GLUT1DS. Disease-causing variants in SLC2A1 are associated with a rare genetic neurometabolic condition known as GLUT1 Deficiency Syndrome (GLUT1DS). While GLUT1DS is typically diagnosed through molecular genetic testing, the diagnostic strategy in some cases includes lumbar puncture to measure cerebrospinal fluid (CSF) glucose to confirm the diagnosis. In a recent study, Mochel and collaborators performed a multicenter validation study of a blood-based biomarker for GLUT1DS. Here is a brief review on their publication and the utility of molecular biomarkers in GLUT1DS and genetic epilepsies more broadly.
Actionability. GLUT1DS is treatable and exemplifies a condition with a clear and precise therapeutic strategy in the clinical setting – initiation of the ketogenic diet. The basis of why the ketogenic diet is effective in GLUT1DS encapsulates the rationale driving precision medicine – it is rooted in directly targeting the underlying disease mechanism of GLUT1DS. In brief, disease-causing variants in SLC2A1, which encodes the major glucose transporter in the brain, leads to impaired glucose transport across the blood-brain barrier (BBB) and results in insufficient glucose availability and brain energy deficiency. However, the ketogenic diet enables the brain to use ketones as an alternate source of energy, which are transported across the blood-brain barrier via the MCT1 transporter, encoded by the gene SLC16A1. The ketogenic diet, if initiated early enough, can be used to clinically manage epilepsy in addition to improve cognitive abilities and long-term outcomes in individuals with GLUT1DS. Accordingly, early diagnosis of SLC2A1 has critical implications and immediate actionability in the clinical care of individuals with GLUT1DS.
Diagnosis. In 2023, GLUT1DS is typically diagnosed through identification of disease-causing variants in SLC2A1 via gene panel or whole exome sequencing in individuals with characteristic clinical features, most notably, generalized epilepsy with early and often refractory onset of absence seizures. As with most genetic epilepsies and neurodevelopmental disorders, the phenotypic spectrum is wide and individuals with GLUT1DS can have paroxysmal movement disorders and cognitive impairment with or without epilepsy. However, in contrast to all other genetic epilepsies, GLUT1DS has a molecular biomarker that can be measured. Low CSF concentration of glucose, known as hypoglycorrhachia, is indicative of GLUT1DS and has also been used as a means of diagnosis. However, this approach entails a lumbar puncture, a relatively invasive procedure to obtain CSF. In addition, for children with neurodevelopmental disorders, this can require sedation in order to safely collect the sample. In their recent study, Mochel and collaborators aimed to validate the diagnostic utility of “METAglut1TM,” a non-invasive blood test to quantify GLUT1. What was the basis of their test, and what did the study find?
Blood-based biomarkers. The METAglut1TM test relies on detection of the GLUT1 transporter on the membrane of erythrocytes, or red blood cells, where GLUT1 is expressed in addition to brain endothelial cells. When assessing METAglut1TM across 428 individuals with GLUT1DS, Mochel and collaborators found that the test had a sensitivity of 80% and specificity of >99% for the diagnosis of GLUT1DS, highlighting the ability of METAglut1TM in ruling out the diagnosis in individuals who do not have GLUT1DS. Prospectively comparing METAglut1TM against CSF glucose as a diagnostic strategy, the study found a slightly higher positive predictive value via the blood test. In brief, the authors present an alternate and non-invasive diagnostic modality that could serve as a secondary validation test for a GLUT1DS diagnosis.
Complementary approaches. This approach centered on biomarker-driven diagnosis can supplement the gold standard practice of genetic sequencing. For example, METAglut1TM can be pursued for further resolution of variants of uncertain significance in SLC2A1 and screening in individuals with atypical or mild presentations in which a GLUT1DS diagnosis is not clear. Given the clinical actionability, ruling out GLUT1DS in individuals with intractable genetic generalized epilepsy and atypical generalized epilepsy is considered standard of care. However, how can we translate this knowledge to other genetic epilepsies?
Endophenotypes. In a recent post, we outlined the potential of disease-specific biomarkers in accelerating rare disease research. These endophenotypes, or “intermediate phenotypes,” are measurable biomarkers that reflect the underlying biology and provide a mechanistic link that can explain variance within and across distinct disease entities. For example, this has implications in conditions with a wide range of neurological features and that constitute robust phenotypic subgroups within the same genetic condition – “diseases within diseases.” In the context of GLUT1DS, investigating why individuals with other genetic epilepsies are successfully treated with the ketogenic diet could provide critical insight into the underlying neurobiology and expand the treatment horizon for a phenotypically and genetically diverse subgroup of individuals with genetic epilepsies more broadly.
This is what you need to know. GLUT1 Deficiency Syndrome (GLUT1DS) is a treatable condition with immediate clinical actionability following diagnosis. In a recent study, Mochel and collaborators provided evidence that support quantification of GLUT1 in blood as a biomarker to reliably distinguish GLUT1DS from other neurological syndromes. While biomarker discovery and development are in its infancy in rare disease, the validation of a molecular blood-based biomarker enabling rapid diagnosis of GLUT1DS represents a significant step in the genetic epilepsies and has critical implications in improving the prognosis of affected individuals.