Joerg Klepper

Glucose transporter type I (Glut1) deficiency syndrome (Glut1DS) is associated with paroxysmal exertion-induced dystonia (PED). Episodes are published as brief, lasting 20 to 30 minutes. Increasingly, Glut1DS patients report prolonged PED of more than 1 hour duration. In a cohort of 60 Glut1DS patients seen in our institution within a 4-year period, a total of 26/60 patients (43%) on ketogenic dietary therapy (KDT) experienced PED. In 18/26 patients (30%), episodes lasted less than 1 hour as previously described. In 8/26 patients (13%), prolonged episodes lasted more than 1 hour up to 1 day despite adequate dietary treatment. We conclude that PED is common in Glut1DS starting in late childhood despite adequate treatment with KDT. Prolonged PED in Glut1DS occurs in a subset of patients, also unresponsive to KDT, and represents a substantial burden to patients and families.

Objective: Ketogenic dietary therapies (KDTs) are the treatment of choice for Glut1 Deficiency Syndrome (Glut1DS), providing dietary ketones as an alternative fuel to the brain and effectively controlling seizures. Recent evidence indicates insufficient seizure control in Glut1DS patients despite adequate KDT and ketosis. Methods: Fifty‐three patients, diagnosed with Glut1DS and treated by KDT, were followed in a single‐center outpatient clinic from 2000 to 2023. Epilepsy, present in 44 patients, was analyzed for seizure control, EEG changes, and potential correlations to clinical and genetic features. Epilepsy response to KDT was defined as a >90% seizure reduction on KDT monotherapy. Results: On KDT monotherapy 27/44 (61%) patients became >90% seizure free, rated as responders. 17/44 were non‐responders. Within this group, 10/17 patients responded to KDT plus antiseizure comedication. In 7 patients, KDT plus antiseizure comedication failed to control seizures. No correlations of seizure control to gender, age at start or type of KDT, or SLC2A1 variants were observed. In responders ( n = 27), EEG epileptic activity, evident in 15/27 patients, improved on KDT in 5 patients. In non‐responders ( n = 17), EEG epileptic activity was evident in 14/17 and improved on KDT in 9 patients. EEG background slowing prior to KDT normalized in KDT in all responders (4/27), but in none of the non‐responders (4/17). Significance: Epilepsy is a dominant feature of Glut1DS. KDT provides efficient seizure control, but failure to control epilepsy is more common than expected. KDT epilepsy response did not correlate with seizure type, clinical, or genetic features, emphasizing the complexity of this entity. Add‐on antiseizure medication can be effective in some patients, without individual drug superiority. Epileptic activity on EEG did not prove a good marker for outcome, but reversible EEG background slowing on KDT might be predictive for favorable seizure control. Plain Language Summary: Impaired glucose transport into the brain causes a brain energy crisis termed Glut1 Deficiency. Ketogenic diets mimic fasting, provide ketones as an alternative fuel, and effectively restore brain function. In our study, this worked for ca. 60% of patients. To our surprise, epilepsy persisted in about 40% of patients despite ketogenic diets for reasons unknown. Additional medication against epilepsy randomly helped in some patients. We analyzed many parameters without finding obvious explanations. Electrical brain activity improvement on ketogenic diets might be a future marker for efficient seizure control.

Glut1 Deficiency Syndrome (Glut1DS) has emerged as a treatable, but complex entity. Increasing data on pathogenic mechanisms, phenotype, genotype, and ketogenic dietary therapies (KDT) are available, as summarized in this review. Many challenges remain: novel symptoms emerge and vary with age. In Glut1DS, KDT in pregnancy and the clinical features in neonates and adults are poorly understood. KDT are ineffective in some patients for reasons yet unknown. Research reaches beyond the concept of brain energy depletion by impaired GLUT1‐mediated glucose transfer across the blood–brain barrier. Novel concepts investigate alternative substrates, transport mechanisms, and metabolic interactions of different brain cell types. Future, yet currently unavailable prospects are neonatal screening for Glut1DS, reliable biomarkers, predictors for outcome, and alternative therapies, along with and beyond KDT.

Glucose transporter type 1 deficiency syndrome (GLUT1DS) commonly presents with early‐onset epilepsy that often resists conventional pharmacological treatment. Ketogenic diet therapy (KDT) is the preferred approach to address the underlying metabolic anomaly. However, a subset of GLUT1DS patients presents resistance to KDT, with the causes remaining elusive. This comprehensive literature review aims to explore the characteristics of KDT failure in GLUT1DS and identify risk factors within this population. Our goal is to improve counseling and prognostication for these patients. So, we conducted a comprehensive literature review on PubMed, focusing on studies documenting pediatric GLUT1DS patients with drug‐resistant epilepsy unresponsive to KDT. We identified five cases of KDT failure in female GLUT1DS patients, aged 10 days to 13 years at diagnosis. Predominant seizure types were absence seizures, with a few cases of clonic, tonic, or myoclonic seizures. EEG consistently revealed 2–3.5 Hz generalized spike‐and‐wave discharges. Genetic investigations revealed point mutations and deletions in two cases each. Despite an in‐depth search, no specific features were found to reliably distinguish KDT non‐responders from responders, underscoring the need for further research. In cases of KDT ineffectiveness for seizure control in GLUT1DS patients, exploring alternative therapeutic strategies becomes imperative to managing symptoms while maintaining quality of life. Large‐scale multicenter studies, facilitated through international collaborations like the European Network for Therapy in Rare Epilepsies (NETRE), hold promise in elucidating the complexities of this patient population and developing personalized therapeutic approaches.Plain Language Summary: Glucose transporter type 1 deficiency syndrome often causes difficult‐to‐treat epilepsy. The ketogenic diet works for many patients, but some do not respond. This review investigated cases of diet failure but could not identify common features among poor responders. Further research is needed to understand these cases and explore alternative treatments.

The ketogenic diet (KD) can have a negative impact on the linear growth and body composition of children. The aims of this study were to review two centers' experience with children who developed height deceleration on the KD and determine if the height deceleration was secondary to growth hormone deficiency (GHD), and if growth hormone therapy (GHT) would be effective and safe (not altering ketosis or seizure frequency). Retrospective chart reviews were performed on patients with KD referred to Endocrinology between 2013 and 2018. Seventeen children were identified. Data reviewed included: demographics, growth velocity, KD ratio, protein/calorie intake, lab results, GH dosage, Tanner stage, and seizure frequency, and endocrine recommendations. Descriptive statistics were performed. Of the 17 children referred to the Endocrine Division, seven children were growth hormone deficient and began GHT. Data were provided for six patients (2 males, 4 females; age 2-7 years at the start of KD) on the KD for >6 years and on GHT for >4 years. Growth for all patients stabilized or increased. IGF-1 z-scores normalized. GHT did not affect seizure frequency or ketosis. GHT in those with GHD can be an appropriate option allowing better growth while still maintaining ketogenic therapy and seizure control.

The aim of this research was to characterize cognitive abilities in patients with Glut1-Deficiency syndrome (Glut1DS) following ketogenic diet therapy (KDT). Methods: The cognitive profiles of eight children were assessed using the Wechsler Intelligence Scale (WISC-IV). The effect of ketogenic diet therapy (KDT) on individual subareas of intelligence was analyzed considering the potential influence of speech motor impairments. Results: Patients with Glut1DS showed a wide range of cognitive performance levels. Some participants showed statistically and clinically significant discrepancies between individual subdomains of intelligence. Both variables, KDT initiation as well as duration, had a positive effect on the overall IQ score. Significant correlations were partially found between the time of KDT initiation and the level of IQ scores, depending on the presence of expressive language test demands of the respective subtests of the WISC-IV. Accordingly, the participants benefited les in the linguistic cognitive domain. The discrepancies in cognitive performance profiles of patients with Glut1DS can be attributed to the possibility of a negative distortion of the results due to the influence of speech motor impairments. Conclusions: The individual access skills of test persons should be more strongly considered in test procedures for the assessment of intelligence to reduce the negative influence of motor deficits on test performance. Specific characterization and systematization of the speech disorder are indispensable for determining the severity of speech motor impairment in Glut1DS. Therefore, a stronger focus on dysarthria during diagnosis and therapy is necessary.

Febrile seizures (FS) are usually self-limiting and cause no morbidity. Nevertheless they represent very traumatic events for families. There is a need to identify key messages that reassure carers and help to prevent inappropriate, anxiety-driven behaviors associated with “fever phobia.” No recommendations have been proposed to date regarding the content of such messages. Using a Delphi process, we have established a consensus regarding the information to be shared with families following a FS. Twenty physicians (child neurologists and pediatricians) from five European countries participated in a three-step Delphi process between May 2018 and October 2019. In the first step, each expert was asked to give 10 to 15 free statements about FS. In the second and third steps, statements were scored and selected according to the expert ranking of importance. A list of key messages for families has emerged from this process, which offer reassurance about FS based on epidemiology, underlying mechanisms, and the emergency management of FS should they recur. Interestingly, there was a high level of agreement between child neurologists and general pediatricians. Conclusion: We propose key messages to be communicated with families in the post-FS clinic setting. What is Known: • Febrile seizures (FS) are traumatic events for families. • No guidelines exist on what information to share with parents following a FS. What is New: • A Delphi process involving child neurologists and pediatricians provides consensual statement about information to deliver after a febrile seizure. • We propose key messages to be communicated with families in the post-FS clinic setting.

Glut1 deficiency syndrome (Glut1DS) is a brain energy failure syndrome caused by impaired glucose transport across brain tissue barriers. Glucose diffusion across tissue barriers is facilitated by a family of proteins including glucose transporter type 1 (Glut1). Patients are treated effectively with ketogenic diet therapies (KDT) that provide a supplemental fuel, namely ketone bodies, for brain energy metabolism. The increasing complexity of Glut1DS, since its original description in 1991, now demands an international consensus statement regarding diagnosis and treatment. International experts (n = 23) developed a consensus statement utilizing their collective professional experience, responses to a standardized questionnaire, and serial discussions of wide‐ranging issues related to Glut1DS. Key clinical features signaling the onset of Glut1DS are eye‐head movement abnormalities, seizures, neurodevelopmental impairment, deceleration of head growth, and movement disorders. Diagnosis is confirmed by the presence of these clinical signs, hypoglycorrhachia documented by lumbar puncture, and genetic analysis showing pathogenic SLC2A1 variants. KDT represent standard choices with Glut1DS‐specific recommendations regarding duration, composition, and management. Ongoing research has identified future interventions to restore Glut1 protein content and function. Clinical manifestations are influenced by patient age, genetic complexity, and novel therapeutic interventions. All clinical phenotypes will benefit from a better understanding of Glut1DS natural history throughout the life cycle and from improved guidelines facilitating early diagnosis and prompt treatment. Often, the presenting seizures are treated initially with antiseizure drugs before the cause of the epilepsy is ascertained and appropriate KDT are initiated. Initial drug treatment fails to treat the underlying metabolic disturbance during early brain development, contributing to the long‐term disease burden. Impaired development of the brain microvasculature is one such complication of delayed Glut1DS treatment in the postnatal period. This international consensus statement should facilitate prompt diagnosis and guide best standard of care for Glut1DS throughout the life cycle.