Clinical, Neuroimaging, and Metabolic Footprint of the Neurodevelopmental Disorder Caused by Monoallelic HK1 Variants.

Background and Objectives: Hexokinase 1 (encoded by HK1) catalyzes the first step of glycolysis, the adenosine triphosphate-dependent phosphorylation of glucose to glucose-6-phosphate. Monoallelic HK1 variants causing a neurodevelopmental disorder (NDD) have been reported in 12 individuals. Methods: We investigated clinical phenotypes, brain MRIs, and the CSF of 15 previously unpublished individuals with monoallelic HK1 variants and an NDD phenotype. Results: All individuals had recurrent variants likely causing gain-of-function, representing mutational hot spots. Eight individuals (c.1370C>T) had a developmental and epileptic encephalopathy with infantile onset and virtually no development. Of the other 7 individuals (n = 6: c.1334C>T; n = 1: c.1240G>A), 3 adults showed a biphasic course of disease with a mild static encephalopathy since early childhood and an unanticipated progressive deterioration with, e.g., movement disorder, psychiatric disease, and stroke-like episodes, epilepsy, starting in adulthood. Individuals who clinically presented in the first months of life had (near)-normal initial neuroimaging and severe cerebral atrophy during follow-up. In older children and adults, we noted progressive involvement of basal ganglia including Leigh-like MRI patterns and cerebellar atrophy, with remarkable intraindividual variability. The CSF glucose and the CSF/blood glucose ratio were below the 5th percentile of normal in almost all CSF samples, while blood glucose was unremarkable. This biomarker profile resembles glucose transporter type 1 deficiency syndrome; however, in HK1-related NDD, CSF lactate was significantly increased in all patients resulting in a substantially different biomarker profile. Discussion: Genotype-phenotype correlations appear to exist for HK1 variants and can aid in counseling. A CSF biomarker profile with low glucose, low CSF/blood glucose, and high CSF lactate may point toward monoallelic HK1 variants causing an NDD. This can help in variant interpretation and may aid in understanding the pathomechanism. We hypothesize that progressive intoxication and/or ongoing energy deficiency lead to the clinical phenotypes and progressive neuroimaging findings.

Effects of Sodium Lactate Infusion in Two Girls with Glucose Transporter 1 Deficiency Syndrome.

BACKGROUND: Glucose is an important fuel for the brain. In glucose transporter 1 deficiency syndrome (GLUT1DS), the transport of glucose across the blood-brain barrier is limited. Most individuals with GLUT1DS present with developmental problems, epilepsy, and (paroxysmal) movement disorders, and respond favorably to the ketogenic diet. Similar to ketones, lactate is an alternative energy source for the brain. The aim of this study is to investigate whether intravenous infusion of sodium lactate in children with GLUT1DS has beneficial effects on their epilepsy. METHODS: We performed a proof of principle study with two subjects with GLUT1DS who were not on a ketogenic diet and suffered from absence epilepsy. After overnight fasting, sodium lactate (600 mmol/L) was infused during 120 minutes, under video electroencephalographic (EEG) recording and monitoring of serum lactate, glucose, electrolytes, and pH. Furthermore, the EEGs were compared with pre-/postprandial EEGs of both subjects, obtained shortly before the study. RESULTS: Fasting EEGs of both subjects showed frequent bilateral, frontocentral polyspike and wave complexes. In one subject, no more epileptic discharges were seen postprandially and after the start of lactate infusion. The EEG of the other subject did not change, neither postprandially nor after lactate infusion. Serum pH, lactate, and sodium changed temporarily during the study. CONCLUSION: This study suggests that sodium lactate infusion is possible in individuals with GLUT1DS, and may have potential therapeutic effects. Cellular abnormalities, beyond neuronal energy failure, may contribute to the underlying disease mechanisms of GLUT1DS, explaining why not all individuals respond to the supplementation of alternative energy sources.

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

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-α1-3-xylose-α1-3-glucose may originate from glycosylated proteins; their decreased levels are hypothetically the consequence of insufficient glucose, one of two substrates for O-glucosylation. Since many proteins are O-glucosylated, this deficiency may affect cellular processes and thus contribute to GLUT1DS pathophysiology. The novel CSF biomarkers have the potential to improve the biochemical diagnosis of GLUT1DS. Our findings imply that brain glucose deficiency in GLUT1DS may cause disruptions at the cellular level that go beyond energy metabolism, underlining the importance of developing treatment strategies that directly target cerebral glucose uptake.

Head circumference in glucose transporter 1 deficiency syndrome: Normal for individuals, abnormal as a group.

In the literature, microcephaly is considered as part of the classical phenotype of glucose transporter 1 deficiency syndrome (GLUT1DS), and previous cohort studies reported a prevalence of microcephaly of around 50%. In our clinical experience, however, only very few patients with GLUT1DS appear to have microcephaly. Therefore, we conducted an observational study among a large cohort of Dutch patients with GLUT1DS to investigate the prevalence of microcephaly, defined as < 2 standard deviations (SD) below the mean. We analysed the head circumference of 54 patients and found a prevalence of microcephaly at last known measurement of 6.5%. Notably, none of the patients had a head circumference < -3 SD. However, we learned that 75.9% of the patients had a head circumference below 0 SD. This study shows that microcephaly occurs less often than previously thought in patients with GLUT1DS, and that primary or secondary microcephaly does not seem to be a sign for clinicians to suspect GLUT1DS. As a group, however, patients with GLUT1DS seem to have decreased head circumference compared to healthy individuals and as such, our study suggests that early brain development and brain growth may be compromised in GLUT1DS.

Lactate infusion as therapeutical intervention: a scoping review.

Traditionally, clinicians consider lactate as a waste product of anaerobic glycolysis. Interestingly, research has shown that lactate may serve as an alternative fuel for the brain to protect it against harm. The increasing scientific awareness of the potential beneficial side of lactate, however, is entering the clinic rather slowly. Following this, and realizing that the application of potential novel therapeutic strategies in pediatric populations often lags behind the development in adults, this review summarizes the key data on therapeutic use of intravenous infusion of sodium lactate in humans. PubMed and clinicaltrial.gov were searched up until November 2021 focusing on interventional studies in humans. Thirty-four articles were included in this review, with protocols of lactate infusion in adults with diabetes mellitus, traumatic brain injury, Alzheimer's disease, and cardiac disease. One study on lactate infusion in children was also included. Results of our literature search show that sodium lactate can be safely administrated, without major side effects. Additionally, the present literature clearly shows the potential benefits of therapeutic lactate infusion under certain pathological circumstances, including rather common clinical conditions like traumatic brain injury. CONCLUSION: This review shows that lactate is a save, alternative energy source for the adult brain warranting studies on the potential therapeutic effects of sodium lactate infusion in children. WHAT IS KNOWN: • Lactate is generally considered a waste product of anaerobic glycolysis. However, lactate also is an alternative fuel for different organs, including the brain. • Lactate infusion is not incorporated in standard care for any patient population. WHAT IS NEW: • Thirty-four studies investigated the therapeutic use of intravenous sodium lactate in different patient populations, all with different study protocols. • Literature shows that lactate infusion may have beneficial effects in case of hypoglycemia, traumatic brain injury, and cardiac failure without the risk of major side effects.