The use of ketogenic diets in children living with drug-resistant epilepsy, glucose transporter 1 deficiency syndrome and pyruvate dehydrogenase deficiency: A scoping review.

BACKGROUND: The ketogenic diet (KD) is a high fat, moderate protein and very low carbohydrate diet. It can be used as a medical treatment for drug-resistant epilepsy (DRE), glucose transporter 1 deficiency syndrome and pyruvate dehydrogenase deficiency. The aim of this scoping review was to map the KD literature, with a focus on epilepsy and associated metabolic conditions, to summarise the current evidence-base and identify any gaps. METHODS: This review was conducted using JBI scoping review methodological guidance and the PRISMA extension for scoping reviews reporting guidance. A comprehensive literature search was conducted in September 2021 and updated in February 2024 using MEDLINE, CINAHL, AMED, EmBASE, CAB Abstracts, Scopus and Food Science Source databases. RESULTS: The initial search yielded 2721 studies and ultimately, data were extracted from 320 studies that fulfilled inclusion criteria for the review. There were five qualitative studies, and the remainder were quantitative, including 23 randomised controlled trials (RCTs) and seven quasi-experimental studies. The USA published the highest number of KD studies followed by China, South Korea and the UK. Most studies focused on the classical KD and DRE. The studies key findings suggest that the KD is efficacious, safe and tolerable. CONCLUSIONS: There are opportunities available to expand the scope of future KD research, particularly to conduct high-quality RCTs and further qualitative research focused on the child's needs and family support to improve the effectiveness of KDs.

Case for supporting astrocyte energetics in glucose transporter 1 deficiency syndrome.

In glucose transporter 1 deficiency syndrome (Glut1DS), glucose transport into brain is reduced due to impaired Glut1 function in endothelial cells at the blood-brain barrier. This can lead to shortages of glucose in brain and is thought to contribute to seizures. Ketogenic diets are the first-line treatment and, among many beneficial effects, provide auxiliary fuel in the form of ketone bodies that are largely metabolized by neurons. However, Glut1 is also the main glucose transporter in astrocytes. Here, we review data indicating that glucose shortage may also impact astrocytes in addition to neurons and discuss the expected negative biochemical consequences of compromised astrocytic glucose transport for neurons. Based on these effects, auxiliary fuels are needed for both cell types and adding medium chain triglycerides (MCTs) to ketogenic diets is a biochemically superior treatment for Glut1DS compared to classical ketogenic diets. MCTs provide medium chain fatty acids (MCFAs), which are largely metabolized by astrocytes and not neurons. MCFAs supply energy and contribute carbons for glutamine and γ-aminobutyric acid synthesis, and decanoic acid can also block α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors. MCTs do not compete with metabolism of ketone bodies mostly occurring in neurons. Triheptanoin, an anaplerotic but also gluconeogenic uneven MCT, may be another potential addition to ketogenic diets, although maintenance of "ketosis" can be difficult. Gene therapy has also targeted both endothelial cells and astrocytes. Other approaches to increase fuel delivery to the brain currently investigated include exchange of Glut1DS erythrocytes with healthy cells, infusion of lactate, and pharmacological improvement of glucose transport. In conclusion, although it remains difficult to assess impaired astrocytic energy metabolism in vivo, astrocytic energy needs are most likely not met by ketogenic diets in Glut1DS. Thus, we propose prospective studies including monitoring of blood MCFA levels to find optimal doses for add-on MCT to ketogenic diets and assessing of short- and long-term outcomes.

Utilization of EEG microstates as a prospective biomarker for assessing the impact of ketogenic diet in GLUT1-DS.

OBJECTIVE: The aim of the study is to analyze microstate patterns in GLUT1-DS, both before and after the ketogenic diet (KD). METHODS: We conducted microstate analysis of a patient with GLUT-1 DS and 27 healthy controls. A systematic literature review and meta-analysis was done. We compared the parameters of the patients with those of healthy controls and the incorporating findings in literature. RESULTS: The durations of the patient were notably shorter, and the occurrence rates were longer than those of healthy controls and incorporating findings from the review. After 10 months of KD, the patient's microstate durations exhibited an increase from 53.05 ms, 57.17 ms, 61.80 ms, and 49.49 ms to 60.53 ms, 63.27 ms, 71.11 ms, and 66.55 ms. The occurrence rates changed from 4.0774 Hz, 4.9462 Hz, 4.8006 Hz, and 4.0579 Hz to 3.3354 Hz, 3.7893 Hz, 3.5956 Hz, and 4.1672 Hz. In healthy controls, the durations of microstate class A, B, C, and D were 61.86 ms, 63.58 ms, 70.57 ms, and 72.00 ms, respectively. CONCLUSIONS: Our findings suggest EEG microstates may be a promising biomarker for monitoring the effect of KD. Administration of KD may normalize the dysfunctional patterns of temporal parameters.

GLUT-1DS resistant to ketogenic diet: from clinical feature to in silico analysis. An exemplificative case report with a literature review.

Glucose transporter type 1 deficiency syndrome (GLUT-1DS) is characterized by alterations in glucose translocation through the blood-brain barrier (BBB) due to mutation involving the GLUT-1 transporter. The fundamental therapy is ketogenic diet (KD) that provide an alternative energetic substrate - ketone bodies that across the BBB via MCT-1 - for the brain. Symptoms are various and include intractable seizure, acquired microcephalia, abnormal ocular movement, movement disorder, and neurodevelopment delay secondary to an energetic crisis for persistent neuroglycopenia. KD is extremely effective in controlling epileptic seizures and has a positive impact on movement disorders and cognitive impairment. Cases of KD resistance are rare, and only a few of them are reported in the literature, all regarding seizure. Our study describes a peculiar case of GLUT-1DS due to a new deletion involving the first codon of SLC2A1 gene determining a loss of function with a resistance to KD admitted to hospital due to intractable episodes of dystonia. This patient presented a worsening of symptomatology at higher ketonemia values but without hyperketosis and showed a complete resolution of symptomatology while maintaining low ketonemia values. Our study proposes an in-silico genomic and proteomic analysis aimed at explaining the atypical response to KD exhibited by our patient. In this way, we propose a new clinical and research approach based on precision medicine and molecular modelling to be applied to patients with GLUT-1DS resistant to first-line treatment with ketogenic diet by in silico study of genetic and altered protein product.

Síndrome de deficiencia del transportador de glucosa tipo 1 (SDGLUT-1) tratado con dieta cetogénica: Caso clínico / Glucose transponer type 7 deficiency síndrome (GLUT-1 SD) treated with ketogenic diet: Report of one case

The glucose transporter type 1 deficiency syndrome (GLUT-1 SD) (OMIM 606777) is an inborn error of metabolism of brain glucose transport. The characteristic clinical manifestations are seizures, hypotonia, developmental delay, microcephaly and hypoglycorrhachia. We report a girl with normal weight and height at birth. At 6 weeks of age she started with convulsions reaching up to 20 myoclonic seizures a day. She was treated with valproate, phenobarbital and carbamazepine without response. Blood analysis including aminoacids and acylcarnitines were all normal. The brain MRI showed frontal atrophy with an increased subarachnoidal space and Electroencephalography was abnormal. Blood glucose was 84 mg/dl and spinal fluid glucose 26 mg/dl with a ratio of 0.31 (Normal Ratio >0.65+00.1). These results suggested the diagnosis of GLUT-1 SD, and was confirmed with erythrocyte glucose uptake of 44 percent (Normal range 80-100 percent). A molecular study found the mutation 969del, C971T in exon 6 of the gene Glut-1. Treatment with a ketogenic diet was started immediately and after 7 days with this diet seizures ceased. Anticonvulsants were progressively suspended. At present, the patient is 6 years old, she continues on a ketogenic diet and supplements with L-carnitine, lipoic acid, vitamins and minerals. Growth and development are normal with an intelligence quotient of 103. It is concluded that it is necessary to include GLUT-1 SD in the differential diagnosis of children with early seizures that are non responsive to pharmacological treatment.