90%). In about 10% of cases, the heterozygous mutations are transmitted as an autosomal-dominant trait, and only exceptionally (less than 1% of cases), as an autosomal-recessive trait [4, 19]. The GLUT1 protein transports glucose across the blood–brain barrier through a mechanism of facilitated diffusion. Consequently, deficiency of GLUT1 results in chronically reduced concentrations of glucose in the brain. We introduced the term “neuroglycopenia” to describe this metabolic state. In fact, gene dosage studies, when modeling glucose transport across the blood–brain barrier, predicted a 90% decrease in brain extracellular glucose concentration with a 50% deficiency of the SLC2A1 gene dosage [20].

Failure to meet the increasing postnatal energy demand of the rapidly growing brain correlates with the onset of seizures in infancy [21], and probably leads to an irreversible cerebral insult and subsequently to other symptoms later in life. While it is thought that the main pathophysiological mechanism of disease in GLUT1 DS is brain energy deficiency due to the reduced availability of glucose, the precise insult to the neuronal circuitry and the effects on the developing brain are still being examined. Studies in a mouse model of GLUT1 DS demonstrated evidence of a defect in the brain microvasculature network [22]. Repletion of the GLUT1 protein in this mouse model during neonatal and early postnatal life normalized angiogenesis and prevented disease, while repletion later in life was devoid of benefit and failed to mitigate major features of the GLUT1 DS phenotype [22]. These experiments support the hypothesis of a critical developmental window when glucose availability is essential for brain growth and network formation, and its deficiency during this critical period leads to permanent brain disturbance.

Further understanding of the physiopathology of GLUT1 DS comes from ¹⁸F-fluorodeoxyglucose positron emission tomographic studies in GLUT1 DS patients. These studies have shown a distinctive pattern of regional thalamocortical and cerebellar hypometabolism (Figure 13.1) [23, 24]. These findings support the notion that cerebral networks involving these regions are vulnerable to nutrient deficiency during postnatal development. It has been postulated that disturbed thalamic metabolism may influence epileptogenicity, while the disturbance of the cerebellar networks may lead to the incoordination and clumsiness that are seen, almost invariably, in GLUT1 DS. Additionally, given the role of thalamic nuclei in integrating information from different cortical association areas, it has been postulated that a disproportionate injury to thalamic metabolism correlates with the movement disorders seen in GLUT1 DS [25].

Figure 13.1 Global hypometabolism with regional vulnerability of temporal, thalamic, and cerebellar circuits in a patient with GLUT1 DS.

Clinical Presentation

GLUT1 DS is characterized by a spectrum of overlapping clinical phenotypes. The majority of patients present with the classic phenotype, that is a developmental encephalopathy characterized by infantile-onset refractory epilepsy, developmental delay, postnatal deceleration of head growth often leading to acquired microcephaly, variable degrees of cognitive impairment, and a complex motor disorder that includes gait ataxia, spasticity, dystonia, and paroxysmal neurological episodes [2–4, 6, 9, 26]. Within the non-classic phenotypes, clinical presentations are diverse and include: (1) benign idiopathic epilepsy syndromes resembling idiopathic epilepsies such as absence epilepsy, idiopathic generalized epilepsy, or myoclonic epilepsy; (2) neurodevelopmental disorders with highly variable motor and intellectual dysfunction; (3) paroxysmal exercise-induced dyskinesias with or without epilepsy; and (4) minimal phenotype with subtle symptoms. The latter is likely underdiagnosed and is often detected in a parent after the diagnosis of their more severely affected offspring [2, 4, 9, 12]. In such cases, the mildly affected parent may represent a mosaic state.

Given the complex spectrum of GLUT1 DS phenotypes, the overlapping clinical features, and the range of severity, a definite classification of GLUT1 DS according to clinical phenotype is not possible. Hully et al. proposed three clinical groups including: (1) classic, (2) epilepsy-dominant, and (3) movement-dominant [6]. Additionally, a useful way to analyze the variable clinical spectrum of GLUT1 DS has been proposed by Pearson et al. by dividing the neurological symptoms of GLUT1 DS into three domains: (1) seizures, (2) movement disorders, and (3) cognitive/behavioral disturbances (Figure 13.2). The classic phenotype of GLUT1 DS is associated with symptoms involving all three domains, while the non-classic phenotypes involve only one or two domains, and symptoms may be intermittent rather than persistent [4].

Figure 13.2 Neurological domains affected in GLUT1 DS.

Natural History

Long-term follow-up of patients with GLUT1 DS has clearly shown that the neurological manifestations evolve with age, likely illustrating the evolving regional pattern of cerebral glucose utilization throughout brain development (Figure 13.3) [5]. In the classic phenotype, onset of symptoms occurs within the first months of life in the majority of patients, while in a minority the onset is after the age of 2 years. At onset, the main clinical manifestation in two-thirds of patients is epilepsy [7]. The second most common initial clinical event in infants is a specific and characteristic type of episodic eye–head movement abnormality that is reported in more than one-third of patients [7, 8]. Recognition of these episodes may be a clue for the diagnosis (see below). Other symptoms in infancy include behavioral or autonomic changes such as paroxysmal breath-holding or episodes of disturbed alertness. After the age of 1 year, autonomic changes and eye movement abnormalities are much less common, indicating that these manifestations are dependent on the developmental state [7].

Figure 13.3 GLUT1 DS symptom prevalence by developmental epoch (Alter AS, Engelstad K, Hinton VJ, Montes J, Pearson TS, Akman CI, et al. Long-term clinical course of Glut1 deficiency syndrome. J Child Neurol. 2015;30(2):160–9.)

Epilepsy in GLUT1 DS reaches its peak in infancy and then wanes during childhood, with seizures becoming less frequent or even disappearing in some patients. Seizure semiology evolves over time; focal seizures are more frequent during infancy, atypical absences and myoclonic seizures start at 24 months, and generalized tonic–clonic seizures typically appear after 3 years of age [6]. Furthermore, developmental delay, ataxia, and microcephaly emerge in infancy or early childhood and remain present thereafter. Dystonia is the only symptom with continually increasing frequency throughout development, emerging by late childhood or adolescence [5]. Paroxysmal neurological events tend to start in early childhood and gradually improve as patients grow older, and in some, the events may disappear [27–31]. Additionally, through a web-based registry available to patients worldwide, it has been noted that 18% of GLUT1 DS patients report obsessive–compulsive traits that appear in childhood and tend to persist thereafter [9].

Diagnosis

Brain imaging in GLUT1 DS either is normal or shows slight brain atrophy, and in one-quarter of cases includes white matter abnormalities, including focal or diffuse supratentorial hyperintensities, prominence of perivascular Virchow–Robin spaces, and delayed myelination [2, 6, 9]. Positron emission tomography scanning is informative and shows a distinctive regional pattern of glucose hypometabolism: global reduction with enhanced regional vulnerability of thalamic, cerebellar, and mesial temporal regions. The basal ganglia often appear to have “increased metabolism” relative to the adjacent thalamic hypometabolism. This is a distinctive pattern consistent with GLUT1 DS (Figure 13.1) [23, 24]. EEG recordings may show generalized spike and wave discharges, diffuse slowing, or focal changes, and often are normal interictally [32, 33].

The distinctive biomarker of the disease is a low CSF glucose concentration (<40 mg/dL or 2.2 mmol/L) in the presence of normoglycemia, with a CSF:blood glucose ratio commonly less than 0.4. CSF glucose values of 41–52 mg/dL may be seen in milder phenotypes [2, 4]. CSF glucose values of less than 60 mg/dL (3.3 mmol/L) should be viewed as probably abnormal, and values less than 40 mg/dL are clearly abnormal. An important caveat is the importance of a simultaneous measurement of CSF lactate. On occasion, low CSF glucose values are seen in patients with mitochondrial diseases but the CSF lactate values distinguish the two “cerebral energy failure” syndromes. The CSF lactate is low normal or abnormally low in GLUT1 DS, and is elevated in mitochondrial diseases.

In our experience, about two-thirds of patients with a clinical presentation consistent with the classic phenotype and low CSF glucose and lactate values have decreased glucose uptake in vitro by isolated fresh erythrocytes [1, 2, 34]. Almost all patients with a decreased erythrocyte glucose uptake will have a disease-causing variant in the SLC2A1 gene. Conversely, almost all patients with a normal uptake assay will have normal molecular sequencing of the SLC2A1 gene [34].

The clinical diagnosis is confirmed with the detection of disease-causing variants in the SLC2A1 gene. However, in approximately 10% of clinically suspected cases, molecular studies fail to detect any mutation [9, 35]. Phenotypic severity is partially explained by the genotype. Patients with missense or splice site mutations tend to have better outcomes than those with deletions or nonsense mutations [2, 3, 6, 34, 36]. The classic phenotype generally occurs de novo, while milder phenotypes are transmitted in an autosomal-dominant or, rarely, an autosomal-recessive manner [19].

Movement Disorders in GLUT1 DS

Motor symptoms are a characteristic feature of both the classic and non-classic phenotypes of GLUT1 DS. These disturbances are seen in the majority of cases, and may be a key clue to the diagnosis [2–6, 9, 13, 25, 26, 30] (Box 13.1). Movement abnormalities in GLUT1 DS are highly variable. The reported frequency of the different motor disorders in GLUT1 DS is variable, likely due to ascertainment bias. Patients typically have more than one motor abnormality [2–4, 25, 26, 31, 37]. The most common motor symptom is a spastic–ataxic gait disorder that usually is recognized between late infancy and early childhood, and reflects combined pyramidal-tract and cerebellar dysfunction. Variable extrapyramidal symptoms, such as dystonia and chorea, are also characteristic and emerge later in childhood or adolescence, superimposed on the chronic pyramidal-tract and cerebellar disturbances [4–6]. Additionally, GLUT1 DS patients may suffer from paroxysmal neurological symptoms that are not epileptic in nature [25]. The phenomenology of these paroxysmal events is quite variable and often involves some type of motor disturbance. In some patients, these paroxysmal events may be the only obvious clinical manifestation [38]. Motor disturbances in GLUT1 DS can be divided into two major categories: (1) persistent movement disorders and (2) paroxysmal movement disorders (Box 13.1).

Paroxysmal Movement Disorders

Paroxysmal non-epileptic intermittent neurological symptoms, often with prominent motor manifestations, occur throughout the whole phenotypic spectrum in GLUT1 DS. In the literature, these events may also be referred to as intermittent or episodic. The frequency of paroxysmal events in GLUT1 DS ranges from 30% to 59% of cases [3, 25, 26, 31]. Although paroxysmal events occur throughout the severity spectrum, it is generally accepted that these signs constitute the main clinical signature of the milder GLUT1 DS forms [28, 38].

Insufficient energy supply to meet demand, possibly leading to synaptic dysfunction, is a proposed mechanism underlying paroxysmal events in GLUT1 DS. Consistent with this hypothesis, precipitating factors of paroxysmal events in GLUT1 DS include conditions with increased energy demand, such as the post-absorptive state (upon awakening, or before meals), fasting, exercise, and vigorous physical activity. Other frequent factors are emotional stress, fever, fatigue, or poor ketogenic diet compliance. Sleep deprivation, temperature changes, and drug-associated factors (e.g. phenobarbital, clonazepam, theophylline) have also been reported. Occasionally, no precipitants are recognized. The most frequent mitigating factors are eating, carbohydrate intake, and resting [3, 6, 9, 15, 25, 26, 28, 29, 31, 38, 42].

The clinical manifestations of GLUT1 DS-associated paroxysmal events are very variable. However, they tend to be stereotyped in each patient. Nosologically, they do not appear to be epileptic in nature. Some patients may experience prominent dysphoria and emotional lability during the events, while others experience confusion or somnolence. The possibility that these episodes may represent a type of focal seizure that is not detectable by scalp EEG has been considered, but factors that argue against this possibility include preserved alertness, the absence of other typical clinical manifestations of seizures, and a normal ictal EEG [25]. Non-motor paroxysmal events may also occur. Examples include migraine headaches, episodes of behavioral and emotional disturbances, cyclical vomiting, or acute sleep episodes [9, 12, 25, 26, 30, 31].

Episodes may start gradually or explosively. When gradual, the episodes present with prominent worsening of the baseline neurological status. In general, patients with the classic phenotype tend to manifest multiple types of paroxysmal events, whereas in non-classic phenotypes patients tend to manifest 1 or 2 types. The duration of episodes ranges from minutes to hours and occasionally days, with the more explosive events being shorter in duration. The frequency ranges from daily, to weekly, to monthly or every few months [6, 9, 25–28, 31, 38, 39, 42, 43, 46, 47].

In the classic phenotype, paroxysmal movement disorders tend to develop later in childhood or during adolescence, as the seizures become less prominent or disappear. In the non-classic phenotypes episodes tend to start in the early or late childhood ages. In general, patients exhibit gradual improvement as they get older, and in some cases, the events may disappear entirely, regardless of whether the patient adheres to the ketogenic diet [5, 6, 9, 26–31, 38, 39, 42, 45]. Paroxysmal events in GLUT1 DS may be categorized in five main types based on their clinical presentation: (1) paroxysmal events with major motor dysfunction; (2) paroxysmal exercised-induced dyskinesia (PED); (3) paroxysmal eye–head movements; (4) paroxysmal events with complex neurological symptoms, and (5) other paroxysmal events

Paroxysmal Events with Major Motor Dysfunction

This group of paroxysmal events includes intermittent episodes of weakness, episodes of ataxia, and episodes of non-kinesigenic dyskinesias. Intermittent episodes of weakness, manifesting as paraparesis, tetraparesis, hemiparesis, or monoparesis, are reported in 29–50% of GLUT1 DS patients [6, 9, 26, 46, 48]. Sudden total body paralysis mimicking periodic paralysis can also occur [15, 25, 31, 38]. The underlying pathophysiology for these episodes of transient neurological symptoms is not certain. Imaging abnormalities are consistent with focal cerebral hypoperfusion [48]. Two mechanisms for this phenomenon have been proposed: hypometabolism related to insufficient glucose supply in the central nervous system, and cerebral blood vessel dysfunction and susceptibility to transient vasospasm. The latter is supported by the known abundance of GLUT1 transporters in cerebral endothelial cells, the developmental impairment of cerebral angiogenesis, and the resulting diminution of brain microvasculature in a mouse model of SLC1A2 haploinsufficiency [22].

Occasionally the pattern of hemiplegic episodes and accompanying clinical features in patients with GLUT1 DS can mimic the syndrome of alternating hemiplegia of childhood [9, 49, 50]. However, in contrast to classic alternating hemiplegia of childhood, the age of presentation of the atypical GLUT1 DS-associated attacks is generally older, there is no associated prominent autonomic or bulbar dysfunction during the attacks, and the episodes are often precipitated by fasting or exercise and mitigated by food, especially carbohydrates. Paroxysmal non-kinesigenic dyskinesia episodes in GLUT1 DS manifest either with chorea or dystonia often involving the limbs, and at times the axial or the orofacial musculature [12, 25, 26, 30, 31]. Paroxysmal episodes of ataxia can also occur, and in some, the episodes may be reminiscent of episodic ataxia [2, 3, 15, 27, 51].

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