Biochemical phenotyping unravels novel metabolic abnormalities and potential biomarkers associated with treatment of GLUT1 deficiency with ketogenic diet

Abstract

Global metabolomic profiling offers novel opportunities for the discovery of biomarkers and for the elucidation of pathogenic mechanisms that might lead to the development of novel therapies. GLUT1 deficiency syndrome (GLUT1-DS) is an inborn error of metabolism due to reduced function of glucose transporter type 1. Clinical presentation of GLUT1-DS is heterogeneous and the disorder mirrors patients with epilepsy, movement disorders, or any paroxysmal events or unexplained neurological manifestation triggered by exercise or fasting. The diagnostic biochemical hallmark of the disease is a reduced cerebrospinal fluid (CSF)/blood glucose ratio and the only available treatment is ketogenic diet. This study aimed at advancing our understanding of the biochemical perturbations in GLUT1-DS pathogenesis through biochemical phenotyping and the treatment of GLUT1-DS with a ketogenic diet. Metabolomic analysis of three CSF samples from GLUT1-DS patients not on ketogenic diet was feasible inasmuch as CSF sampling was used for diagnosis before to start with ketogenic diet. The analysis of plasma and urine samples obtained from GLUT1-DS patients treated with a ketogenic diet showed alterations in lipid and amino acid profiles. While subtle, these were consistent findings across the patients with GLUT1-DS on ketogenic diet, suggesting impacts on mitochondrial physiology. Moreover, low levels of free carnitine were present suggesting its consumption in GLUT1-DS on ketogenic diet. 3-hydroxybutyrate, 3-hydroxybutyrylcarnitine, 3-methyladipate, and N-acetylglycine were identified as potential biomarkers of GLUT1-DS on ketogenic diet. This is the first study to identify CSF, plasma, and urine metabolites associated with GLUT1-DS, as well as biochemical changes impacted by a ketogenic diet. Potential biomarkers and metabolic insights deserve further investigation.

Differential Ketogenic Diet-Induced Shift in CSF Lipid/Carbohydrate Metabolome of Pediatric Epilepsy Patients With Optimal Vs. No Anticonvulsant Response

“…For instance, KD did not elevate cortisol in CSF, whereas it has been reported to do so in plasma; these latter studies, were, however, in rheumatoid arthritis patients [19,51]. Cappuccio et al reported elevated plasma hydroxybutyryl-and acetyl-carnitine and lower methylmalonyl-carnitine in KD-treated glucose transporter 1 deficient patients [16], similar to the present results. Also, Schoeler et al demonstrated a stronger -hydroxybutyrate response to KD treatment in patients with optimal clinical response vs. those with no response; however, they also reported that optimal responders had higher baseline CSF -hydroxybutyrate and octanoyl-and acetyl-carnitine [21].…”

“…Clearly many systemic changes occur with dietary therapy, making it difficult to sort out key mechanisms of efficacy. To date a number of studies have examined changes in blood metabolites aside from ketone bodies and glucose, typically examining a limited number of predetermined compounds to address specific hypotheses [15][16][17][18][19][20][21]. While cerebrospinal fluid (CSF) is significantly more difficult to collect than blood, analysis of CSF metabolites may be more relevant to KD mechanisms in epilepsy [22][23][24][25].…”

Metabolomics in the clinic: A review of the shared and unique features of untargeted metabolomics for clinical research and clinical testing

“…Clinical metabolomics testing, such as for IEM screening, is a nascent testing approach that is amenable to multiple sample types, can substitute tens of smaller assays, and represents an important proof‐of‐principle to support future pre‐clinical and clinical applications for metabolomics . Expanding on this, additional studies will provide new insights into acute and chronic diseases such as cardiovascular disease, hypertension, cancer, inflammatory disease, autoimmune disease, metabolic disorders, and neurological diseases.…”

“…With the end use clearly stated, it is recommended that the 100 s of metabolites from clinical metabolomics research be filtered to a short list of 1 to 10 biomarkers for subsequent targeted analytical assay development, validation, and algorithm development described by Xia et al 13 Clinical metabolomics testing, such as for IEM screening, is a nascent testing approach that is amenable to multiple sample types, [37][38][39] can substitute tens of smaller assays, and represents an important proof-of-principle to support future pre-clinical and clinical applications for metabolomics. [37][38][39]80,84,85,88,89,95,96 Expanding on this, additional studies will provide new insights into acute and chronic diseases such as cardiovascular disease, hypertension, cancer, inflammatory disease, autoimmune disease, metabolic disorders, and neurological diseases. Genome-wide association studies can link genotypes to biochemical profiles, 97,98 and future analyses will provide increased resolution into the penetrance of the genotypes and the clinical accuracy of the biochemical profiles associated with these genetic predispositions.…”

Glucose transporter deficienc y syndrome type 1: a case report

“…Основные методы диагностики заболевания сводятся к проведению люмбальной пункции с целью определения уровня глюкозы в ликворе и молекулярно-генетическому тестированию. Специфическим маркером синдрома дефицита GLUT1 является низкая концентрация глюкозы в спинномозговой жидкости (<2 ммоль / л) [5]. Соотношение уровней глюкозы в спинномозговой жидкости и глюкозы в крови обычно составляет менее 0,4 [23].…”