The clinical and biochemical hallmarks generally associated with <scp>GLUT1DS</scp> may be caused by defects in genes other than <scp><i>SLC2A1</i></scp>

Sanchez‐Lijarcio, Obdulia; Yubero, Dèlia; Leal, Fátima; Couce, María L.; Gutiérrez-Solana, Luis González; López‐Laso, Eduardo; García‐Cazorla, Àngels; Pías‐Peleteiro, Leticia; Brea, Begoña de Azua; Ibáñez-Micó, Salvador; Mateo-Martínez, Gonzalo; Troncoso-Schifferli, Mónica; Witting-Enriquez, Scarlet; Ugarte, Magdalena; Artuch, Rafael; Pérez, Belén

doi:10.1111/cge.14138

Cited by 5 publications

(5 citation statements)

References 18 publications

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“… b Except for the variant of Patient 10, c.1390G>C (p.Ala646Pro), all variants have been reported previously. 30 , 31 c Reference ranges given between brackets are provided by the laboratory that performed the CSF analysis. d Combination of mild to moderate intellectual disability, epilepsy, and movement disorder.…”

Section: Methodsmentioning

confidence: 99%

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Novel cerebrospinal fluid biomarkers of glucose transporter type 1 deficiency syndrome: Implications beyond the brain's energy deficit

Peters

Merx

Kooijman

et al. 2022

J of Inher Metab Disea

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We used next-generation metabolic screening to identify new biomarkers for improved diagnosis and pathophysiological understanding of glucose transporter type 1 deficiency syndrome (GLUT1DS), comparing metabolic cerebrospinal fluid (CSF) profiles from 12 patients to those of 116 controls. This confirmed decreased CSF glucose and lactate levels in patients with GLUT1DS and increased glutamine at group level. We identified three novel biomarkers significantly decreased in patients, namely gluconic + galactonic acid, xylose-α1-3-glucose, and xylose-α1-3-xylose-α1-3-glucose, of which the latter two have not previously been identified in body fluids. CSF concentrations of gluconic + galactonic acid may be reduced as these metabolites could serve as alternative substrates for the pentose phosphate pathway. Xylose-α1-3-glucose and xylose-

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Section: Methodsmentioning

confidence: 99%

“… f Patients 3 and 4 are siblings and have been described previously as P26 and P25, respectively. 31 g Reference range is defined by p5–p95 of the control population. …”

Section: Methodsmentioning

confidence: 99%

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Novel cerebrospinal fluid biomarkers of glucose transporter type 1 deficiency syndrome: Implications beyond the brain's energy deficit

Peters

Merx

Kooijman

et al. 2022

J of Inher Metab Disea

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“…For instance, a frameshift deletion in the PURA gene, coding for a transcriptional and translational regulator protein, led to hypoglycorrhachia, along with a lowered Glut1 expression on the membrane of peripheral red blood cells [ 47 ]. Sometimes the hallmarks of the clinical and biological picture may be given by other genes, coding for different membrane transporters such as SLC9A6, enzymes, receptors or transcriptional factors, or involving other mechanisms such as protein recycling [ 48 ]. In individual patients, mutations reported to modify the clinical picture in Glut1DS-involved genes include SCN8A , ATP1A3 , KCNQ2 , NALCN , DNM1 , MAN2B and UNC13A [ 48 ].…”

Section: Genetics and Metabolic Changesmentioning

confidence: 99%

“…Sometimes the hallmarks of the clinical and biological picture may be given by other genes, coding for different membrane transporters such as SLC9A6, enzymes, receptors or transcriptional factors, or involving other mechanisms such as protein recycling [ 48 ]. In individual patients, mutations reported to modify the clinical picture in Glut1DS-involved genes include SCN8A , ATP1A3 , KCNQ2 , NALCN , DNM1 , MAN2B and UNC13A [ 48 ].…”

Section: Genetics and Metabolic Changesmentioning

confidence: 99%

One Molecule for Mental Nourishment and More: Glucose Transporter Type 1—Biology and Deficiency Syndrome

et al. 2022

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Glucose transporter type 1 (Glut1) is the main transporter involved in the cellular uptake of glucose into many tissues, and is highly expressed in the brain and in erythrocytes. Glut1 deficiency syndrome is caused mainly by mutations of the SLC2A1 gene, impairing passive glucose transport across the blood–brain barrier. All age groups, from infants to adults, may be affected, with age-specific symptoms. In its classic form, the syndrome presents as an early-onset drug-resistant metabolic epileptic encephalopathy with a complex movement disorder and developmental delay. In later-onset forms, complex motor disorder predominates, with dystonia, ataxia, chorea or spasticity, often triggered by fasting. Diagnosis is confirmed by hypoglycorrhachia (below 45 mg/dL) with normal blood glucose, 18F-fluorodeoxyglucose positron emission tomography, and genetic analysis showing pathogenic SLC2A1 variants. There are also ongoing positive studies on erythrocytes’ Glut1 surface expression using flow cytometry. The standard treatment still consists of ketogenic therapies supplying ketones as alternative brain fuel. Anaplerotic substances may provide alternative energy sources. Understanding the complex interactions of Glut1 with other tissues, its signaling function for brain angiogenesis and gliosis, and the complex regulation of glucose transportation, including compensatory mechanisms in different tissues, will hopefully advance therapy. Ongoing research for future interventions is focusing on small molecules to restore Glut1, metabolic stimulation, and SLC2A1 transfer strategies. Newborn screening, early identification and treatment could minimize the neurodevelopmental disease consequences. Furthermore, understanding Glut1 relative deficiency or inhibition in inflammation, neurodegenerative disorders, and viral infections including COVID-19 and other settings could provide clues for future therapeutic approaches.

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The diagnostic and prognostic role of cerebrospinal fluid biomarkers in glucose transporter 1 deficiency: a systematic review

Mastrangelo,

Manti,

Ricciardi

et al. 2024

Eur J Pediatr

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The purpose of this study is to investigate the diagnostic and prognostic role of cerebrospinal fluid (CSF) biomarkers in the diagnostic work-up of glucose transporter 1 (GLUT1) deficiency. Reported here is a systematic review according to PRISMA guidelines collecting clinical and biochemical data about all published patients who underwent CSF analysis. Clinical phenotypes were compared between groups defined by the levels of CSF glucose (≤ 2.2 mmol/L versus > 2.2 mmol/L), CSF/blood glucose ratio (≤ 0.45 versus > 0.45), and CSF lactate (≤ 1 mmol/L versus > 1 mmol/L). Five hundred sixty-two patients fulfilled the inclusion criteria with a mean age at the diagnosis of 8.6 ± 6.7 years. Patients with CSF glucose ≤ 2.2 mmol/L and CSF/blood glucose ratio ≤ 0.45 presented with an earlier onset of symptoms (16.4 ± 22.0 versus 54.4 ± 45.9 months, p < 0.01; 15.7 ± 23.8 versus 40.9 ± 38.0 months, p < 0.01) and received an earlier molecular genetic confirmation (92.1 ± 72.8 versus 157.1 ± 106.2 months, p < 0.01). CSF glucose ≤ 2.2 mmol/L was consistently associated with response to ketogenic diet (p = 0.018) and antiseizure medications (p = 0.025). CSF/blood glucose ratio ≤ 0.45 was significantly associated with absence seizures (p = 0.048), paroxysmal exercise‐induced dyskinesia (p = 0.046), and intellectual disability (p = 0.016) while CSF lactate > 1 mmol/L was associated with a response to antiseizure medications (p = 0.026) but not to ketogenic diet.Conclusions:This systematic review supported the diagnostic usefulness of lumbar puncture for the early identification of patients with GLUT1 deficiency responsive to treatments especially if they present with co-occurring epilepsy, movement, and neurodevelopmental disorders. What is Known: • Phenotypes of GLUT1 deficiency syndrome range between early epileptic and developmental encephalopathy to paroxysmal movement disorders and developmental impairment What is New: • CSF blood/glucose ratio may predict better than CSF glucose the diagnosis in children presenting with early onset absences • CSF blood/glucose ratio may predict better than CSF glucose the diagnosis in children presenting with paroxysmal exercise induced dyskinesia and intellectual disability. • CSF glucose may predict better than CSF blood/glucose and lactate the response to ketogenic diet and antiseizure medications.

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The clinical and biochemical hallmarks generally associated with GLUT1DS may be caused by defects in genes other than SLC2A1

Cited by 5 publications

References 18 publications

Novel cerebrospinal fluid biomarkers of glucose transporter type 1 deficiency syndrome: Implications beyond the brain's energy deficit

Novel cerebrospinal fluid biomarkers of glucose transporter type 1 deficiency syndrome: Implications beyond the brain's energy deficit

One Molecule for Mental Nourishment and More: Glucose Transporter Type 1—Biology and Deficiency Syndrome

The diagnostic and prognostic role of cerebrospinal fluid biomarkers in glucose transporter 1 deficiency: a systematic review

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