Clinical and genetic characteristics of glucose transporter 1 deficiency syndrome in a large cohort of Chinese patients

The SLC2A1 gene, located on chromosome 1p34.2, encodes glucose transporter protein 1 (GLUT1), which facilitates glucose transport across the blood–brain barrier into neurons and glial cells. Mutations in SLC2A1 result in either dysfunction or reduced expression of GLUT1, impairing glucose delivery to the brain. This condition, known as GLUT1 deficiency syndrome (Glut1DS), was first described by De Vivo in 1991 [1]. Characteristic symptoms include early onset drug-resistant epilepsy, developmental delay, spasticity, ataxia, and dystonia. Dysarthria and speech impairment are also significant clinical features of Glut1DS. To date, over 500 cases have been reported globally [2]. The first Chinese case, diagnosed by the Department of Pediatrics at Peking University First Hospital, was reported in 2012 [3]. The phenotypic spectrum of Glut1DS has expanded to include paroxysmal exercise-induced dyskinesia (PED), complex movement disorders, and intellectual disability. Prevalence estimates range from 1.65 to 4.13 per 100,000 live births in Europe and North America [4, 5]. Low cerebrospinal fluid (CSF) glucose levels with normal blood glucose levels are key diagnostic markers, and pathogenic SLC2A1 variants confirm the diagnosis. Ketogenic diet therapy is the first-line intervention for Glut1DS, significantly controlling seizures, improving motor and cognitive impairments, and preventing irreversible brain damage from delayed treatment. However, due to its rarity, complex presentations, and potential for false-negative genetic results, diagnosing Glut1DS remains challenging. In China, limited research [6, 7] on Glut1DS has contributed to insufficient awareness and a lack of standardized diagnostic and treatment guidelines. This study aims to summarize the clinical and genetic characteristics of Chinese Glut1DS patients and evaluate the outcomes and side effects of ketogenic diet therapy.

Glut1DS is a treatable neurogenetic metabolic disorder, with the majority of cases being sporadic. Approximately 90% of cases are caused by de novo heterozygous mutations in the SLC2A1 gene, following an autosomal dominant inheritance pattern, while a minority exhibit autosomal recessive inheritance [9]. Most familial cases demonstrate autosomal dominant inheritance with incomplete penetrance. The specific inheritance pattern depends on the relative pathogenicity of SLC2A1 mutations and the degree of haploinsufficiency. In our cohort, familial cases accounted for 12.5% with autosomal dominant inheritance. Missense mutations were the predominant type, with most SLC2A1 mutations inherited paternally. Probands generally exhibited more severe symptoms with earlier onset compared to their parents, who are often mildly symptomatic or asymptomatic carriers. This is understandable, as severely affected individuals tend not to have children, whereas asymptomatic patients may pass on the condition.

Glut1DS manifests in two major clinical phenotypes: classic and non-classic. The classic type constitutes approximately 90% of cases, with early onset (within 1 to 6 months after birth) and late-onset (> 2 years) subcategories [10]. The non-classic phenotype, accounting for approximately 10% of cases, typically has later onset and a milder presentation, often including PED with or without seizures, paroxysmal or persistent movement disorders with episodic worsening, and developmental delays. In our cohort, classic cases accounted for 70%, while non-classic cases accounted for 30%, underscoring how advancements in next-generation sequencing have expanded the spectrum of clinical phenotypes by identifying atypical cases.

The clinical features of Glut1DS are age-specific, with episodic eye–head movements and seizures often presenting in infancy, followed by developmental delays, movement disorders, and ataxia emerging later. In adolescent and adult patients, movement disorders are the most frequently reported symptoms [8]. Leary et al. [11] reported that generalized tonic–clonic and absence seizures were the most frequent types in the cohort. Early onset absence epilepsy (before four years of age), myoclonic–atonic epilepsy, idiopathic generalized epilepsy, childhood absence epilepsy, and eyelid myoclonia epilepsy [12] could be associated with pathogenic SLC2A1 mutations. Additionally, patients with Glut1DS can experience epileptic spasms. Among our cohort, 77% (69/90) of patients experienced seizures, with 36% (25/69) exhibiting two or more seizure types. Generalized seizures (64%, 44/69) were more prevalent than focal seizures (48%, 33/69). Generalized tonic–clonic and myoclonic seizures predominated, followed by absence, atonic, generalized tonic, myoclonic–atonic seizures, and eyelid myoclonia. No spasms were observed in our cohort.

In pediatric patients, symptoms such as abnormal eye and head movements may precede seizure onset, typically within six months after birth. The eye movements are rapid, brief, multidirectional, and occur at intervals of 200–800 ms, often accompanied by frequent head movements in the same direction [13]. This unique paroxysmal eye–head movement, associated with the deficiency in the high energy demands of the developing visual system, represents a hallmark symptom in the early stages of Glut1DS, second only to seizures. Pearson et al. [13] found that 15 out of 18 cases presented with paroxysmal eye–head movements within the first six months of life, and seven out of eight continued to experience them until age six. Ten of 16 children exhibited these movements prior to the onset of seizures. The incidence of paroxysmal eye head movement in our cohort was 19%, which is lower than reported in the literature. This may be related to parental neglect during early stages of the disease. Clinicians should focus on the presence of this symptom when taking the medical history of a child with suspected symptoms.

Diagnostic markers of Glut1DS include diminished CSF glucose levels (< 2.8 mmol/L), with more than 90% of patients having levels < 2.2 mmol/L, a reduced CSF-to-blood glucose ratio (< 0.45 in most cases), and normal or slightly low lactate levels [8, 14]. Differential diagnoses include other conditions causing low CSF glucose, such as hypoglycemia, central nervous system (CNS) infections, genetic metabolic disorders, subarachnoid hemorrhage, and status epilepticus. Notably, disorders such as neurodevelopmental disorders with visual defects and brain anomalies caused by monoallelic HK1 variants should also be differentiated. Although HK1 variants may exhibit low CSF glucose levels similar to Glut1DS, HK1-associated NDD [15] are characterized by elevated CSF lactate levels. In our cohort, 90% (66/73) of patients exhibited low CSF glucose levels below 2.2 mmol/L, and 87% (62/73) showed a CSF-to-blood glucose ratio below 0.45, highlighting its critical role in diagnosis.

Glut1DS is primarily caused by pathogenic mutations in SLC2A1, with about 90% of patients harboring the mutations. Among these, 90% arise de novo, while 10% are inherited. The mutations include missense, deletions, insertions, splice-site, and nonsense variants (84%), with 13% consisting of single- or multi-exon deletions or complete gene deletions [10, 16]. Less common mutations, such as intronic and start codon variants, have also been reported. For patients with a strong clinical suspicion but negative results in exonic sequencing and copy-number variation testing, MLPA and non-coding region analyses should be considered [17]. Since the initial discovery of SLC2A1 mutations as the cause of Glut1DS by Seidner et al. [18] in 1998, more than 430 mutations have been identified. Mutation hotspots include Asn34, Gly91, Ser113, Arg126, Arg153, Arg264, Thr295, Arg330, and Arg333 [10, 19‐21]. In our cohort, the most frequently observed mutations were Arg333 (eight cases), Arg330 (six cases), Asn34 and Arg126 (three cases each), Arg153 (two cases), and Arg264 and Thr295 (one case each). Notably, high-frequency mutations specific to Chinese patients included Arg92 (three cases), Cys133 (two cases), and Met1 (two cases). The remaining 60 variants were unique to individual probands. Exon 4 represented a significant mutation hotspot, accounting for 24% of mutations globally [22] and 27% in our cohort. Additionally, 10% of patients in our study exhibited substantial fragment deletions.

The ketogenic diet is the first-line treatment for Glut1DS. A study in 2020 by Schwantje et al. [23] involving 270 Glut1DS patients, highlighted its efficacy: 83% of epileptic patients showed improvement, while 17% remained unchanged. Among 127 patients with movement disorders, 82% improved, 17% remained stable, and 1% worsened. For 58 patients with cognitive impairments, 59% improved, 40% remained stable, and 1% worsened. Seizures responded within days to weeks of ketogenic therapy initiation, with earlier treatment yielding better outcomes. Movement and cognitive impairments improved within months. Notably, these patients followed the classic ketogenic diet and the Modified Atkins diet. It appears that the efficacy of the classic ketogenic diet in controlling seizures is higher than that of the modified Atkins diet. In our cohort, 82% of patients achieved complete resolution of seizures following ketogenic diet therapy, while 7% experienced a seizure reduction of over 50%, 2% had a reduction of less than 50%, and 9% showed no improvement. Among 49 patients with movement disorders, 38% experienced complete resolution, 55% showed improvement, and 7% exhibited no change. The time required for symptom improvement ranged from 1 week to 6 months. Among 71 patients who adhered to the diet for over 6 months, 68% demonstrated cognitive and language improvements, while 32% showed no significant change. Cognitive improvements in our cohort exceeded previous findings, underscoring the need for stricter developmental scales in future evaluations.

For patients unresponsive to ketogenic therapy [24], alternative approaches have been or will be explored, including gene replacement therapy, GLUT1 protein supplementation [25], targeted compounds [26], zinc sulfate, sodium lactate [27], diazoxide [28], acetazolamide [29], and exchange transfusion [30]. However, these treatments remain experimental, and further validation is required.

In vitro studies [8] reveal that certain compounds, such as caffeine, phenobarbital, diazepam, valproate, ethanol, and chloral hydrate, inhibit glucose transport, whereas carbamazepine, phenytoin, topiramate, and zonisamide do not exhibit such effects. Hence, anticonvulsants lacking inhibitory properties should be preferred for Glut1DS patients with suboptimal responses to ketogenic therapy. Although valproate reduces GLUT1 activity in red blood cells by 20% to 30% in vitro, it was effective in controlling seizures in some patients in our cohort, highlighting discrepancies between in vitro and clinical outcomes [31]. Thus, valproate should be used cautiously, but should not be categorically contraindicated in Glut1DS management.

In conclusion, this study describes the phenotypic and genotypic characteristics of 90 patients with Glut1DS, expanding the clinical and genetic spectrum of the disorder. The ketogenic diet remains the first-line treatment and is generally well tolerated by patients. Early identification and diagnosis followed by the prompt initiation of a ketogenic diet can significantly improve prognosis. However, some children do not respond to the ketogenic diet, highlighting the need for further research into alternative therapies.