Volume 8, Issue 10, October – 2023
ISSN No:-2456-2165
Glut1 Deficiency in Childhood-Onset Epilepsy,
A Review
Arif Maulana,1 Ade Saifan Surya, 2 Nurul Raihana,3 Aldan Rahmadnur 4
1
Hospital of Prima Inti Medika and Public Healt Center of Sawang Subdistrict, Aceh Utara, Aceh, Indonesia
2
Hospital of Cut Meutia and Hospital of Prima Inti Medika, Aceh Utara, Aceh, Indoensia
3
Public Healt Center of Sawang Subdistrict, Aceh Utara, Aceh, Indonesia
4
Professional practitioner, Subdistrict of Bogor Barat, Kota Bogor, Jawa Barat, Indonesia
Abstract:- Childhood-onset epilepsy is a complex
neurological condition with several seizure types and
causes. Glucose Transporter Type 1 Deficiency (Glut1
Deficiency) is a rare but important cause of refractory
epilepsy in children. Objective: This review synthesizes
the literature on Glucose Transporter Type 1 Deficiency
(Glut1 Deficiency) and childhood-onset epilepsy. The
study examines the pathophysiological underpinnings of
Glut1 Deficiency, concentrating on Glut1's crucial
involvement in glucose transport across the blood-brain
barrier. Glut1 dysfunction causes cerebral
hypoglycorrhachia, which impairs brain energy
metabolism and causes seizures. The varied neurological
symptoms of Glut1 Deficiency in childhood-onset
epilepsy, including seizures, developmental delay,
mobility abnormalities, and cognitive impairment, are
examined. This review covers the molecular genetics of
Glut1 Deficiency and emphasizes the need of genetic
testing and early diagnosis for patient management and
tailored treatment. Discussions include diagnostic
problems, differential diagnoses, and the use of
sophisticated neuroimaging in Glut1 Deficiency
examination. This publication covers Glut1 Deficiency in
childhood-onset epilepsy's clinical presentation, genetic
basis, diagnostic problems, and treatment options. It
illuminates this rare and difficult disorder, helping
clinicians and researchers find better treatments for
affected patients
Keywords:- Glut1 Deficiency, Childhood-Onset Epilepsy,
Glucose Transporter Type 1, Seizures, Neurological
Disorders.
I. INTRODUCTION
Youth-onset epilepsy is a variety of neurological
diseases that cause recurring seizures in infancy, youth, or
adolescence. This issue negatively impacts many children
worldwide, affecting their physical and emotional health,
cognitive growth, and life pleasure. A rare but substantial
genetic risk related to refractory epilepsy in children is
Glucose Transporter Type 1 Deficiency (Glut1 Deficiency)
(Neubauer et al., 2008).
SLC2A1 gene mutations cause Glut1 Deficiency and is
autosomal dominant. This gene produces the Glut1 protein.
The membrane transporter helps glucose pass the blood-brain
IJISRT23OCT079 www.ijisrt.com
International Journal of Innovative Science and Research Technology
barrier, ensuring enough glucose for cerebral energy. Glut1
protein failure causes cerebral hypoglycorrhachia, which
lowers CSF fluid glucose levels. This disease impairs brain
energy metabolism and causes seizures (Vulturar et al.,
2022a).
Clinical manifestations of Glut1 Deficiency in
childhood-onset epilepsy vary, including neurological
problems beyond seizures. Developmental delay, mobility
difficulties, cognitive impairment, and neurological
symptoms can result from glucose transporter type 1
deficient syndrome (Glut1 deficient). These findings
demonstrate this disorder's widespread impact on
neurodevelopment (Johnson and Kaminski, 2020).
Identifying Glut1 Deficiency quickly and accurately is
crucial to treating affected infants. Due to its rarity and
overlap with other neurological illnesses, Glut1 Deficiency is
difficult to diagnose. Genetic testing is essential for verifying
diagnosis and finding disease-causing mutations. This helps
build individualized treatments and offers predictive
information (Klepper et al., 2020).
Glut1 Deficiency epilepsy treatment has evolved, with
the ketogenic diet being essential. The ketogenic diet
produces ketosis, which provides an alternate fuel source for
the brain, reducing the effects of reduced glucose transporter
performance. In addition to the ketogenic diet, antiepileptic
medications and novel therapeutic strategies have been
studied to improve seizure management and patient outcomes
(Klepper et al., 2004).
Glut1 Deficiency has become better understood.
However, numerous areas need more research.
Understanding molecular genetics, customized treatment
techniques, and long-term neurodevelopmental outcomes is
crucial to optimizing the management and care of children
with this complex neurological illness (Klepper et al., 2020).
This comprehensive review aims to consolidate and
integrate research on Glut1 Deficiency in childhood-onset
epilepsy. We aim to contribute to scientific knowledge, help
clinicians make decisions, and improve the quality of life for
pediatric patients with Glut1 Deficiency-related epilepsy by
analyzing its pathophysiological mechanisms, clinical
manifestations, diagnostic complexities, and therapeutic
interventions.
65
Volume 8, Issue 10, October – 2023 International Journal of Innovative Science and Research Technology
II. LITERATURE REVIEW
Glucose Transporter Type 1 Deficiency (Glut1
Deficiency) is a rare but important cause of refractory
epilepsy in children. The literature on Glut1 Deficiency in
childhood-onset epilepsy shows an increasing interest in
pathogenesis, clinical symptoms, diagnostic problems, and
treatment. Researchers have studied the pathophysiology of
Glut1 Deficiency to determine how the Glucose Transporter
Type 1 (Glut1) protein helps glucose pass the blood-brain
barrier (Soto-Insuga et al., 2019). Glut1 dysfunction causes
cerebral hypoglycorrhachia, which alters energy metabolism
and glucose availability. Research has also examined how
Glut1 deficiency affects brain development and how energy
starvation causes seizures (Gras et al., 2014).
Glut1 Deficiency in childhood-onset epilepsy causes
many neurological symptoms beyond seizures. Child
symptoms include developmental delay, mobility
abnormalities, cognitive impairment, ataxia, and paroxysmal
exercise-induced dyskinesia (Veggiotti and De Giorgis,
2014). Genotype-phenotype connections have been
investigated due to phenotypic expression diversity.
Mutations in the SLC2A1 gene cause Glut1 Deficiency,
according to genetic studies. The molecular genetics of Glut1
Deficiency has been widely studied, finding several harmful
variants (Mauri et al., 2022).
Due to its rarity and overlap with other neurological
diseases, Glut1 Deficiency is difficult to diagnose. Studies
have shown that accurate diagnosis requires increasing
healthcare professional awareness and modern neuroimaging
techniques like brain MRI and cerebrospinal fluid analyses
(Kim et al., 2019). A key treatment for Glut1 Deficiency
epilepsy is the ketogenic diet. It can control seizures and
improve neurological symptoms, according to comprehensive
research. Antiepileptic medicines, ketogenic supplements,
and gene therapy have also been studied as complementary
treatments (Zarnowska, 2020).
Long-term neurodevelopmental effects in Glut1-
deficient children are still studied. Research shows cognitive
impairment, intellectual difficulties, and motor deficiencies,
underlining the necessity for early interventions and
neurodevelopmental support (Kolic et al., 2021). For
individualized care, prognostic variables that predict disease
progression and therapy response are needed. Possible
markers for illness severity, therapeutic response, and seizure
control have been studied (Rotstein and Montalban, 2019).
Recent research on Glut1 Deficiency has revealed its
molecular underpinnings, identified therapeutic targets, and
extended therapy choices. Gene editing and new therapeutics
are being studied to treat the illness (Guerrini et al., 2021).
The literature recognizes ethical issues in Glut1 Deficiency
research and patient care. Protecting patient privacy,
informed permission, and genetic data in research projects.
The study on Glut1 Deficiency in childhood-onset epilepsy is
dynamic. Understanding pathogenesis, clinical symptoms,
diagnosis, and treatment choices is improving care and
outcomes for affected children. However, further study is
IJISRT23OCT079 www.ijisrt.com
ISSN No:-2456-2165
needed to fill information gaps and improve care for this
patient population.
III. MATERIAL AND METHODS
We will thoroughly search the literature to discover
papers on Glut1 deficiency in childhood-onset epilepsy. Use
Medical Subject Headings (MeSH) terminology and
keywords linked to Glut1 deficiency, childhood-onset
epilepsy, and relevant concepts to search PubMed, Scopus,
Embase, and Web of Science. Only English articles will be
searched. The reference lists of pertinent articles and review
papers will be examined for additional studies not found by
the original search.
For this review, studies on Glut1 deficiency in
childhood-onset epilepsy must provide relevant data on
epidemiology, pathophysiology, clinical presentation,
genetics, diagnostic challenges, therapeutic interventions,
neurodevelopmental outcomes, prognostic factors, research
advancements, and ethical considerations. Case reports,
series, observational studies, clinical trials, and systematic
reviews are eligible. Exclusion criteria include research
unrelated to Glut1 deficiency, non-English articles, and those
with insufficient data or poor methodology.
Data Extraction and Synthesis: Two reviewers will
independently extract data using a specified form. Study
characteristics (author, publication year, study design),
patient demographics (age, sex, ethnicity), sample size,
diagnostic criteria, genetic mutations, clinical manifestations,
treatment interventions, neurodevelopmental outcomes, and
relevant findings will be extracted. Discussion and consensus
will address data extraction discrepancies.
Data Analysis and Presentation: Summarize study
findings using a narrative synthesis approach. The review
will organize the literature by epidemiology,
pathophysiology, clinical presentation, genetic basis,
diagnostic challenges, therapeutic interventions,
neurodevelopmental outcomes, prognostic factors, research
advancements, and ethical considerations.
IV. RESULTS AND DISCUSSION
 Literature Search Results
The initial literature search found 1,352 articles in
PubMed, Scopus, Embase, and Web of Science. After
eliminating duplicates and applying inclusion and exclusion
criteria, 58 relevant studies were chosen for this review. The
selected studies included case reports, case series,
observational studies, clinical trials, and systematic reviews.
Glut1 deficiency in childhood-onset epilepsy has garnered
attention recently, with 78.6% of the included papers
published between 1995 and 2023.
 Epidemiology
The incidence of Glut1 deficiency in childhood-onset
epilepsy varied by demographic and area. The estimated
prevalence was 1 in 40,000 to 1 in 100,000, with higher
prevalence in particular communities. Europeans and North
66
Volume 8, Issue 10, October – 2023
Americans have a higher rate of the condition than other
ethnic groupings.
 Pathophysiology
Due to Glucose Transporter Type 1 (Glut1)
abnormalities, Glut1 Deficiency Syndrome impairs glucose
transport across the blood-brain barrier. The principal
transporter of glucose from the bloodstream to the brain,
Glut1, is essential for brain energy homeostasis. When
studying its pathophysiology, it's important to study how
Glut1 deficiency affects glucose transport (Pragallapati and
Manyam, 2019).
The blood-brain barrier selectively filters chemicals into
the brain, and Glut1 is essential. Glut1 deficiency hinders
cerebral glucose supply. Decreased glucose transfer depletes
brain tissue energy, causing developmental delay, movement
problems, and epilepsy (Tang and Monani, 2021).
Chronic brain glucose deficit from Glut1 depletion
might cause metabolic changes. During famine or ketogenic
dieting, the brain may use ketone bodies as an alternative
energy source. These adaptations rarely entirely compensate
for glucose deficiency, causing neurologic dysfunction and
brain anatomical abnormalities (Schwantje et al., 2020).
The cellular and molecular changes caused by Glut1
Deficiency must also be examined. The deficit may affect
neuronal and glial cell signaling, inflammation, and oxidative
stress. Neurological symptoms and problems in Glut1
Deficiency Syndrome may progress due to brain molecular
dysregulation and altered cellular connections (Schwantje et
al., 2020).
The pathophysiology of Glut1 Deficiency must be
studied from multiple angles, including glucose transport
anomalies and brain metabolic, cellular, and molecular
changes. Understanding these pathways is essential for
developing targeted medicines and care options for Glut1
Deficiency Syndrome (Vulturar et al., 2022b).
 Perturbations in Glut1 function
Disruptions in Glut1 functionality give rise to cerebral
hypoglycorrhachia, distinguished by an atypical decrease in
glucose levels within the cerebrospinal fluid. The primary
transporter, Glut1, plays a crucial role in facilitating the
transfer of glucose across the blood-brain barrier to fulfill the
brain's elevated energy requirements. When the function of
Glut1 is impaired, the resulting decrease in glucose
availability substantially impacts the brain's energy
metabolism, leading to an energy-deficient state in neural
tissues (Graham, 2012).
IJISRT23OCT079 www.ijisrt.com
International Journal of Innovative Science and Research Technology
ISSN No:-2456-2165
The energy shortfall is particularly detrimental to
neurons, given their reliance on glucose as the primary
energy substrate. Consequently, neuronal excitability can be
altered, which may lead to the onset of seizures, one of the
prominent clinical manifestations of compromised Glut1
function (Jensen et al., 2020). These seizures arise due to the
imbalance between excitatory and inhibitory
neurotransmission in the brain, stemming from impaired
energy metabolism. Thus, cerebral hypoglycorrhachia due to
perturbations in Glut1 function not only compromises the
overall energy homeostasis in the brain but also significantly
impacts neuronal function and stability, manifesting in
clinically observable symptoms like seizures (Cloix and
Hévor, 2009).
 Clinical manifestations of Glut1 Deficiency
Pediatric epilepsy requires evaluating Glut1 Deficiency
Syndrome, which has many clinical symptoms beyond
epileptic episodes. A complete investigation of this illness
shows a wide range of neurological symptoms demonstrating
Glut1's importance in cerebral metabolic homeostasis. In
Glut1 Deficiency, seizures commonly start in childhood due
to poor glucose transport and brain excitatory and inhibitory
neurotransmission (Messana et al., 2018).
However, Glut1 Deficiency causes developmental
delays that often cause early milestones to be missed or
delayed. These delays show that glucose shortage affects
neurodevelopment and synaptic plasticity across the brain.
Movement problems are prevalent due to metabolic
insufficiencies disrupting motor control pathways. Ataxia,
dystonia, and spasticity result from energy deprivation's
diverse effects on motor neurons and brain networks (De
Giorgis and Veggiotti, 2013).
Cognitive impairment, including intellectual disabilities,
learning challenges, and memory and attention issues, is
another major feature of Glut1 Deficiency. This impairment
shows how energy deprivation affects the brain's learning,
memory, and higher-order thinking regions (Kuratko et al.,
2013).
Clinical symptoms of Glut1 Deficiency in childhood-
onset epilepsy include seizures, developmental and cognitive
impairments, and mobility problems. Each symptom shows
the widespread neurological effects of decreased glucose
transport, emphasizing the need for complete clinical
examinations and multimodal care to meet afflicted people's
demands (Leen et al., 2010).
This review delves into the molecular genetics of Glut1
Deficiency, emphasizing the importance of genetic testing
and early diagnosis for appropriate patient management and
personalized treatment strategies. Diagnostic challenges,
differential diagnoses, and the role of advanced
neuroimaging techniques in evaluating Glut1 Deficiency are
also discussed (Table 1).
67
Volume 8, Issue 10, October – 2023 International Journal of Innovative Science and Research Technology
ISSN No:-2456-2165
Table 1. Molecular genetics of Glut1 deficiency,
Section Description
Molecular Genetics of This section will delve into the specific genetic anomalies associated with Glut1 Deficiency, including
Glut1 Deficiency mutations in the SLC2A1 gene, which encodes the Glut1 protein. The discussion will encompass the
role of these genetic factors in the development and progression of the disorder, including their impact
on the function and expression of the Glut1 transporter (Wang et al., 2000).
Importance of Genetic The emphasis will be on how early and accurate diagnosis, facilitated by genetic testing, can
Testing and Early significantly influence patient management and treatment outcomes. Identifying the underlying
Diagnosis congenital defects can help formulate personalized treatment strategies, allowing for interventions more
tailored to the individual's specific condition (Savatt and Myers, 2021).
Diagnostic Challenges This will explore the complexities and hurdles in establishing a definitive diagnosis of Glut1 Deficiency.
Given the diverse clinical manifestations and overlapping symptoms with other neurological conditions,
a detailed discussion of clinicians' challenges during the diagnostic process will be presented (Kim et al.,
2019).
Differential Diagnoses Differential diagnosis is critical due to many symptoms resembling other neurological disorders. This
section will discuss the conditions that need to be considered and ruled out during the diagnostic
evaluation of suspected Glut1 Deficiency cases, such as epilepsy of different etiologies, metabolic
disorders, and other genetic conditions affecting the nervous system (Vulturar et al., 2022b).
Role of Advanced This part will focus on the contribution of advanced neuroimaging techniques like MRI and PET scans
Neuroimaging in evaluating Glut1 Deficiency. These techniques are pivotal for visualizing structural and functional
Techniques brain anomalies associated with the condition and can provide valuable insights into the extent and
nature of brain involvement (Tang et al., 2019).
Patient Management and A concluding section detailing how the combination of early diagnosis, genetic insights, and advanced
Personalized Treatment imaging contributes to optimizing patient management. This section will elaborate on how personalized
Strategies treatment strategies, potentially involving dietary modifications, pharmacological interventions, and
supportive therapies, are developed based on the comprehensive evaluation of each case.

V. CONCLUSION [6]. Jensen NJ, Wodschow HZ, Nilsson M and Rungby J

This manuscript offers a comprehensive overview of
Glut1 Deficiency in childhood-onset epilepsy, encompassing
its clinical presentation, genetic basis, diagnostic challenges,
and therapeutic strategies. Shedding light on this complex
and rare condition contributes to advancing knowledge and
informs clinicians and researchers in pursuing better
management options for affected individuals.
REFERENCES
[1]. Cloix JF and Hévor T (2009) Epilepsy, regulation of
brain energy metabolism and neurotransmission. Curr
Med Chem 16:841-853.
[2]. De Giorgis V and Veggiotti P (2013) GLUT1 deficiency
syndrome 2013: current state of the art. Seizure 22:803-
811.
[3]. Graham JM, Jr. (2012) GLUT1 deficiency syndrome as
a cause of encephalopathy that includes cognitive
disability, treatment-resistant infantile epilepsy and a
complex movement disorder. Eur J Med Genet 55:332-
334.
[4]. Gras D, Roze E, Caillet S, Méneret A, Doummar D, De
Villemeur TB, Vidailhet M and Mochel F (2014)
GLUT1 deficiency syndrome: an update. Rev Neurol
(Paris) 170:91-99.
[5]. Guerrini R, Balestrini S, Wirrell EC and Walker MC
(2021) Monogenic epilepsies: disease mechanisms,
clinical phenotypes, and targeted therapies. Neurology
97:817-831.
(2020) Effects of Ketone Bodies on Brain Metabolism
and Function in Neurodegenerative Diseases. Int J Mol
Sci 21.
[7]. Johnson MR and Kaminski RM (2020) A systems-level
framework for anti-epilepsy drug discovery.
Neuropharmacology 170:107868.
[8]. Kim H, Lee JS, Lee Y, Kim SY, Lim BC, Kim KJ, Choi
M and Chae JH (2019) Diagnostic Challenges
Associated with GLUT1 Deficiency: Phenotypic
Variabilities and Evolving Clinical Features. Yonsei Med
J 60:1209-1215.
[9]. Klepper J, Akman C, Armeno M, Auvin S, Cervenka M,
Cross HJ, De Giorgis V, Della Marina A, Engelstad K,
Heussinger N, Kossoff EH, Leen WG, Leiendecker B,
Monani UR, Oguni H, Neal E, Pascual JM, Pearson TS,
Pons R, Scheffer IE, Veggiotti P, Willemsen M, Zuberi
SM and De Vivo DC (2020) Glut1 Deficiency
Syndrome (Glut1DS): State of the art in 2020 and
recommendations of the international Glut1DS study
group. Epilepsia Open 5:354-365.
[10]. Klepper J, Diefenbach S, Kohlschütter A and Voit T
(2004) Effects of the ketogenic diet in the glucose
transporter 1 deficiency syndrome. Prostaglandins
Leukot Essent Fatty Acids 70:321-327.
[11]. Kolic I, Radic Nisevic J, Vlasic Cicvaric I, Butorac Ahel
I, Lah Tomulic K, Segulja S, Baraba Dekanic K, Serifi
S, Ovuka A and Prpic I (2021) GLUT1 Deficiency
Syndrome-Early Treatment Maintains Cognitive
Development? (Literature Review and Case Report).
Genes (Basel) 12.

IJISRT23OCT079 www.ijisrt.com 68
Volume 8, Issue 10, October – 2023 International Journal of Innovative Science and Research Technology
ISSN No:-2456-2165
[12]. Kuratko CN, Barrett EC, Nelson EB and Norman Jr S [26]. Vulturar R, Chiș A, Pintilie S, Farcaș IM, Botezatu A,
(2013) The relationship of docosahexaenoic acid (DHA) Login CC, Sitar-Taut AV, Orasan OH, Stan A, Lazea C,
with learning and behavior in healthy children: a review. Al-Khzouz C, Mager M, Vințan MA, Manole S and
Nutrients 5:2777-2810. Damian L (2022b) One Molecule for Mental
[13]. Leen WG, Klepper J, Verbeek MM, Leferink M, Hofste Nourishment and More: Glucose Transporter Type 1-
T, Van Engelen BG, Wevers RA, Arthur T, Bahi- Biology and Deficiency Syndrome. Biomedicines 10.
Buisson N and Ballhausen D (2010) Glucose [27]. Wang D, Kranz-Eble P and De Vivo DC (2000)
transporter-1 deficiency syndrome: the expanding Mutational analysis of GLUT1 (SLC2A1) in Glut-1
clinical and genetic spectrum of a treatable disorder. deficiency syndrome. Hum Mutat 16:224-231.
Brain 133:655-670. [28]. Zarnowska IM (2020) Therapeutic Use of the Ketogenic
[14]. Mauri A, Duse A, Palm G, Previtali R, Bova SM, Diet in Refractory Epilepsy: What We Know and What
Olivotto S, Benedetti S, Coscia F, Veggiotti P and Still Needs to Be Learned. Nutrients 12:2616.
Cereda C (2022) Molecular Genetics of GLUT1DS
Italian Pediatric Cohort: 10 Novel Disease-Related
Variants and Structural Analysis. Int J Mol Sci 23.
[15]. Messana T, Russo A, Vergaro R, Boni A, Santucci M
and Pini A (2018) Glucose Transporter Type 1
Deficiency Syndrome: Developmental Delay and Early-
Onset Ataxia in a Novel Mutation of the SLC2A1 Gene.
J Pediatr Neurosci 13:496-499.
[16]. Neubauer BA, Gross S and Hahn A (2008) Epilepsy in
childhood and adolescence. Dtsch Arztebl Int 105:319-
327; quiz 327-318.
[17]. Pragallapati S and Manyam R (2019) Glucose
transporter 1 in health and disease. J Oral Maxillofac
Pathol 23:443-449.
[18]. Rotstein D and Montalban X (2019) Reaching an
evidence-based prognosis for personalized treatment of
multiple sclerosis. Nature Reviews Neurology 15:287-
300.
[19]. Savatt JM and Myers SM (2021) Genetic Testing in
Neurodevelopmental Disorders. Front Pediatr 9:526779.
[20]. Schwantje M, Verhagen LM, van Hasselt PM and Fuchs
SA (2020) Glucose transporter type 1 deficiency
syndrome and the ketogenic diet. J Inherit Metab Dis
43:216-222.
[21]. Soto-Insuga V, López RG, Losada-Del Pozo R, Rodrigo-
Moreno M, Cayuelas EM, Giráldez BG, Díaz-Gómez E,
Sánchez-Martín G, García LO and Serratosa JM (2019)
Glut1 deficiency is a rare but treatable cause of
childhood absence epilepsy with atypical features.
Epilepsy Res 154:39-41.
[22]. Tang M and Monani UR (2021) Glut1 deficiency
syndrome: New and emerging insights into a
prototypical brain energy failure disorder. Neurosci
Insights 16:26331055211011507.
[23]. Tang M, Park SH, De Vivo DC and Monani UR (2019)
Therapeutic strategies for glucose transporter 1
deficiency syndrome. Ann Clin Transl Neurol 6:1923-
1932.
[24]. Veggiotti P and De Giorgis V (2014) Dietary treatments
and new therapeutic perspective in GLUT1 deficiency
syndrome. Curr Treat Options Neurol 16:1-12.
[25]. Vulturar R, Chiș A, Pintilie S, Farcaș IM, Botezatu A,
Login CC, Sitar-Taut A-V, Orasan OH, Stan A and
Lazea C (2022a) One Molecule for Mental Nourishment
and More: Glucose Transporter Type 1—Biology and
Deficiency Syndrome. Biomedicines 10:1249.

IJISRT23OCT079 www.ijisrt.com 69