Glucose transporter type 1 deficiency syndrome (GLUT1DS) is a genetic condition associated with complex neurologic symptoms, including epilepsy. Ketogenic diet therapy (KDT) is considered the standard treatment for GLUT1DS. This retrospective study identified trends in treatment with KDT for patients with GLUT1DS to optimize the current standards of care.MethodsA retrospective chart review was performed to identify patients at a pediatric institution with GLUT1DS receiving the ketogenic diet.ResultsTwelve patients were identified; 10 met inclusion criteria. A classic ketogenic diet (cKD) with a 3:1 ratio provides effective support for patients in this sample.ConclusionResults of the study suggest that a 3:1 ratio of KDT, which may increase tolerance and adherence and reduce adverse effects, may be acceptable in patients with GLUT1DS.

Glucose transporter type 1 deficiency syndrome (Glut1DS) is a treatable neurogenetic metabolic disorder caused by pathogenic variants in the SLC2A1 gene. The relationship between genotype and phenotype has not been extensively studied in large cohorts within China. This study aimed to analyze the clinical and genetic characteristics and the genotype-phenotype correlation in Chinese children with Glut1DS. Clinical data of Glut1DS patients, including age of onset, clinical manifestations, cerebrospinal fluid (CSF) analysis, and SLC2A1 gene variants, were collected and analyzed. A total of 93 patients with Glut1DS were included, among whom 65 (70%) were classical phenotypes (including 55 early-onset classical cases and 10 late-onset classical cases), and 28 (30%) were non-classical phenotypes. Significant differences were observed among early-onset classical, late-onset classical, and non-classical groups in terms of age of onset (p < 0.001), episodic psychiatric/behavioral abnormalities (p = 0.012), CSF glucose levels (p < 0.001), and the ratio of CSF glucose to blood glucose (p = 0.003). Genetic variant analysis identified 40 previously reported and 32 novel SLC2A1 variants. These variants were classified into three types: Type A (missense and in-frame indel variants, n = 52), Type B (frameshift, nonsense, splicing site, and initiation codon variants, n = 32), and Type C (single/multiple exon or whole-gene deletions, n = 9). No statistically significant difference was found in the distribution of these three genotypes across early-onset classical, late-onset classical, and non-classical phenotype. However, there were differences in age of onset among the three genetic variant groups (p = 0.009), with Type A variants showing a later age of onset compared to Type B variants (p = 0.014). No significant differences were observed among the three variant groups regarding CSF glucose levels, the ratio of CSF glucose to blood glucose, or CSF lactate levels. Furthermore, patients with identical variants exhibited phenotypic variability, for example, among eight patients (9%) harboring the c.997C>T (p.Arg333Trp) variant, six had early-onset classical phenotypes, while two had non-classical phenotypes. Glut1DS predominantly manifests as the classical phenotype, with the early-onset classical phenotype presenting at the youngest age and exhibiting the most severe clinical symptoms. Patients with this type also showed lower CSF glucose levels and a lower CSF glucose to blood glucose ratio compared to other types. Missense and in-frame indel variants were associated with a later age of onset compared to other types of genetic variants. No significant correlations were found between genotype and clinical classification or CSF glucose levels.

Mutations in the SLC2A1 gene cause glucose transporter type 1 deficiency syndrome (Glut1DS). This study aimed to investigate the clinical and molecular genetics characteristics of Chinese patients with Glut1DS. The clinical data of patients with Glut1DS were analyzed retrospectively. SLC2A1 mutation analysis was performed using Sanger sequencing or next-generation sequencing (NGS). Multiplex ligation-dependent probe amplification (MLPA) was conducted in patients with negative results. A total of 90 patients were diagnosed with Glut1DS, including 63 (70%) classic type and 27 (30%) non-classic type. Seizures occurred in 69 patients (77%), movement disorders were observed in 58 (68%), and episodic eye-head movements were noted in 17 (19%). Cerebrospinal fluid (CSF) glucose levels were available for 73 patients (81%), ranging from 1.0 to 2.6 mmol/L (median 1.9 mmol/L), with 90% (66/73) of patients showing levels below 2.2 mmol/L. Additionally, CSF-to-blood glucose ratios measured in 71 patients (79%) ranged from 0.20 to 0.63 (median 0.37), with 87% (62/71) of patients having ratios below 0.45. Genetic analysis identified 69 variants of the SLC2A1 gene including 39 previously reported and 30 unreported variants. The two most common variants were c.997C > T (p.Arg333Trp) and c.988C > T (p.Arg330*). Following ketogenic diet therapy, seizures were controlled in 47 of 57 patients (82%), movement disorders resolved in 18 of 47 patients (38%), and improved in 26 of 47 patients (55%). The clinical manifestations of Glut1DS primarily include seizures, movement disorders, and developmental delay. Most affected children had CSF glucose levels below 2.2 mmol/L, with CSF-to-blood glucose ratios under 0.45. Two of the most common SLC2A1 variants were identified in our cohort. Ketogenic diet therapy was effective in controlling seizures, improving movement disorders, and was well tolerated.

Glucose transporter type 1 deficiency syndrome (GLUT1DS) is a disorder caused by variants in the SLC2A1 gene. Clinical features are heterogeneous, from the classic presentation to milder later-onset phenotypes. We describe the case of a male patient with adult-onset paroxysmal dyskinesia in a mild phenotype of GLUT1DS (NM_006516.4 c.998G > A, p. Arg333Gln).

To elucidate the clinical and genetic characteristics of familial cases with Glucose transporter type 1 deficiency syndrome (Glut1DS). A survey of family history was conducted on children (proband) with Glut1DS who had visited Peking University First Hospital between November 2008 and April 2024 by focusing on the clinical manifestations of family members. Peripheral venous blood (2 mL) was collected from the pediatric patients and their parents. Genomic DNA was extracted and sequenced subsequently. Sanger sequencing was performed to validate the identified variant sites of the SLC2A1 gene in the probands and their family members. The pathogenicity of suspected variants was analyzed according to the 2015 American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines for the Interpretation of Sequence Variants. The clinical features, auxiliary examinations, and mutational characteristics of family members with SLC2A1 variants were analyzed. This study has been approved by the Clinical Research Ethics Committee of Peking University First Hospital (Ethics No. 2021 Research 332). Among 87 cases with Glut1DS, 10 families with autosomal dominate inherited cases were identified, accounting for 11.0% of the cases. Of the 11 children, 8 were boys and 3 were girls. The onset of the disease had ranged from 3 months to 120 months (median 6 months), with 4 cases of early-onset classic type, 2 cases of late-onset classic type, and 5 cases of non-classic type. Six children had seizures, and 7 exhibited movement disorders. Seven children underwent developmental assessment, of which 3 had mild developmental delay, 2 were borderline, and 2 were normal. Nine children underwent lumbar puncture. The cerebrospinal fluid glucose levels ranged from 1.45 to 2.25 mmol/L (median 1.86 mmol/L), and the cerebrospinal fluid to blood glucose ratios ranged from 0.29 to 0.44 (median 0.35). Among the 8 fathers with SLC2A1 gene variants, 4 were asymptomatic, 2 developed paroxysmal exercise-induced movement disorders (PED) in childhood and adulthood, respectively. 1 had poor memory since childhood, 1 developed migraines during adolescence, and his sister was an asymptomatic carrier. The father with childhood-onset PED had a cerebrospinal fluid test with CSF glucose of 1.85 mmol/L. Of the 3 mothers with SLC2A1 gene mutations, 1 was an asymptomatic carrier; 2 developed PED in childhood and after the age of 20, respectively. The mother who developed PED in childhood also had psychomotor developmental delay. Genetic testing results revealed that among 10 families, 8 carried missense variants, 1 carried a nonsense variant, and 1 carried a small fragment insertion leading to a frameshift variant. Among the 11 cases, SLC2A1 gene variants in 8 children were inherited from their fathers, while in 3 cases, the variants were inherited from their mothers. The pathogenicity of the genetic variants was evaluated according to the Standards and Guidelines for the Interpretation of Sequence Variants published by the ACMG. Among the 8 variants identified in the 10 families, 4 were classified as pathogenic variants, 1 as likely pathogenic, and 3 as variants of uncertain significance (VUS). Four variant sites, including c.204_205insTCTC (p.V69fs), c.412G>C (p.G138R), c.431T>G (p.V144G), and c.875A>G (p.Y292C), were not previously reported in the literature. Among these, the latter three were categorized as VUS. Familial Glut1DS account for 11.0% of the cases in China, with the majority of SLC2A1 gene variants inherited from the fathers, predominantly missense mutations, and with an autosomal dominant inheritance pattern. Probands tend to have earlier onset and more severe symptoms than their parents, who often present with mild or no symptoms.