Congenital Sucrase-Isomaltase Deficiency: Same Mutation with Different Clinical Presentations.

BACKGROUND/AIMS:  Congenital sucrase-isomaltase deficiency is an autosomal recessive inherited disaccharidase deficiency characterized by chronic osmotic diarrhea. In this study, the genotype-phenotype relationships of close relatives of an index case with congenital sucrase-isomaltase deficiency were investigated. MATERIALS AND METHODS:  A 23-month-old female patient with a sucrase-isomaltase gene c.317G>A (p.C106Y) homozygous mutation was diagnosed as an index case and her pedigree analysis was performed subsequently. The family members with and without sucrase- isomaltase gene mutations were compared in terms of clinical symptoms. RESULTS:  The study included 109 cases [mean age ± SD: 22.6 ± 17.2 years (0.1-75 years), 61 males (56%)] of 130 family members of the index case. Sucrase-isomaltase gene c.317G>A (p.C106Y) heterozygous mutation was detected in 27 cases (24.7%); 14 (51.9%) were male and had a mean age of 23.2 ± 18.3 years. The most common complaints of 12 (44.4%) symptomatic patients with mutations were abdominal pain (37%), gas irritability (33.3%), bloating (22.2%), and foul-smelling stools (18.5%). Compared with the cases without mutation, a statistically significant difference was observed in the incidence of gas irritability, foul-smelling stool, ≥2 gastrointestinal symptoms, postprandial complaints, and food allergy (P = .005, P = .047, P = .049, P = .017, P = .021, respectively). Sacrosidase enzyme replacement was applied to 7 patients whose symptoms did not improve with dietary elimination. Clinical response was obtained after enzyme treatment. CONCLUSION:  Despite its autosomal recessive inheritance, congenital sucrase-isomaltase deficiency can also be symptomatic in heterozygous individuals. Further studies are required to clarify the genotype-phenotype relationship and management of the disease.

Neuromuscular dysfunction and pathogenesis in triosephosphate isomerase deficiency.

Triosephosphate isomerase deficiency (TPI Df) is a rare multisystem disorder with severe neuromuscular symptoms which arises exclusively from mutations within the TPI1 gene. Studies of TPI Df have been limited due to the absence of mammalian disease models and difficulties obtaining patient samples. Recently, we developed a novel murine model of TPI Df which models the most common disease-causing mutation in humans, TPI1E105D. Using our model in the present study, the underlying pathogenesis of neuromuscular symptoms has been elucidated. This is the first report detailing studies of neuromuscular pathology within a murine model of TPI Df. We identified several contributors to neuromuscular symptoms, including neurodegeneration in the brain, alterations in neurotransmission at the neuromuscular junction, and reduced muscle fiber size. TPI Df mice also exhibited signs of cardiac pathology and displayed a deficit in vascular smooth muscle functionality. Together, these findings provide insight into pathogenesis of the neuromuscular symptoms in TPI Df and can guide the future development of therapeutics.

Inherited glycosylphosphatidylinositol deficiency: a review from molecular and clinical perspectives.

Glycosylphosphatidylinositol (GPI) is a highly conserved post-translational modification in eukaryotes, which is essential for anchoring various proteins to the cell surface. Dysfunction of GPI biogenesis leads to human diseases, such as inherited GPI deficiency (IGD) caused by germline mutations in GPI-related genes. With accumulating reports on individuals with IGD, there has been increasing interest and studies on disease mechanism, diagnosis, and therapy. This review outlines the biosynthetic pathway of GPI-anchored proteins (GPI-APs) and summarizes clinical IGD cases from a molecular perspective. We also review current diagnostic and therapeutic approaches for IGD. Finally, we discuss future research directions to facilitate the understanding and treatment of GPI-related disorders.

GLUT1DS focus on dysarthria.

RESEARCH PURPOSE: GLUT1 deficiency syndrome (GLUT1DS) is a rare genetic disorder caused by a mutation in the SLC2A1 gene that limits the transport of glucose across the blood-brain barrier. Speech disorders and dysarthria are typical findings in patients with GLUT1DS, but have never been deeply phenotyped. The aim of the present study was to characterize speech abilities in a sample of patients with GLUT1DS. RESULTS: 30 patients with GLUT1DS were recruited. We reported impairments in different speech and oromotor domains: the speech was characterized by dysarthria, inaccurate articulation of consonants, abnormal nasal resonance, errors in intonation and prosody and low intelligibility. We observed difficulties in motor planning and programming. Moreover, we observed a significant difference between the dysarthric level of impairment with genotype groups. CONCLUSIONS: The presence of a speech disorder in patients with GLUT1DS represents a core feature of the syndrome. Our findings suggest that patients with GLUT1DS would benefit from a comprehensive neurocognitive assessment to detect strengths and weaknesses of the speech profile. Understanding the speech and language phenotype in GLUT1DS is critical for planning early intervention to positively influence the global development of patients with GLUT1DS.

[Genetics of sucrose metabolism disorders in different population groups].

The study of the genetic determinants of the disaccharidase activity opens up new prospects for improving diagnostics and choosing medical tactics in gastroenterology. The aim of the study was to systematize the data on the role of the sucrase-isomaltase gene (SI) in regulating sucrose metabolism and the contribution of SI mutations to the prevalence of sucrose malabsorption disorders (sucrase-isomaltase deficiency, SID) and certain forms of enterological pathology in different population groups. Material and methods. A review of the peer-reviewed scientific literature, mainly in the PubMed database (https://pubmed.ncbi.nlm.nih.gov) and eLibrary (https://elibrary.ru), was conducted using key words: carbohydrate malabsorption, sucrase, sucrase-isomaltase deficiency, sucrase-isomaltase SI gene. The search depth was not specified, but particular attention was paid to recent publications. The gnomAD database (https://www.ncbi.nlm. nih.gov/snp/rs781470490) was also used. Results. According to the review results, 37 out of 150 known SI gene mutations have been confirmed to contribute to reduced sucrase activity or restricted sucrase production. The prevalence of point mutations in the SI gene is estimated at 0.0006%, but carrier rates of the SI delAG deletion (rs781470490), manifested as homozygosity in SID, are very high (5-21%) in indigenous populations of Arctic regions in East Asia and America. Medicalgenetic research methods improve the accuracy of differential diagnosis of primary and secondary SID and other forms of disaccharide and polysaccharide malabsorption. The formation of databases on the prevalence of genetic determinants of sucrase-isomaltase insufficiency is a promising way to refine the epidemiology of SID. There is an increased (0.2-2.3%) risk of clinical manifestations of SID in homozygous carriers of the SI delAG mutation in the Chukotka, Kamchatka, and Northern Priochotye populations. Verification of reports on a less pronounced tendency to lipid metabolism disorders in SI delAG carriers compared with the control group is recommended. Conclusion. Manifestations of mutant SI variants in the phenotype are associated with the presence of accompanying carbohydrate malabsorption variants and specific gut microbiota. The SI 15Phe variant (rs9290264) may contribute to the development of irritable bowel syndrome.

Case for supporting astrocyte energetics in glucose transporter 1 deficiency syndrome.

In glucose transporter 1 deficiency syndrome (Glut1DS), glucose transport into brain is reduced due to impaired Glut1 function in endothelial cells at the blood-brain barrier. This can lead to shortages of glucose in brain and is thought to contribute to seizures. Ketogenic diets are the first-line treatment and, among many beneficial effects, provide auxiliary fuel in the form of ketone bodies that are largely metabolized by neurons. However, Glut1 is also the main glucose transporter in astrocytes. Here, we review data indicating that glucose shortage may also impact astrocytes in addition to neurons and discuss the expected negative biochemical consequences of compromised astrocytic glucose transport for neurons. Based on these effects, auxiliary fuels are needed for both cell types and adding medium chain triglycerides (MCTs) to ketogenic diets is a biochemically superior treatment for Glut1DS compared to classical ketogenic diets. MCTs provide medium chain fatty acids (MCFAs), which are largely metabolized by astrocytes and not neurons. MCFAs supply energy and contribute carbons for glutamine and γ-aminobutyric acid synthesis, and decanoic acid can also block α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors. MCTs do not compete with metabolism of ketone bodies mostly occurring in neurons. Triheptanoin, an anaplerotic but also gluconeogenic uneven MCT, may be another potential addition to ketogenic diets, although maintenance of "ketosis" can be difficult. Gene therapy has also targeted both endothelial cells and astrocytes. Other approaches to increase fuel delivery to the brain currently investigated include exchange of Glut1DS erythrocytes with healthy cells, infusion of lactate, and pharmacological improvement of glucose transport. In conclusion, although it remains difficult to assess impaired astrocytic energy metabolism in vivo, astrocytic energy needs are most likely not met by ketogenic diets in Glut1DS. Thus, we propose prospective studies including monitoring of blood MCFA levels to find optimal doses for add-on MCT to ketogenic diets and assessing of short- and long-term outcomes.

Glucose transporter-1 deficiency syndrome with extreme phenotypic variability in a five-generation family carrying a novel SLC2A1 variant.

BACKGROUND AND PURPOSE: Glucose transporter-1 (GLUT1) deficiency syndrome (GLUT1-DS) is a metabolic disorder due to reduced expression of GLUT1, a glucose transporter of the central nervous system. GLUT1-DS is caused by heterozygous SLC2A1 variants that mostly arise de novo. Here, we report a large family with heterogeneous phenotypes related to a novel SLC2A1 variant. METHODS: We present clinical and genetic features of a five-generation family with GLUT1-DS. RESULTS: The 14 (nine living) affected members had heterogeneous phenotypes, including seizures (11/14), behavioral disturbances (5/14), mild intellectual disability (3/14), and/or gait disabilities (2/14). Brain magnetic resonance imaging revealed hippocampal sclerosis in the 8-year-old proband, who also had drug-responsive absences associated with attention-deficit/hyperactivity disorder. His 52-year-old father, who had focal epilepsy since childhood, developed paraparesis related to a reversible myelitis associated with hypoglycorrhachia. Molecular study detected a novel heterozygous missense variant (c.446C>T) in exon 4 of SLC2A1 (NM: 006516.2) that cosegregated with the illness. This variant causes an amino acid replacement (p.Pro149Leu) at the fourth transmembrane segment of GLUT1, an important domain located at its catalytic core. CONCLUSIONS: Our study illustrates the extremely heterogenous phenotypes in familial GLUT1-DS, ranging from milder classic phenotypes to more subtle neurological disorder including paraparesis. This novel SLC2A1 variant (c.446C>T) provides new insight into the pathophysiology of GLUT1-DS.

Exploring genetic variants in congenital monosaccharide-disaccharide metabolism: Carrier ratios and phenotypic insights.

OBJECTIVES: Adverse food reactions, often underestimated, encompass congenital monosaccharide-disaccharide metabolism disorders, yielding diverse outcomes such as abdominal pain, diarrhea, bleeding disorders, and even death. This study retrospectively scrutinized genetic variants linked to these disorders in a cohort subjected to whole-exome sequence analysis (WES), determining carrier frequencies and genotype-phenotype correlations. METHODS: Data from 484 patients, were retrospectively analyzed using a gene panel (ALDOB, FBP1, GALE, GALK1, GALM, GALT, LCT, SLC2A2, SLC5A1, SI) for congenital monosaccharide-disaccharide metabolism disorders. WES was performed on patients using the xGen Exome Research Panel v2 kit, utilizing Next Generation Sequence Analysis (NGS). The study encompassed pathogenic, likely pathogenic, and variant of uncertain significance (VUS) variants. RESULTS: Among 484 patients (244 female, 240 male), 17.35% carried 99 variants (67 distinct) in the analyzed genes. Pathogenic/likely pathogenic allele frequency stood at 0.013, while VUS allele frequency was 0.088. Notably, 44% (37/84) of patients harboring mutations manifested at least one relevant phenotype. Carriage frequencies ranged from 1:25 (SI gene) to 1:968 (GALE gene), with the estimated disease frequency spanning from 1:2500 to 1:3748000. CONCLUSIONS: Our study underscores clinical manifestations in heterozygous carriers of recessive genetic disorders, addressing gaps in carrier frequencies and phenotypic effects for congenital monosaccharide-disaccharide metabolism disorders. This knowledge can improve these conditions' diagnosis and management, potentially preventing adverse food reactions and their associated complications.

Congenital sucrase-isomaltase deficiency in Türkiye; a single center experience.

BACKGROUND: Congenital sucrase-isomaltase deficiency (CSID) is a rare inherited carbohydrate malabsorption disorder caused by sucrase-isomaltase (SI) gene variants. In CSID, an autosomal recessively inherited disease, symptoms can also be seen in individuals with heterozygous mutations. METHODS: The variant spectrum was evaluated retrospectively in individuals who presented with chronic diarrhea between 2014 and 2022 and had undergone genetic testing of the SI gene considering CSID due to diet-related complaints. RESULTS: Ten patients with chronic diarrhea were genetically evaluated with SI gene sequencing. In patients diagnosed with CSID and whose symptoms improved with enzyme replacement therapy, the genetic mutation zygosity was found to be heterozygous at a rate of 90%. In 10% of the patients, the mutation was homozygous. Limiting consuming sucrose and isomaltose foods reduced the patients' complaints, but the symptoms did not disappear completely. With the initiation of sacrosidase enzyme replacement therapy, the patient's complaints completely disappeared. CONCLUSION: In CSID, defined as an autosomal recessive disease, clinical symptoms can also be seen in heterozygous cases previously described as carriers, and these patients also benefit from sacrosidase enzyme replacement therapy. In light of these findings, the autosomal recessive definition of CSID does not fully characterize the disease.What is Known:CSID is a rare inherited carbohydrate malabsorption disorder caused by sucrase-isomaltase gene variants.In congenital sucrase-isomaltase deficiency, an autosomal recessively inherited disorder, symptoms can also be seen in individuals with heterozygous mutations.What is new:Severe disease symptoms can also be seen in heterozygous cases, which were thought to be carriers because the disease was previously described as autosomal recessive.Sacrosidase enzyme replacement therapy also eliminates the disease symptoms in patients with heterozygous CSID mutations.This is the second study on sucrase-isomaltase enzyme deficiency pediatric groups in Türkiye and Europe.

This is the study to evaluate the congenital sucrase-isomaltase enzyme deficiency in chronic diarrhea cases covering adults and childhood in our country and the clinical features and treatment response characteristics of the variants detected in these patients.In addition, another aim of our study is that sucrase­isomaltase enzyme deficiency should be considered in the differential diagnosis and should be kept in mind, especially in cases with chronic diarrhea whose cause cannot be determined in childhood.

Genetic and acquired sucrase-isomaltase deficiency: A clinical review.

Genetic sucrase-isomaltase deficiency (GSID) is an inherited deficiency in the ability to digest sucrose and potentially starch due to mutations in the sucrase-isomaltase (SI) gene. Congenital sucrase-isomaltase deficiency is historically considered to be a rare condition affecting infants with chronic diarrhea as exposure to dietary sucrose begins. Growing evidence suggests that individuals with SI variants may present later in life, with symptoms overlapping with those of irritable bowel syndrome. The presence of SI genetic variants may, either alone or in combination, affect enzyme activity and lead to symptoms of different severity. As such, a more appropriate term for this inherited condition is GSID, with a recognition of a spectrum of severity and onset of presentation. Currently, disaccharidase assay on duodenal mucosal tissue homogenates is the gold standard in diagnosing SI deficiency. A deficiency in the SI enzyme can be present at birth (genetic) or acquired later, often in association with damage to the enteric brush-border membrane. Other noninvasive diagnostic alternatives such as sucrose breath tests may be useful but require further validation. Management of GSID is based on sucrose and potentially starch restriction tailored to the individual patients' tolerance and symptoms. As this approach may be challenging, additional treatment with commercially available sacrosidase is available. However, some patients may require continued starch restriction. Further research is needed to clarify the true prevalence of SI deficiency, the pathobiology of single SI heterozygous mutations, and to define optimal diagnostic and treatment algorithms in the pediatric population.

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.

SLC5A1 Variants in Turkish Patients with Congenital Glucose-Galactose Malabsorption.

Congenital glucose-galactose malabsorption is a rare autosomal recessive disorder caused by mutations in SLC5A1 encoding the apical sodium/glucose cotransporter SGLT1. We present clinical and molecular data from eleven affected individuals with congenital glucose-galactose malabsorption from four unrelated, consanguineous Turkish families. Early recognition and timely management by eliminating glucose and galactose from the diet are fundamental for affected individuals to survive and develop normally. We identified novel SLC5A1 missense variants, p.Gly43Arg and p.Ala92Val, which were linked to disease in two families. Stable expression in CaCo-2 cells showed that the p.Ala92Val variant did not reach the plasma membrane, but was retained in the endoplasmic reticulum. The p.Gly43Arg variant, however, displayed processing and plasma membrane localization comparable to wild-type SGLT1. Glycine-43 displays nearly invariant conservation in the relevant structural family of cotransporters and exchangers, and localizes to SGLT1 transmembrane domain TM0. p.Gly43Arg represents the first disease-associated variant in TM0; however, the role of TM0 in the SGLT1 function has not been established. In summary, we are expanding the mutational spectrum of this rare disorder.

Prospective Multicenter Validation of a Simple Blood Test for the Diagnosis of Glut1 Deficiency Syndrome.

BACKGROUND AND OBJECTIVE: GLUT1 deficiency syndrome (Glut1DS) is a treatable neurometabolic disease that causes a wide range of neurologic symptoms in children and adults. However, its diagnosis relies on an invasive test, that is, a lumbar puncture (LP) to measure glycorrhachia, and sometimes complex molecular analyses of the SLC2A1 gene. This procedure limits the number of patients able to receive the standard of care. We wished to validate the diagnostic performance of METAglut1, a simple blood test that quantifies GLUT1 on the erythrocyte surface. METHODS: We performed a multicenter validation study in France, involving 33 centers. We studied 2 patient cohorts: a prospective cohort consisting of patients with a clinical suspicion of Glut1DS explored through the reference strategy, that is, LP and analyses of the SLC2A1 gene, and a retrospective cohort that included patients previously diagnosed with Glut1DS. All patients were blind-tested with METAglut1. RESULTS: We analyzed 428 patients in the prospective cohort, including 15 patients newly diagnosed with Glut1DS, and 67 patients in the retrospective cohort. METAglut1 was 80% sensitive and >99% specific for the diagnosis of Glut1DS. Concordance analyses showed a substantial agreement between METAglut1 and glycorrhachia. In the prospective cohort, the positive predictive value of METAglut1 was slightly higher than that of glycorrhachia. METAglut1 succeeded to identify patients with Glut1DS with SCL2A1 mosaicism and variants of unknown significance. DISCUSSION: METAglut1 is an easily performed, robust, and noninvasive diagnostic test for the diagnosis of Glut1DS, which allows wide screening of children and adults, including those with atypical forms of this treatable condition. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that a positive METAglut1 test accurately distinguishes patients with suspected GLUT1 deficiency syndrome from other neurologic syndromes as compared with invasive and genetic testing.

Quantitative determination of SLC2A1 variant functional effects in GLUT1 deficiency syndrome.

OBJECTIVE: The goal of this study is to demonstrate the utility of a growth assay to quantify the functional impact of single nucleotide variants (SNVs) in SLC2A1, the gene responsible for Glut1DS. METHODS: The functional impact of 40 SNVs in SLC2A1 was quantitatively determined in HAP1 cells in which SLC2A1 is required for growth. Donor libraries were introduced into the endogenous SLC2A1 gene in HAP1-Lig4KO cells using CRISPR/Cas9. Cell populations were harvested and sequenced to quantify the effect of variants on growth and generate a functional score. Quantitative functional scores were compared to 3-OMG uptake, SLC2A1 cell surface expression, CADD score, and clinical data, including CSF/blood glucose ratio. RESULTS: Nonsense variants (N = 3) were reduced in cell culture over time resulting in negative scores (mean score: -1.15 ± 0.17), whereas synonymous variants (N = 10) were not depleted (mean score: 0.25 ± 0.12) (P < 2e-16). Missense variants (N = 27) yielded a range of functional scores including slightly negative scores, supporting a partial function and intermediate phenotype. Several variants with normal results on either cell surface expression (p.N34S and p.W65R) or 3-OMG uptake (p.W65R) had negative functional scores. There is a moderate but significant correlation between our functional scores and CADD scores. INTERPRETATION: Cell growth is useful to quantitatively determine the functional effects of SLC2A1 variants. Nonsense variants were reliably distinguished from benign variants in this in vitro functional assay. For facilitating early diagnosis and therapeutic intervention, future work is needed to determine the functional effect of every possible variant in SLC2A1.

Deficiencia del transportador de glucosa tipo 1: aspectos clínicos, diagnóstico y terapéutica / Glucose transporter type 1 deficiency syndrome: clinical aspects, diagnosis, and treatment

El síndrome de deficiencia del transportador de glucosa tipo 1 es una enfermedad de causa genética, que involucra el gen SLC2A1. En general, se presenta durante los primeros años de vida con retraso en la adquisición de pautas madurativas, epilepsia farmacorresistente y desórdenes del movimiento. La clínica y la disminución de glucosa en líquido cefalorraquídeo permiten sospechar el diagnóstico, el cual debe ser confirmado mediante el estudio molecular del gen SLC2A1. Debido a que se trata de una enfermedad poco frecuente y de expresión clínica variable, el diagnóstico precoz suele representar un desafío para los equipos de salud. Este es importante, ya que la implementación de la terapia cetogénica logra controlar las manifestaciones clínicas y mejora el pronóstico a largo plazo. Presentamos una revisión sobre el déficit del transportador de glucosa tipo 1, que abarca sus características clínicas, bioquímicas, moleculares y terapéuticas.

Glucose transporter type 1 deficiency with a typical onset is a genetic disorder associated with the SLC2A1 gene. Usually appears during the first years of life with severe developmental delay, drugresistant epilepsy, and movement disorders. Diagnosis is suspected based on clinical manifestations and a low glucose level in cerebrospinal fluid, and should be confirmed by the molecular genetic study of the SLC2A1 gene. As it is a rare disease with variable clinical expression, early diagnosis is often challenging for the healthcare team. Nevertheless, this is important because early implementation of ketogenic therapy will lead to control of the clinical manifestations and a better long-term prognosis. Here we review the glucose transporter type 1 deficiency syndrome focusing on its clinical, biochemical, molecular, and therapeutic characteristics.

Glucose transporter type 1 deficiency syndrome: clinical aspects, diagnosis, and treatment. / Deficiencia del transportador de glucosa tipo 1: aspectos clínicos, diagnóstico y terapéutica.

Glucose transporter type 1 deficiency with a typical onset is a genetic disorder associated with the SLC2A1 gene. Usually appears during the first years of life with severe developmental delay, drugresistant epilepsy, and movement disorders. Diagnosis is suspected based on clinical manifestations and a low glucose level in cerebrospinal fluid,and should be confirmed by the molecular genetic study of the SLC2A1 gene. As it is a rare disease with variable clinical expression, early diagnosis is often challenging for the healthcare team. Nevertheless, this is important because early implementation of ketogenic therapy will lead to control of the clinical manifestations and a better long-term prognosis. Here we review the glucose transporter type 1 deficiency syndrome focusing on its clinical, biochemical, molecular, and therapeutic characteristics.

El síndrome de deficiencia del transportador de glucosa tipo 1 es una enfermedad de causa genética, que involucra el gen SLC2A1. En general, se presenta durante los primeros años de vida con retraso en la adquisición de pautas madurativas, epilepsia farmacorresistente y desórdenes del movimiento. La clínica y la disminución de glucosa en líquido cefalorraquídeo permiten sospechar el diagnóstico, el cual debe ser confirmado mediante el estudio molecular del gen SLC2A1. Debido a que se trata de una enfermedad poco frecuente y de expresión clínica variable, el diagnóstico precoz suele representar un desafío para los equipos de salud. Este es importante, ya que la implementación de la terapia cetogénica logra controlar las manifestaciones clínicas y mejora el pronóstico a largo plazo. Presentamos una revisión sobre el déficit del transportador de glucosa tipo 1, que abarca sus características clínicas, bioquímicas, moleculares y terapéuticas.