RARE DISEASE
Classic glucose transporter type 1 deficiency syndrome
Classic glucose transporter type 1 deficiency syndrome
Classic glucose transporter type 1 deficiency syndrome
Synonyms: Classic GLUT1 deficiency syndrome, Classic GLUT1-DS, De Vivo disease, Encephalopathy due to GLUT1 deficiency
Synonyms: Classic GLUT1 deficiency syndrome, Classic GLUT1-DS, De Vivo disease, Encephalopathy due to GLUT1 deficiency
Synonyms: Classic GLUT1 deficiency syndrome, Classic GLUT1-DS, De Vivo disease, Encephalopathy due to GLUT1 deficiency
Drug discovery
3
drugs
With orphan designations
Overview
Classic Glucose Transporter Type 1 Deficiency Syndrome (GLUT1-DS) – rare autosomal dominant neurometabolic disorder caused by SLC2A1 mutations, impairing glucose transport across the blood-brain barrier. Core features include infantile-onset epilepsy (e.g., absence, myoclonic-atonic seizures), acquired microcephaly, developmental delay, and paroxysmal movement disorders (ataxia, dystonia). Diagnosis relies on hypoglycorrhachia (CSF/blood glucose ratio <0.4) and genetic confirmation. Early ketogenic diet therapy improves seizures and motor symptoms but does not reverse cognitive deficits [1][2][6].
Burden
Neurological: Persistent intellectual disability, speech deficits, and movement disorders despite treatment [9][16].
Lifelong management: Ketogenic diet adherence challenges (18% non-compliance), with risks of atherosclerosis and bone demineralization [5][9].
Psychosocial impact: Developmental delays, therapy needs (physical, occupational), and caregiver strain [19][20].
Therapies
First-line: Ketogenic diet (≥90% fat calories) to bypass glucose dependency, improving seizures (83% efficacy) and movement disorders [5][9][16].
Avoidances: Phenobarbital, valproic acid (worsen symptoms) [6][8].
Emerging options: Gene therapy, triheptanoin, and ketone esters under investigation [5][17].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
144 drug discovery papers about Classic glucose transporter type 1 deficiency syndrome, with 1 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
144 drug discovery papers about Classic glucose transporter type 1 deficiency syndrome, with 1 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-03-15 | "Not always the magic bullet"-Insufficient seizure control by ketogenic dietary therapies in Glut1 Deficiency Syndrome.
Ketogenic dietary therapies (KDTs) are the treatment of choice for Glut1 Deficiency Syndrome (Glut1DS), providing dietary ketones as an alternative fuel to the brain and effectively controlling seizures. Recent evidence indicates insufficient seizure control in Glut1DS patients despite adequate KDT and ketosis. Fifty-three patients, diagnosed with Glut1DS and treated by KDT, were followed in a single-center outpatient clinic from 2000 to 2023. Epilepsy, present in 44 patients, was analyzed for seizure control, EEG changes, and potential correlations to clinical and genetic features. Epilepsy response to KDT was defined as a >90% seizure reduction on KDT monotherapy. On KDT monotherapy 27/44 (61%) patients became >90% seizure free, rated as responders. 17/44 were non-responders. Within this group, 10/17 patients responded to KDT plus antiseizure comedication. In 7 patients, KDT plus antiseizure comedication failed to control seizures. No correlations of seizure control to gender, age at start or type of KDT, or SLC2A1 variants were observed. In responders (n = 27), EEG epileptic activity, evident in 15/27 patients, improved on KDT in 5 patients. In non-responders (n = 17), EEG epileptic activity was evident in 14/17 and improved on KDT in 9 patients. EEG background slowing prior to KDT normalized in KDT in all responders (4/27), but in none of the non-responders (4/17). Epilepsy is a dominant feature of Glut1DS. KDT provides efficient seizure control, but failure to control epilepsy is more common than expected. KDT epilepsy response did not correlate with seizure type, clinical, or genetic features, emphasizing the complexity of this entity. Add-on antiseizure medication can be effective in some patients, without individual drug superiority. Epileptic activity on EEG did not prove a good marker for outcome, but reversible EEG background slowing on KDT might be predictive for favorable seizure control. Impaired glucose transport into the brain causes a brain energy crisis termed Glut1 Deficiency. Ketogenic diets mimic fasting, provide ketones as an alternative fuel, and effectively restore brain function. In our study, this worked for ca. 60% of patients. To our surprise, epilepsy persisted in about 40% of patients despite ketogenic diets for reasons unknown. Additional medication against epilepsy randomly helped in some patients. We analyzed many parameters without finding obvious explanations. Electrical brain activity improvement on ketogenic diets might be a future marker for efficient seizure control.
2026-02-05 | In search of "what really matters": Insights from a web-based survey on Patient-Centered Outcomes in GLUT1DS.
Glucose Transporter Type 1 Deficiency Syndrome (GLUT1DS) is a rare genetic disorder caused by mutations in the SLC2A1 gene. Core symptoms include epilepsy, movement disorders, and neurocognitive impairment. While ketogenic dietary therapies remain the gold standard for treatment, challenges persist in ensuring adherence, with varying responses across patients. Limited knowledge exists regarding the broader impact of GLUT1DS on patients and caregivers, highlighting the need for a patient-centered care approach. In collaboration with the Italian GLUT1DS Association, a survey was developed to assess Patient-Centered Outcomes, covering demographic data, symptoms, daily life challenges and treatment experiences. The survey was distributed online to patients and caregivers, yielding 83 responses. Data were analyzed using descriptive statistics, t-tests, and chi-square analyses to explore the relationship between core symptoms and broader life impacts. Movement disorders were identified as a major barrier to daily activities, particularly leisure and social engagement. Cognitive impairments were linked to academic struggles, and speech/language impairments, especially dysarthria, emerged as a significant burden. Sleep disturbances were common, with restless sleep in younger patients and excessive daytime sleepiness in older ones. Although ketogenic therapies improved energy and memory, challenges in patient autonomy persisted. Delayed disease awareness and difficulty with educational and occupational transitions were also reported. GLUT1DS has a broad impact beyond core symptoms. A comprehensive, multidisciplinary care approach is essential for optimizing quality of life. These findings offer critical insights for refining clinical management strategies and shaping future research on patient-reported outcomes in GLUT1DS.
2025-09-30 | Toward a working definition of ketogenic diet resistance in GLUT1 deficiency syndrome.
The ketogenic diet (KD) is the standard treatment for glucose transporter type 1 deficiency syndrome (GLUT1-DS), typically yielding seizure reduction and cognitive/motor gains. However, a small subset of patients shows limited or no clinical benefit. This phenomenon, referred to as "KD resistance," remains poorly understood and inconsistently defined. We propose a working definition, outline evaluation domains, summarize candidate mechanisms, and indicate management steps. Narrative review of published evidence and expert opinion across clinical, biochemical, EEG, and adherence domains. KD resistance may be considered when all are present: (1) confirmed therapeutic ketosis (serial blood β-hydroxybutyrate ≥2.0-2.5 mmol/L on repeated measurements); (2) adequate dietary adherence verified by dietetic assessment and, when available, validated tools; (3) sufficient trial duration (≥3 months; longer for primarily cognitive/motor goals); and (4) lack of meaningful improvement on symptom-relevant standardized measures. EEG interictal epileptiform discharge burden can be used as an adjunct marker but is not required. KD resistance may involve several dimensions: failure to achieve therapeutic ketosis, lack of symptom improvement despite confirmed ketosis, or challenges with adherence that limit efficacy. Possible contributing factors include genotypic variability in SLC2A1, mitochondrial dysfunction, impaired blood-brain barrier transport, hormonal influences, and epigenetic regulation. We outline a multidomain evaluation framework with suggested metrics, summarize candidate mechanisms (ketone transport/utilization, mitochondrial function, neurotransmission, ion channels/neuromodulators, inflammation/oxidative stress, epigenetic regulation), and indicate when to introduce a KD-compatible anti-seizure medication. The proposed definition and framework standardize terminology and reporting, guide decisions for suboptimal responders, and set priorities for multicenter validation.
2025-09-04 | Adult-onset non-kinesigenic paroxysmal dyskinesia in GLUT1 deficiency syndrome.
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).
2025-06-19 | Structural Insights into the Substrate Egress Pathways Explains Specificity and Inhibition of Human Glucose Transporters (GLUT1 and GLUT9).
Glucose transporters (GLUTs) play critical roles in cellular energy homeostasis and substrate-specific transport. Dysfunctional mutations can cause GLUT1 deficiency syndrome, and excessive expression of GLUT1 is linked to cancer progression, while abnormal regulation of urate transport by GLUT9 is associated with hyperuricemia and gout. In this study, machine-learning-driven molecular dynamics simulations have been employed to investigate the mechanistic insights into the substrate egress pathways of GLUT1 and GLUT9, including the inhibition mechanism of GLUT9 by apigenin. Our findings reveal that intracellular helices play a crucial role in facilitating the transition from inward-closed to -open conformations in both transporters. Additionally, aromatic residues, F291 and W388 in GLUT1 and W336 and F435 in GLUT9, are identified as key mediators of conformational changes. Analysis of substrate exit pathways provides mechanistic insights into transport profiles and aligns with clinically observed mutations. Furthermore, the inhibitory effect of apigenin on GLUT9 is shown to arise from steric hindrance due to increased substrate size rather than stable interactions. These findings enhance our understanding of GLUT transporter dynamics and highlight the potential of targeting substrate pathways for therapeutic intervention.
gene therapies
2025-04-16 | A transgene harboring the human Glucose Transporter1 (GLUT1) gene locus ameliorates disease in GLUT1 deficiency syndrome model mice.
Proper brain function relies on an adequate supply of energy - mainly glucose - to power neuronal activity. Delivery of this nutrient to the neuropil is mediated by the Glucose Transporter1 (GLUT1) protein. Perturbing glucose supply to the brain is profoundly damaging and exemplified by the neurodevelopmental disorder, GLUT1 deficiency syndrome (GLUT1DS). Resulting from haploinsufficiency of the SLC2A1 (GLUT1) gene, GLUT1DS is characterized by intractable infantile-onset seizures and a disabling movement disorder. Ketogenic diets, which supply the brain with an alternate energy source, ketone bodies, are currently the preferred therapeutic option for Glut1DS patients but do not address the underlying cause - low brain glucose - of the disease. One intuitively appealing therapeutic strategy that does, involves restoring GLUT1 levels to the patient brain. Here, we demonstrate that transgenic expression of the human GLUT1 genomic locus in a mouse model of GLUT1DS raises brain GLUT1 levels and reduces disease burden. Augmenting GLUT1 levels in mutants correspondingly raised cerebrospinal fluid (CSF) glucose levels, improved motor performance and reduced the frequency of seizures characteristically observed in GLUT1DS. Interestingly, the increased GLUT1 in mutants harboring the human GLUT1 locus was at least partly the result of an increase in murine Slc2a1 (Glut1) activity, most likely the effect of a long non-coding RNA (lncRNA) embedded in the human transgene. Collectively, our work has not only shown that repleting human GLUT1 mitigates GLUT1DS but also has yielded transgenic mice that constitute a useful tool to test and optimize clinically promising agents designed to stimulate this gene for therapeutic purposes.
2024-05-07 | GLUT-1DS resistant to ketogenic diet: from clinical feature to in silico analysis. An exemplificative case report with a literature review.
Glucose transporter type 1 deficiency syndrome (GLUT-1DS) is characterized by alterations in glucose translocation through the blood-brain barrier (BBB) due to mutation involving the GLUT-1 transporter. The fundamental therapy is ketogenic diet (KD) that provide an alternative energetic substrate - ketone bodies that across the BBB via MCT-1 - for the brain. Symptoms are various and include intractable seizure, acquired microcephalia, abnormal ocular movement, movement disorder, and neurodevelopment delay secondary to an energetic crisis for persistent neuroglycopenia. KD is extremely effective in controlling epileptic seizures and has a positive impact on movement disorders and cognitive impairment. Cases of KD resistance are rare, and only a few of them are reported in the literature, all regarding seizure. Our study describes a peculiar case of GLUT-1DS due to a new deletion involving the first codon of SLC2A1 gene determining a loss of function with a resistance to KD admitted to hospital due to intractable episodes of dystonia. This patient presented a worsening of symptomatology at higher ketonemia values but without hyperketosis and showed a complete resolution of symptomatology while maintaining low ketonemia values. Our study proposes an in-silico genomic and proteomic analysis aimed at explaining the atypical response to KD exhibited by our patient. In this way, we propose a new clinical and research approach based on precision medicine and molecular modelling to be applied to patients with GLUT-1DS resistant to first-line treatment with ketogenic diet by in silico study of genetic and altered protein product.
2017-01-20 | Brain microvasculature defects and Glut1 deficiency syndrome averted by early repletion of the glucose transporter-1 protein
Haploinsufficiency of the SLC2A1 gene and paucity of its translated product, the glucose transporter-1 (Glut1) protein, disrupt brain function and cause the neurodevelopmental disorder, Glut1 deficiency syndrome (Glut1 DS). There is little to suggest how reduced Glut1 causes cognitive dysfunction and no optimal treatment for Glut1 DS. We used model mice to demonstrate that low Glut1 protein arrests cerebral angiogenesis, resulting in a profound diminution of the brain microvasculature without compromising the blood-brain barrier. Studies to define the temporal requirements for Glut1 reveal that pre-symptomatic, AAV9-mediated repletion of the protein averts brain microvasculature defects and prevents disease, whereas augmenting the protein late, during adulthood, is devoid of benefit. Still, treatment following symptom onset can be effective; Glut1 repletion in early-symptomatic mutants that have experienced sustained periods of low brain glucose nevertheless restores the cerebral microvasculature and ameliorates disease. Timely Glut1 repletion may thus constitute an effective treatment for Glut1 DS.
cell therapies
2024-11-04 | Generation of human induced pluripotent stem cell lines derived from two glucose transporter 1 deficiency syndrome patients.
Glucose transporter 1 deficiency syndrome (GLUT1DS), caused by impaired glucose transport at the blood-brain barriers, leads to various central nervous system dysfunctions. A comprehensive understanding of the underlying disease pathogenesis is still lacking. In this study, we have generated GLUT1DS-specific human induced pluripotent stem cells (hiPSCs) derived from two patients. These established GLUT1DS-specific hiPSC lines showed self-renewal and pluripotency and carried heterozygous frameshift or missense mutations in the responsible SLC2A1 gene. These novel cell resources provide new avenues for understanding disease mechanisms and developing new therapies for GLUT1DS.
2023-03-04 | Red blood cells as glucose carriers to the human brain: Modulation of cerebral activity by erythrocyte exchange transfusion in Glut1 deficiency (G1D).
Red blood cells circulating through the brain are briefly but closely apposed to the capillary endothelium. We hypothesized that this contact provides a nearly direct pathway for metabolic substrate transfer to neural cells that complements the better characterized plasma to endothelium transfer. While brain function is considered independent of normal fluctuations in blood glucose concentration, this is not borne out by persons with glucose transporter I (GLUT1) deficiency (G1D). In them, encephalopathy is often ameliorated by meal or carbohydrate administration, and this enabled us to test our hypothesis: Since red blood cells contain glucose, and since the red cells of G1D individuals are also deficient in GLUT1, replacing them with normal donor cells via exchange transfusion could augment erythrocyte to neural cell glucose transport via mass action in the setting of unaltered erythrocyte count or plasma glucose abundance. This motivated us to perform red blood cell exchange in 3 G1D persons. There were rapid, favorable and unprecedented changes in cognitive, electroencephalographic and quality-of-life measures. The hypothesized transfer mechanism was further substantiated by in vitro measurement of direct erythrocyte to endothelial cell glucose flux. The results also indicate that the adult intellect is capable of significant enhancement without deliberate practice. ClinicalTrials.gov registration: NCT04137692 https://clinicaltrials.gov/ct2/show/NCT04137692.
small molecules
2026-03-15 | "Not always the magic bullet"-Insufficient seizure control by ketogenic dietary therapies in Glut1 Deficiency Syndrome.
Ketogenic dietary therapies (KDTs) are the treatment of choice for Glut1 Deficiency Syndrome (Glut1DS), providing dietary ketones as an alternative fuel to the brain and effectively controlling seizures. Recent evidence indicates insufficient seizure control in Glut1DS patients despite adequate KDT and ketosis. Fifty-three patients, diagnosed with Glut1DS and treated by KDT, were followed in a single-center outpatient clinic from 2000 to 2023. Epilepsy, present in 44 patients, was analyzed for seizure control, EEG changes, and potential correlations to clinical and genetic features. Epilepsy response to KDT was defined as a >90% seizure reduction on KDT monotherapy. On KDT monotherapy 27/44 (61%) patients became >90% seizure free, rated as responders. 17/44 were non-responders. Within this group, 10/17 patients responded to KDT plus antiseizure comedication. In 7 patients, KDT plus antiseizure comedication failed to control seizures. No correlations of seizure control to gender, age at start or type of KDT, or SLC2A1 variants were observed. In responders (n = 27), EEG epileptic activity, evident in 15/27 patients, improved on KDT in 5 patients. In non-responders (n = 17), EEG epileptic activity was evident in 14/17 and improved on KDT in 9 patients. EEG background slowing prior to KDT normalized in KDT in all responders (4/27), but in none of the non-responders (4/17). Epilepsy is a dominant feature of Glut1DS. KDT provides efficient seizure control, but failure to control epilepsy is more common than expected. KDT epilepsy response did not correlate with seizure type, clinical, or genetic features, emphasizing the complexity of this entity. Add-on antiseizure medication can be effective in some patients, without individual drug superiority. Epileptic activity on EEG did not prove a good marker for outcome, but reversible EEG background slowing on KDT might be predictive for favorable seizure control. Impaired glucose transport into the brain causes a brain energy crisis termed Glut1 Deficiency. Ketogenic diets mimic fasting, provide ketones as an alternative fuel, and effectively restore brain function. In our study, this worked for ca. 60% of patients. To our surprise, epilepsy persisted in about 40% of patients despite ketogenic diets for reasons unknown. Additional medication against epilepsy randomly helped in some patients. We analyzed many parameters without finding obvious explanations. Electrical brain activity improvement on ketogenic diets might be a future marker for efficient seizure control.
2026-02-05 | In search of "what really matters": Insights from a web-based survey on Patient-Centered Outcomes in GLUT1DS.
Glucose Transporter Type 1 Deficiency Syndrome (GLUT1DS) is a rare genetic disorder caused by mutations in the SLC2A1 gene. Core symptoms include epilepsy, movement disorders, and neurocognitive impairment. While ketogenic dietary therapies remain the gold standard for treatment, challenges persist in ensuring adherence, with varying responses across patients. Limited knowledge exists regarding the broader impact of GLUT1DS on patients and caregivers, highlighting the need for a patient-centered care approach. In collaboration with the Italian GLUT1DS Association, a survey was developed to assess Patient-Centered Outcomes, covering demographic data, symptoms, daily life challenges and treatment experiences. The survey was distributed online to patients and caregivers, yielding 83 responses. Data were analyzed using descriptive statistics, t-tests, and chi-square analyses to explore the relationship between core symptoms and broader life impacts. Movement disorders were identified as a major barrier to daily activities, particularly leisure and social engagement. Cognitive impairments were linked to academic struggles, and speech/language impairments, especially dysarthria, emerged as a significant burden. Sleep disturbances were common, with restless sleep in younger patients and excessive daytime sleepiness in older ones. Although ketogenic therapies improved energy and memory, challenges in patient autonomy persisted. Delayed disease awareness and difficulty with educational and occupational transitions were also reported. GLUT1DS has a broad impact beyond core symptoms. A comprehensive, multidisciplinary care approach is essential for optimizing quality of life. These findings offer critical insights for refining clinical management strategies and shaping future research on patient-reported outcomes in GLUT1DS.
2025-09-30 | Toward a working definition of ketogenic diet resistance in GLUT1 deficiency syndrome.
The ketogenic diet (KD) is the standard treatment for glucose transporter type 1 deficiency syndrome (GLUT1-DS), typically yielding seizure reduction and cognitive/motor gains. However, a small subset of patients shows limited or no clinical benefit. This phenomenon, referred to as "KD resistance," remains poorly understood and inconsistently defined. We propose a working definition, outline evaluation domains, summarize candidate mechanisms, and indicate management steps. Narrative review of published evidence and expert opinion across clinical, biochemical, EEG, and adherence domains. KD resistance may be considered when all are present: (1) confirmed therapeutic ketosis (serial blood β-hydroxybutyrate ≥2.0-2.5 mmol/L on repeated measurements); (2) adequate dietary adherence verified by dietetic assessment and, when available, validated tools; (3) sufficient trial duration (≥3 months; longer for primarily cognitive/motor goals); and (4) lack of meaningful improvement on symptom-relevant standardized measures. EEG interictal epileptiform discharge burden can be used as an adjunct marker but is not required. KD resistance may involve several dimensions: failure to achieve therapeutic ketosis, lack of symptom improvement despite confirmed ketosis, or challenges with adherence that limit efficacy. Possible contributing factors include genotypic variability in SLC2A1, mitochondrial dysfunction, impaired blood-brain barrier transport, hormonal influences, and epigenetic regulation. We outline a multidomain evaluation framework with suggested metrics, summarize candidate mechanisms (ketone transport/utilization, mitochondrial function, neurotransmission, ion channels/neuromodulators, inflammation/oxidative stress, epigenetic regulation), and indicate when to introduce a KD-compatible anti-seizure medication. The proposed definition and framework standardize terminology and reporting, guide decisions for suboptimal responders, and set priorities for multicenter validation.
2025-09-04 | Adult-onset non-kinesigenic paroxysmal dyskinesia in GLUT1 deficiency syndrome.
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).
2025-06-19 | Structural Insights into the Substrate Egress Pathways Explains Specificity and Inhibition of Human Glucose Transporters (GLUT1 and GLUT9).
Glucose transporters (GLUTs) play critical roles in cellular energy homeostasis and substrate-specific transport. Dysfunctional mutations can cause GLUT1 deficiency syndrome, and excessive expression of GLUT1 is linked to cancer progression, while abnormal regulation of urate transport by GLUT9 is associated with hyperuricemia and gout. In this study, machine-learning-driven molecular dynamics simulations have been employed to investigate the mechanistic insights into the substrate egress pathways of GLUT1 and GLUT9, including the inhibition mechanism of GLUT9 by apigenin. Our findings reveal that intracellular helices play a crucial role in facilitating the transition from inward-closed to -open conformations in both transporters. Additionally, aromatic residues, F291 and W388 in GLUT1 and W336 and F435 in GLUT9, are identified as key mediators of conformational changes. Analysis of substrate exit pathways provides mechanistic insights into transport profiles and aligns with clinically observed mutations. Furthermore, the inhibitory effect of apigenin on GLUT9 is shown to arise from steric hindrance due to increased substrate size rather than stable interactions. These findings enhance our understanding of GLUT transporter dynamics and highlight the potential of targeting substrate pathways for therapeutic intervention.
gene therapies
2025-04-16 | A transgene harboring the human Glucose Transporter1 (GLUT1) gene locus ameliorates disease in GLUT1 deficiency syndrome model mice.
Proper brain function relies on an adequate supply of energy - mainly glucose - to power neuronal activity. Delivery of this nutrient to the neuropil is mediated by the Glucose Transporter1 (GLUT1) protein. Perturbing glucose supply to the brain is profoundly damaging and exemplified by the neurodevelopmental disorder, GLUT1 deficiency syndrome (GLUT1DS). Resulting from haploinsufficiency of the SLC2A1 (GLUT1) gene, GLUT1DS is characterized by intractable infantile-onset seizures and a disabling movement disorder. Ketogenic diets, which supply the brain with an alternate energy source, ketone bodies, are currently the preferred therapeutic option for Glut1DS patients but do not address the underlying cause - low brain glucose - of the disease. One intuitively appealing therapeutic strategy that does, involves restoring GLUT1 levels to the patient brain. Here, we demonstrate that transgenic expression of the human GLUT1 genomic locus in a mouse model of GLUT1DS raises brain GLUT1 levels and reduces disease burden. Augmenting GLUT1 levels in mutants correspondingly raised cerebrospinal fluid (CSF) glucose levels, improved motor performance and reduced the frequency of seizures characteristically observed in GLUT1DS. Interestingly, the increased GLUT1 in mutants harboring the human GLUT1 locus was at least partly the result of an increase in murine Slc2a1 (Glut1) activity, most likely the effect of a long non-coding RNA (lncRNA) embedded in the human transgene. Collectively, our work has not only shown that repleting human GLUT1 mitigates GLUT1DS but also has yielded transgenic mice that constitute a useful tool to test and optimize clinically promising agents designed to stimulate this gene for therapeutic purposes.
2024-05-07 | GLUT-1DS resistant to ketogenic diet: from clinical feature to in silico analysis. An exemplificative case report with a literature review.
Glucose transporter type 1 deficiency syndrome (GLUT-1DS) is characterized by alterations in glucose translocation through the blood-brain barrier (BBB) due to mutation involving the GLUT-1 transporter. The fundamental therapy is ketogenic diet (KD) that provide an alternative energetic substrate - ketone bodies that across the BBB via MCT-1 - for the brain. Symptoms are various and include intractable seizure, acquired microcephalia, abnormal ocular movement, movement disorder, and neurodevelopment delay secondary to an energetic crisis for persistent neuroglycopenia. KD is extremely effective in controlling epileptic seizures and has a positive impact on movement disorders and cognitive impairment. Cases of KD resistance are rare, and only a few of them are reported in the literature, all regarding seizure. Our study describes a peculiar case of GLUT-1DS due to a new deletion involving the first codon of SLC2A1 gene determining a loss of function with a resistance to KD admitted to hospital due to intractable episodes of dystonia. This patient presented a worsening of symptomatology at higher ketonemia values but without hyperketosis and showed a complete resolution of symptomatology while maintaining low ketonemia values. Our study proposes an in-silico genomic and proteomic analysis aimed at explaining the atypical response to KD exhibited by our patient. In this way, we propose a new clinical and research approach based on precision medicine and molecular modelling to be applied to patients with GLUT-1DS resistant to first-line treatment with ketogenic diet by in silico study of genetic and altered protein product.
2017-01-20 | Brain microvasculature defects and Glut1 deficiency syndrome averted by early repletion of the glucose transporter-1 protein
Haploinsufficiency of the SLC2A1 gene and paucity of its translated product, the glucose transporter-1 (Glut1) protein, disrupt brain function and cause the neurodevelopmental disorder, Glut1 deficiency syndrome (Glut1 DS). There is little to suggest how reduced Glut1 causes cognitive dysfunction and no optimal treatment for Glut1 DS. We used model mice to demonstrate that low Glut1 protein arrests cerebral angiogenesis, resulting in a profound diminution of the brain microvasculature without compromising the blood-brain barrier. Studies to define the temporal requirements for Glut1 reveal that pre-symptomatic, AAV9-mediated repletion of the protein averts brain microvasculature defects and prevents disease, whereas augmenting the protein late, during adulthood, is devoid of benefit. Still, treatment following symptom onset can be effective; Glut1 repletion in early-symptomatic mutants that have experienced sustained periods of low brain glucose nevertheless restores the cerebral microvasculature and ameliorates disease. Timely Glut1 repletion may thus constitute an effective treatment for Glut1 DS.
cell therapies
2024-11-04 | Generation of human induced pluripotent stem cell lines derived from two glucose transporter 1 deficiency syndrome patients.
Glucose transporter 1 deficiency syndrome (GLUT1DS), caused by impaired glucose transport at the blood-brain barriers, leads to various central nervous system dysfunctions. A comprehensive understanding of the underlying disease pathogenesis is still lacking. In this study, we have generated GLUT1DS-specific human induced pluripotent stem cells (hiPSCs) derived from two patients. These established GLUT1DS-specific hiPSC lines showed self-renewal and pluripotency and carried heterozygous frameshift or missense mutations in the responsible SLC2A1 gene. These novel cell resources provide new avenues for understanding disease mechanisms and developing new therapies for GLUT1DS.
2023-03-04 | Red blood cells as glucose carriers to the human brain: Modulation of cerebral activity by erythrocyte exchange transfusion in Glut1 deficiency (G1D).
Red blood cells circulating through the brain are briefly but closely apposed to the capillary endothelium. We hypothesized that this contact provides a nearly direct pathway for metabolic substrate transfer to neural cells that complements the better characterized plasma to endothelium transfer. While brain function is considered independent of normal fluctuations in blood glucose concentration, this is not borne out by persons with glucose transporter I (GLUT1) deficiency (G1D). In them, encephalopathy is often ameliorated by meal or carbohydrate administration, and this enabled us to test our hypothesis: Since red blood cells contain glucose, and since the red cells of G1D individuals are also deficient in GLUT1, replacing them with normal donor cells via exchange transfusion could augment erythrocyte to neural cell glucose transport via mass action in the setting of unaltered erythrocyte count or plasma glucose abundance. This motivated us to perform red blood cell exchange in 3 G1D persons. There were rapid, favorable and unprecedented changes in cognitive, electroencephalographic and quality-of-life measures. The hypothesized transfer mechanism was further substantiated by in vitro measurement of direct erythrocyte to endothelial cell glucose flux. The results also indicate that the adult intellect is capable of significant enhancement without deliberate practice. ClinicalTrials.gov registration: NCT04137692 https://clinicaltrials.gov/ct2/show/NCT04137692.
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Drug Discovery Landscape
3 orphan drug designations for Classic glucose transporter type 1 deficiency syndrome.
3 orphan drug designations for Classic glucose transporter type 1 deficiency syndrome.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
mixture of decanoic acid (C10; tricaprin) and octanoic acid (C8; tricaprylin) | small molecules | FDA | 2024-07-16 | — | Aimmune Nestlé US R&D LLC |
Triheptanoin | small molecules | EMA | 2015-05-21 | — | Ultragenyx Netherlands B.V. |
triheptanoin | small molecules | FDA | 2014-10-21 | — | Ultragenyx Pharmaceutical, Inc. |
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