Glut1 deficiency syndrome: clinical guidelines

List of Abbreviations

BBB — blood-brain barrier

LGID — low glycemic index diet

GI — gastrointestinal tract

IVD — in vitro diagnostics

KD — ketogenic diet

CT — computed tomography

MAD — modified Atkins diet

MRI — magnetic resonance imaging

AED — antiepileptic drug

CSF — cerebrospinal fluid

US — ultrasound

CNS — central nervous system

EEG — electroencephalography

BE — base excess

CNS (Columbia Neurological Score) — Columbia Neurological Score

FDG-PET — [18F]fluorodeoxyglucose PET

Glut1 (glucose transporter type 1) — unirectional glucose transporter protein

HGMD (Human Gene Mutation Database) — Human Gene Mutation Database

LCT — long-chain triglycerides

MCT — medium-chain triglycerides

MCT1 — monocarboxylate transporter 1

MLPA — multiplex ligation-dependent probe amplification

RDA — recommended dietary allowances

Terms and Definitions

Ketogenic diet (KD) — a method of medical nutrition therapy based on a high-fat, sharply carbohydrate-restricted diet that stimulates ketone body production in the body.

Glut1 (glucose transporter type 1) — a glucose transporter protein responsible for glucose transport from the blood into the brain across the blood-brain barrier.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Glut1 deficiency syndrome (synonyms: Glut1 deficiency, GLUT1 DS, De Vivo disease) is a hereditary disorder characterized by early-onset epileptic encephalopathy, pharmacoresistant epilepsy, microcephaly, psychomotor delay, ataxia, dysarthria, paroxysmal dyskinesias (choreoathetosis/dystonia), and alternating hemiplegia of varying severity.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Glut1 deficiency syndrome is caused by mutations in the SLC2A1 gene located on the short arm of chromosome 1 (1p34.2). The SLC2A1 gene, which encodes the Glut1 protein, consists of 10 exons and 9 introns. The international Human Gene Mutation Database (HGMD) describes over 300 different mutations in the SLC2A1 gene [1]. Pathogenic variants include missense mutations, nonsense mutations, small intragenic deletions/insertions, and splice site variants.

The SLC2A1 gene encodes a unidirectional glucose transporter protein (Glut1) responsible for glucose transport from the blood into the brain across the blood-brain barrier (BBB).

In most cases, the disease is caused by a heterozygous mutation in the SLC2A1 gene arising de novo. Transmission of a pathogenic variant from a mildly affected parent, likely due to tissue mosaicism, is less common [2]. Rare cases of autosomal recessive inheritance have also been described [3, 4].

Mutations in the SLC2A1 gene impair Glut1 protein function, disrupting glucose transport into the brain and depriving it of its primary energy source [5, 6].

The Glut protein family consists of three subclasses and includes 12 protein variants. These transporter proteins facilitate passive diffusion of glucose across tissue barriers through energy-dependent mechanisms. Glut1 is expressed in vascular endothelial cells of the BBB and mediates glucose entry into the brain. Glut2 is associated with Fanconi-Bickel syndrome. Glut3 mediates glucose entry across the neuronal plasma membrane, Glut4 is an insulin-regulated glucose transporter in adipose tissue, heart, and skeletal muscle responsible for insulin-mediated glucose transport, and Glut5 is expressed in the intestine, testes, and kidneys. The function of Glut7 is currently unknown.

The Glut1 protein is a key mediator responsible for delivering glucose across the BBB [2]. Figure 1 illustrates transporters for various substances across the blood-brain barrier.

Figure 1 Transport of various substances across the BBB

1.3 Epidemiology of the Disease or Condition

Glut1 deficiency syndrome is a panethnic disorder; its estimated prevalence ranges from 1:83,000 to 1:100,000 newborns according to various studies [7, 8].

Studies have shown that Glut1 deficiency syndrome accounts for 10–12% of absence epilepsy cases (typical and atypical), 0.7–1% of tonic-clonic seizures, 0–5% of myoclonic, atonic, and myoclonic-atonic seizures, 0.6% of refractory seizure cases, and 2.7% of epilepsies associated with intellectual disability and/or various movement disorders [8, 9, 10, 11].

1.4 Features of Coding the Disease or Condition

According to ICD-10, the disease belongs to Chapter VI — Diseases of the nervous system, episodic and paroxysmal disorders, other forms of generalized epilepsy and epileptic syndromes — G40.4.

Exercise-induced paroxysmal dyskinesia and epilepsy, formerly known as dystonia 18 — DYT18, or DYT-SLC2A1 [12], and paroxysmal choreoathetosis with spasticity — DYT9 [13], are now recognized as part of the phenotypic spectrum of Glut1 deficiency syndrome.

1.5 Classification of the disease or condition

Variants of Glut1 deficiency syndrome, differing in age of onset and neurological manifestations.

1. Classic form of Glut1 deficiency syndrome (90% of cases)

Seizures occur between 1 month and 2 years of age, less commonly after 2 years. This form is characterized by psychomotor retardation, paroxysmal eye movements (saccadic movements and ocular opsoclonus), dysarthria, microcephaly, and movement disorders including ataxia, alternating hemiplegia, and dystonic or choreic hyperkinesia [14, 15];

2. Non-classic form of Glut1 deficiency syndrome (10% of cases)

Patients have milder manifestations compared to the classic form. Epileptic seizures are less frequent, while paroxysmal dyskinesias are more pronounced: intermittent ataxia, choreoathetosis, dystonia, and alternating hemiplegia. Several disorders caused by Glut1 deficiency are currently known [15, 16, 17]:

1. Paroxysmal choreoathetosis with episodic ataxia and spasticity (familial hemiplegic migraine type 9 / early-onset torsion dystonia 9 — DYT9);

2. Exercise-induced paroxysmal dyskinesia with or without epilepsy (torsion dystonia type 18 — DYT18; Glut1 deficiency syndrome type 2);

3. Atypical childhood absence epilepsy phenotype;

4. Epilepsy phenotype with myoclonic-atonic seizures.

Some clinical manifestations of these disorders may overlap with those observed in classic Glut1 deficiency syndrome [18].

1.6 Clinical presentation of the disease or condition

The classic variant of Glut1 deficiency syndrome is characterized by manifestation in the first months of life. Epileptic seizures are polymorphic: tonic-clonic, myoclonic, atypical absences, atonic, and myoclonic-atonic; they can occur with varying frequency—from monthly to daily—and are characterized by pronounced resistance to antiepileptic drug therapy. Episodes of apnea, cyanosis, and paroxysmal eye movements may occur. Subsequently, movement disorders join (ataxia, dystonia, spastic muscle tone abnormalities), and microcephaly develops. Electroencephalography (EEG) often reveals generalized or focal epileptiform changes. An important pathognomonic sign of the disease is a decrease in seizure frequency and EEG abnormalities after food intake [19].

Epilepsy in Glut1 deficiency syndrome reaches its peak in the first years of life, then as the child grows, seizures become less frequent or even disappear in some patients by adolescence and adulthood. The nature of seizures changes over time: focal seizures are more common in infancy, atypical absences and myoclonic seizures begin from the second year of life, and generalized tonic-clonic seizures usually appear after 3 years of age [2]. Developmental delay, ataxia, and microcephaly occur in infancy or early childhood. Dystonia is the only symptom whose frequency steadily increases, manifesting in late childhood or adolescence [14]. Paroxysmal neurological phenomena generally begin in early childhood, become milder and less frequent as patients grow older, and in some cases may disappear completely [20, 21, 12, 22, 23]. Obsessive-compulsive disorders have been described in 18% of patients with Glut1 deficiency syndrome [2].

In the non-epileptic course of the disease, movement disorders predominate: paroxysmal dyskinesias (choreoathetosis/dystonia/tremor), ataxia, and varying degrees of alternating hemiplegia. Depending on the timing of manifestation, the frequency of various symptoms may vary (Appendix G1).

Currently, Glut1 deficiency syndrome is viewed as a disorder with a continuum of clinical phenotypes differing in age of manifestation, severity of clinical manifestations, and rate of progression [24, 25]. Genotype-phenotype correlation in Glut1 deficiency syndrome is presented in Appendix G2.

Epilepsy in Glut1 deficiency syndrome

Pharmacoresistant epilepsy is often the first symptom of Glut1 deficiency syndrome [2, 26]. Any type of epileptic seizure can be observed [27]. Generalized epileptic seizures are most frequently observed, with focal ones being less common [28, 29]. Early manifestation of absence seizures (up to 4 years of age) and epilepsy with myoclonic-atonic seizures (Doose syndrome) are often caused by pathogenic mutations in the SLC2A1 gene. Epileptic seizures in classic Glut1 deficiency syndrome debut between one and six months of age and are often the first clinical symptom. In some children, epileptic seizures are preceded by episodes of apnea and paroxysmal eye movements resembling opsoclonus [30]. In infancy, focal seizures manifest as paroxysmal head and eye movements, as well as complex atypical absences and atonic seizures. EEG may show focal, multifocal, and generalized discharges.

As the child grows, several types of seizures may be noted: generalized and focal tonic, clonic, tonic-clonic, myoclonic, atypical absences, atonic, and unclassified [31]. Regional, multiregional, or generalized activity may be recorded on the EEG (including generalized rhythmic activity at 2–4 Hz corresponding to atypical and typical absences).

Seizure frequency varies among patients: some experience them daily, while others have single seizures separated by intervals of days, weeks, months, or years. Seizure frequency does not correlate with disease severity. Seizures are often combined with developmental delay or ataxia.

The clinical phenotypes of Glut1 deficiency syndrome often share phenotypic similarities with classic syndromes of idiopathic generalized epilepsy, such as childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and, less commonly, epilepsy with isolated convulsive seizures [32].

The fact that mutations in the SLC2A1 gene are more common in patients with early-onset epilepsy, including early-onset absence epilepsy and myoclonic-atonic epilepsy, suggests potential age-dependent mechanisms [2, 24, 32, 33, 34, 35]. This phenomenon can be explained by brain maturation and glucose transport, as proven using positron emission tomography [36], and age-dependent expression of the SLC2A1 gene [18]. Thus, it can be stated that molecular genetic testing of the SLC2A1 gene is justified in all children with absence seizures, especially when they begin before 4 years of age. This will allow earlier initiation of effective treatment and genetic counseling for the family [24].

Intellectual impairment

Patients with Glut1 deficiency syndrome exhibit cognitive impairments of varying severity, ranging from learning difficulties to severe intellectual disability. Pharmacoresistant epileptic encephalopathy in Glut1 deficiency syndrome typically leads to intellectual impairment, whereas isolated intellectual deficit is rarely observed.

Speech and language developmental disorders of varying severity are observed in all patients. Dysarthria accompanied by dysfluency (excessively interrupted speech) is common. Perceptive and expressive language skills are impaired.

Social and adaptive behavior is not affected; patients usually feel comfortable in a group and school environment and communicate well with others. Autism spectrum disorders are rarely observed.

Movement disorders

Movement disorders are characterized by ataxia, dystonia, and chorea, and can be constant or paroxysmal [16, 37, 38, 39]. An important diagnostic criterion is their tendency to worsen during fasting, physical exertion, or exposure to other environmental factors such as intercurrent illness, infections, fever, anxiety, and dietary indiscretion. Sometimes the provoking trigger cannot be identified [37, 38, 40, 41, 42, 43, 44].

Variants of movement disorders in Glut1 deficiency syndrome:

• Ataxia

• Ataxia with pyramidal signs

• Dystonia

• Chorea

• Tremor

• Myoclonus

• Dyspraxia

• Tics

• Stereotypies

• Paroxysmal movement disorders

• Paroxysmal phenomena with pronounced motor dysfunction

• Exercise-induced paroxysmal dyskinesias

• Paroxysmal eye movements

• Paroxysmal phenomena with complex neurological symptoms

Other paroxysmal phenomena:

• Migraine

• Cyclic vomiting

• Sleep deprivation [45].

Gait abnormalities

Patients with Glut1 deficiency syndrome typically exhibit delayed motor development. They begin walking later, and patients with the severe variant of the disease are unable to walk independently [9, 20, 30, 40, 42, 44, 46, 47]. A typical gait abnormality in Glut1 deficiency syndrome is ataxia [2, 6, 23, 48, 49]. This is accompanied by spasticity and, consequently, a spastic-ataxic gait characterized by instability, leg stiffness, shortened stride length and reduced heel strike, as well as a wide-based gait (unlike the scissors gait seen in spastic diplegia in cerebral palsy) [48, 50]. Some patients exhibit upper limb dystonic posturing while walking, while others show choreoathetosis [48]. Other, less common gait abnormalities observed in severe phenotypes of Glut1 deficiency syndrome include spastic and, predominantly, dystonic gaits [6, 48, 51]. Episodic gait disturbance during physical exertion or fasting is characteristic. Some authors describe an inability to stand for long periods due to ataxia, which improves after eating [24, 48]. This periodic gait disturbance resembles other genetic disorders, such as Segawa disease, and suggests a possible common pathophysiological mechanism of the disease, such as synaptic dysfunction. Glut1 deficiency syndrome is not considered a neurodegenerative disease, but progression of spasticity and, less commonly, ataxia may be observed during puberty. This worsening may be temporary [2, 14, 22, 52].

Dystonia

Dystonia is the second most common movement disorder in Glut1 deficiency syndrome. It is reported to occur in 20–86% of patients with the classical phenotype and in 13% of patients with the non-classical phenotype [2, 6, 23, 33, 48, 53]. The severity of dystonia in Glut1 deficiency syndrome varies and mainly presents as postural dystonia or action dystonia affecting the distal limbs, most commonly the upper limbs. Specific dystonia and dystonic tremor have been reported in some patients [2, 12, 17, 25, 51, 52, 54, 55].

Tremor

Tremor occurs in more than 70% of patients with Glut1 deficiency syndrome with the classical phenotype [48]. It is characterized as a terminal action tremor and is combined with ataxia, dysarthria, dyssynergia, impaired trunk movement coordination, and ocular dyspraxia, reflecting the severity of cerebellar dysfunction in this disease [48, 56, 57]. Postural and dystonic tremors have been observed in a subset of patients. Signs of parkinsonism are a rare symptom in Glut1 deficiency syndrome, and cases with resting tremor have not been reported [20, 35, 51, 55].

Choreic hyperkinesias have been described in 3–75% of patients according to various publications, which likely reflects ascertainment bias for this symptom [2, 6, 48]. Chorea is often mild, affecting only the face and distal upper extremities.

Myoclonus

Myoclonus in Glut1 deficiency syndrome is usually of epileptic origin. However, non-epileptic myoclonus, including startle, action, and postural myoclonus, has also been reported in individual patients [32, 48, 49].

Dyspraxia

Patients with Glut1 deficiency syndrome frequently exhibit dyspraxia, characterized by motor planning difficulties during specific movements. Ocular and oral-buccal dyspraxia is described in 20% of patients with the classical phenotype [48], characterized by impaired hand-eye coordination, fine motor disorganization, and clumsiness [2, 25].

Stereotypies and tics

Stereotypies and tics have been described in some patients with Glut1 deficiency syndrome [48], but they are not specific symptoms of the disease, given the high prevalence of these benign movement disorders in the general population.

Paroxysmal movement disorders

Paroxysmal non-epileptic intermittent neurological symptoms, often with prominent motor manifestations, are described in patients with Glut1 deficiency syndrome across various phenotypes. The frequency of paroxysmal non-epileptic attacks ranges from 30% to 59% of cases [6, 23, 49]. Although such paroxysmal states occur in patients with different phenotypes, it is generally accepted that they are more characteristic of milder forms of Glut1 deficiency syndrome [17, 21].

Inadequate energy supply, likely leading to synaptic dysfunction, is the proposed mechanism underlying paroxysmal attacks in Glut1 deficiency syndrome. Consequently, provoking factors include conditions requiring increased energy expenditure, such as the post-awakening state or pre-prandial state, fasting, and heightened physical activity. Other frequent provoking factors include emotional stress, fever, fatigue, or non-compliance with the ketogenic diet. Sleep deprivation, temperature changes, and medication-related factors (e.g., phenobarbital**, clonazepam**, theophylline) have also been reported. Sometimes triggers are not identified. The most frequent mitigating factors are eating, carbohydrate consumption, and rest [2, 6, 12, 17, 21, 23, 32, 48, 49, 51].

The clinical manifestations of paroxysmal attacks associated with Glut1 deficiency syndrome are highly diverse. However, in each individual patient, they tend to be stereotyped. Nosologically, they are not of epileptic origin. Some patients may experience marked dysphoria and emotional lability during attacks, while others experience confusion or drowsiness. Episodes may represent a type of focal seizure that is undetectable by EEG, but factors refuting this theory include preserved consciousness, the absence of other typical clinical seizure manifestations, and a normal ictal EEG [48]. Non-motor paroxysmal phenomena, such as migraine, episodes of behavioral and emotional disorders, cyclic vomiting, or sudden sleep episodes, may also occur [2, 22, 23, 25, 48, 49].

Episodes may begin gradually or abruptly. With gradual progression, episodes manifest as a noticeable worsening of baseline neurological status. Overall, patients with a classical disease course tend to develop multiple types of paroxysmal attacks, whereas patients with a non-classical course tend to exhibit one or two types of attacks. The duration of episodes ranges from minutes to hours, and occasionally days, with abruptly occurring events being shorter in duration. Frequency varies from daily to weekly, monthly, or once every few months [2, 17, 20, 21, 23, 25, 48, 49, 51, 52, 58].

In the classical phenotype, paroxysmal movement disorders typically develop later in childhood or adolescence, when epileptic seizures become less pronounced or resolve. In non-classical phenotypes, episodes usually begin in early or late childhood. Overall, patients show a gradual improvement as they grow older, and in some cases, the phenomena may resolve completely, regardless of whether the patient adheres to a ketogenic diet [2, 12, 14, 17, 20–23, 25, 51, 55].

Paroxysmal phenomena with severe motor dysfunction

This group of paroxysmal states includes periodic episodes of weakness, ataxia, and non-kinesigenic dyskinesias. Periodic episodes of weakness, manifesting as paraparesis, tetraparesis, hemiparesis, or monoparesis, are observed in 29–50% of patients with Glut1 deficiency syndrome [2, 49, 59]. Sudden generalized body paralysis mimicking periodic paralysis may also occur [17, 18, 23, 48].

The pathophysiology underlying transient neurological symptoms remains undefined. Neuroimaging reveals signs of focal cerebral hypoperfusion [59]. Two mechanisms for this phenomenon have been proposed: hypometabolism associated with inadequate glucose delivery to the central nervous system, cerebral blood vessel dysfunction, and a predisposition to transient vasospasm. The latter is supported by the known abundance of Glut1 transporters in cerebral endothelial cells, impaired cerebral angiogenesis, and the resulting reduction in cerebral microvessels in a mouse model with SLC1A2 haploinsufficiency [37].

Sometimes the pattern of hemiplegia episodes and concurrent clinical manifestations in patients with Glut1 deficiency syndrome can mimic alternating hemiplegia of childhood [2, 60, 61]. However, unlike classic alternating hemiplegia of childhood, the age of onset of atypical attacks associated with Glut1 deficiency syndrome is typically older, marked autonomic or bulbar dysfunction is not observed during attacks, and episodes frequently occur due to fasting or exercise and are alleviated after meals, especially those rich in carbohydrates. Episodes of paroxysmal non-kinesigenic dyskinesia in Glut1 deficiency syndrome manifest as either chorea or dystonia, frequently involving the extremities and occasionally the axial or orofacial musculature [22, 23, 25, 48, 49]. Attacks of paroxysmal ataxia may also occur, which in some cases can resemble episodic ataxia [6, 20, 32, 36, 62].

Paroxysmal Exercise-Induced Dyskinesias

Paroxysmal exercise-induced dyskinesia and epilepsy, formerly known as dystonia 18 (DYT18) [20, 21, 48, 49], and paroxysmal choreoathetosis with spasticity, formerly known as dystonia 9 [12], are now recognized as part of the phenotypic spectrum of Glut1 deficiency syndrome.

Paroxysmal exercise-induced dyskinesia and epilepsy differ clinically from classic Glut1 deficiency syndrome in that most affected individuals have a normal interictal neurological status and normal head circumference, and exercise-induced dyskinesia develops at a later age [20, 21, 48, 49]. Cerebrospinal fluid (CSF) glucose concentrations tend to be higher (41–52 mg/dL) than in classic Glut1 deficiency syndrome [12].

Two families with paroxysmal choreoathetosis with spasticity have been described who presented with paroxysmal, predominantly exercise-induced dyskinesia between one and 15 years of age [22], caused by heterozygous pathogenic variants in the SLC2A1 gene — p.Arg212Cys and p.Arg126Cys. Triggers for the dyskinesia included prolonged physical exertion, anxiety, and emotional stress. With age, dyskinesias occurred less frequently or ceased. Associated symptoms included progressive spastic paraparesis, mild ataxia, mild to moderate cognitive impairment, and epileptic seizures.

Other paroxysmal phenomena have also been described in the literature [21, 23, 37, 47]. However, it remains unclear whether these events represent epileptic or non-epileptic phenomena. Neurological signs, which typically vary and may depend on factors such as hunger or fatigue, include the following:

• confusion;

• lethargy;

• drowsiness;

• recurrent headaches, migraines;

• sleep disorders;

• unilateral paresis;

• total body paralysis;

• intermittent ataxia;

• chorea;

• action dystonia of the limbs;

• cerebellar action tremor;

• writer's cramp;

• dystonic tremor (described as the sole sign in a mother and daughter) [63];

• parkinsonism;

• myoclonus;

• dyspraxia;

• non-kinesigenic dyskinesias.

Paroxysmal Eye Movements

Patients with Glut1 deficiency syndrome exhibit paroxysmal abnormal eye movements [25, 30, 31, 51, 80]. Eye movement abnormalities are the initial neurological sign in 38% of patients [32]. Based on a retrospective analysis of 101 patients with genetically confirmed Glut1 deficiency syndrome and video analysis of eye movement episodes, the characteristics of paroxysmal abnormal eye movements in infancy have been described [30].

The eye movements are rapid, multidirectional, and often accompanied by head movements in the same direction. The movements are always clearly separated in time by intervals, typically ranging from 200 to 800 ms, which corresponds to an average eye movement frequency of approximately 2 per second. These features are most consistent with gaze-head saccadic shifts, which are characterized by the presence of intersaccadic intervals, aligned eye and head movement direction, and the optional presence of a head component. Paroxysmal gaze-head saccades may be a specific sign of Glut1 deficiency syndrome in infancy.

Eye movements in Glut1 deficiency syndrome have been described as opsoclonus. However, unlike the eye movements observed by the authors, opsoclonus lacks a fixation interval between movements and is not associated with head movement in the same direction. The pathophysiological mechanism underlying paroxysmal saccades in Glut1 deficiency syndrome is unknown. Gaze shifts generally serve to bring an object of interest detected in the peripheral visual field onto the fovea, where it can be examined in greater detail. In the mature nervous system, gaze control involves both active signals driving the eyes and active signals suppressing eye movements and thereby promoting fixation [34]. A gaze shift often involves both eye saccades and head movements. The signals for head and eye movements originate in the paramedian pontine reticular formation (for horizontal eye movements) and the mesencephalic reticular formation (for vertical eye movements) [35]. The neural gaze control network includes the superior colliculus, the frontal lobe, and the posterior parietal cortex [16, 18, 36, 37]. The dorsal raphe nucleus suppresses brainstem saccade generators, the substantia nigra pars reticulata suppresses the superior colliculus, and neurons in the frontal lobe identify objects in the visual field that are inappropriate targets for saccades [38, 39, 48].

The aforementioned episodes are characterized by marked involuntary repetitive gaze saccades. Symptoms almost invariably manifest during the first 6 months of life, when the visual system is rapidly maturing and the ability to suppress reflexive saccades to visual stimuli is developing [49]. Because neurons of the dorsal raphe nucleus and parts of the substantia nigra conduct impulses at high rates, except during eye movements, it is possible that their activity is impaired by Glut1 deficiency, thereby enabling inappropriate saccades to occur. Energy deprivation is one of the mechanisms hypothesized to underlie other paroxysmal events in Glut1 deficiency syndrome [14]. Consistent with this hypothesis, episodic eye movements were triggered by fatigue, arousal, or fasting and resolved in some patients with the ketogenic diet (KD).

The possibility that these episodes represent a type of focal seizure undetectable by scalp EEG cannot be entirely excluded, but is unlikely. The absence of other typical clinical seizure manifestations and a normal ictal EEG suggest that these phenomena are non-epileptic. Most patients had coexisting epilepsy, which manifested at the same age as the eye movement episodes in 10 patients. In 6 patients, the first seizure occurred only 7 to 21 months after the onset of the eye movement episodes.

Eye movement episodes arose before 6 months of age in 83% of the studied patients. Among 8 patients with known episode progression, the frequency of episodes decreased by late infancy and resolved in all but one by 8 years of age. Thus, these episodes represent an age-dependent manifestation of the disorder, likely related to a specific stage of brain development.

Brief paroxysmal episodes of eye and head movements, for which we propose the term aberrant gaze saccades, are a characteristic and early feature of Glut1 deficiency syndrome in infancy. Failure to meet energy demands is a probable pathophysiological mechanism. Because early diagnosis improves the long-term prognosis of patients with Glut1 deficiency syndrome, it is vital that neurologists recognize these episodes as an early diagnostic criterion for the disease [65].

1.7 Differential Diagnosis

The differential diagnosis of Glut1 deficiency syndrome includes the following conditions:

• other causes of decreased CSF glucose concentration, including conditions causing chronic or transient hypoglycemia (e.g., familial hyperinsulinism);

• all conditions with neonatal seizures and acquired microcephaly; in particular, early forms of Rett syndrome, Angelman syndrome, and infantile forms of neuronal ceroid lipofuscinosis;

• opsoclonus-myoclonus syndrome [38, 57];

• unspecified epileptic encephalopathies with developmental delays;

• familial epilepsies with an autosomal dominant inheritance pattern;

• episodes of paroxysmal neurological dysfunction responsive to or prevented by carbohydrate intake, especially when manifesting as alternating hemiparesis, ataxia, cognitive dysfunction, or seizures;

• other movement disorders, including dystonia.

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diagnosis of Glut1 deficiency syndrome is established based on a combination of anamnesis, clinical data, and the results of laboratory tests (biochemical and molecular genetic).

Please note that, in accordance with the requirements for developing clinical guidelines, each recommendation statement must be accompanied by its recommendation grade and evidence level based on the grading systems for the levels of evidence certainty (LEC) and recommendation credibility levels (RCL). For many statements, the RCL and LEC will be low due to the lack of high-design clinical studies addressing them. Despite this, they are essential elements of patient evaluation for establishing a diagnosis and selecting treatment strategies.

2.1 Complaints and Anamnesis

When taking the medical history and assessing complaints, it is important to pay attention to the following complaints and anamnestic events:

• Positive family history (similar mild symptoms in one of the proband's parents)

• Psychomotor development delay with slow acquisition of psychomotor skills

• Seizures

• Speech impairment

• Movement disorders in the limbs

• Gait disturbance

Complaints in classic GLUT1 deficiency (~ 90%)

• Seizures with onset before the age of two years (most commonly between 1 and 6 months of age)

• Psychomotor retardation

• Paroxysmal ocular movements (opsoclonus)

• Dysarthria

• Acquired microcephaly

• Complex movement disorders, including:

• Ataxia

• Dystonia

• Chorea

• Tremor

Complaints in non-classic GLUT1 deficiency (~ 10%)

• Frequent paroxysmal dyskinesias, including:

• Paroxysmal ataxia

• Choreoathetosis

• Dystonia

• Alternating hemiplegia

• Paroxysmal vertigo

• Paroxysmal paralysis

• Complaints corresponding to parkinsonian clinical features

• Paroxysmal muscle pain at night

• Episodes of recurrent vomiting

• Stroke-like episodes

Patients also complain of headache. Decreased visual acuity is significantly less common [49, 66]. Exacerbation of clinical symptoms is typical during periods of hyperthermia, after physical exertion, during fasting, and in intercurrent illnesses. All patients with Glut1 deficiency syndrome exhibit progressive global developmental delay. Intellectual impairment, verbal dysfunction (dysarthria), and motor disturbances develop [18, 67].

2.2 Physical Examination

During the examination, attention should be paid to the following main clinical manifestations of Glut1 deficiency syndrome:

• Microcephaly (found in half of the patients)

• Epileptic seizures

• Dysarthria

• Ataxia

• Choreoathetosis

• Tremor

• Spastic muscle tone abnormalities

• Alternating hemiplegia

• Muscle hypotonia

• Dystonia

• Paroxysmal ocular movements

• Dizziness

• Hepatosplenomegaly.

2.3 Laboratory Diagnostics

The main laboratory methods for confirming the diagnosis include biochemical studies and molecular genetic testing (searching for mutations in the SLC2A1 gene).

Comments: In Glut1 deficiency syndrome, CSF glucose is decreased below 60 mg/dL (range: 16.2–52 mg/dL); in more than 90% of cases, it is below 40 mg/dL, and in approximately 10%, it is 41–52 mg/dL. The test is performed after a four-hour fast. A blood sample is obtained immediately prior to lumbar puncture: the blood concentration of glucose must be normal to rule out hypoglycemia as the cause of hypoglycorrhachia. A CSF glucose level <2.2 mmol/L is considered pathognomonic for Glut1 deficiency syndrome (occurring in 90% of cases).

The CSF-to-blood glucose ratio in patients is typically less than 0.4 (ranging from 0.19 to 0.59); however, this value is less informative than the absolute CSF glucose level.

CSF glucose levels of 41–52 mg/dL may be observed in milder phenotypes [24, 62]. CSF glucose values below 60 mg/dL (3.3 mmol/L) should be considered probable deviations from normal.

Comments: the diagnosis of Glut1 deficiency syndrome is established based on the clinical picture, normal blood glucose values, decreased CSF glucose content (<60 mg/dL), and the detection of a pathogenic variant in the SLC2A1 gene in a heterozygous state. The disease is inherited in an autosomal dominant manner. 84% of patients have point mutations in the SLC2A1 gene, which can be detected primarily by massively parallel sequencing (exome analysis or targeted gene panels) or direct Sanger sequencing.

In 90% of patients, the disease develops as a result of a sporadic (de novo) pathogenic variant in the SLC2A1 gene. In 10% of cases, the mutation is inherited from one of the parents, who is either asymptomatic or has mild manifestations of the disease as a consequence of tissue mosaicism.

In the absence of genetic confirmation of the diagnosis, but in the presence of a clinical picture characteristic of Glut1 deficiency syndrome as well as decreased CSF glucose levels, it is indicated to follow the clinical guidelines for Glut1 deficiency syndrome.

The risk of developing the disease for the children of a proband with Glut1 deficiency syndrome is 50%.

Comments: in case of negative Sanger sequencing results, testing by MLPA is performed.

Large deletions or duplications of the SLC2A1 gene are detected in 13% of patients, for which the MLPA (multiplex ligation-dependent probe amplification) method is used [17].

In the absence of genetic confirmation of the diagnosis, but in the presence of a clinical picture characteristic of Glut1 deficiency syndrome as well as decreased CSF glucose levels, it is indicated to follow the clinical guidelines for Glut1 deficiency syndrome.

Comments: it is necessary to examine total hemoglobin, red blood cells, white blood cells, platelets in the blood, differential leukocyte count (leukocyte formula), and erythrocyte sedimentation rate. Atypical clinical variants in rare cases may be accompanied by hemolytic anemia. The study is performed during dynamic follow-up; the frequency is determined individually.

Comments: it is necessary to test blood total protein, blood albumin, blood urea, blood creatinine, blood triglycerides, blood cholesterol, low-density lipoprotein cholesterol, blood lipoproteins, blood alkaline phosphatase activity, blood total bilirubin, blood free and conjugated bilirubin, blood 25-OH vitamin D, blood glucose, blood aspartate aminotransferase activity, blood alanine aminotransferase activity, blood amylase activity, blood sodium, blood potassium, blood total calcium, and serum total magnesium. A ketogenic diet is prescribed for Glut1 deficiency syndrome; the results of the general therapeutic blood chemistry panel should be evaluated upon introduction of this diet and throughout its maintenance.

Comments: During the initiation phase of the ketogenic diet, these parameters are evaluated every 1–3 days, and subsequently as clinically indicated once stable ketosis is achieved.

Comments: A ketogenic diet is prescribed for Glut1 deficiency syndrome; the condition of internal organs must be assessed during its introduction and throughout the course of adherence.

Comments: to evaluate the efficacy of the KD, regular self-monitoring of blood ketone and glucose levels is required—twice daily using an IVD home-use blood glucose/ketone monitoring system (device, lancets, test strips). Test strips must be compatible with the blood ketone and glucose meter.

Comments: to evaluate the efficacy of the KD, regular self-monitoring of blood glucose levels is required—twice daily using an IVD home-use blood glucose/ketone monitoring system (device, lancets, test strips). Test strips must be compatible with the blood glucose meter.

2.4 Instrumental Diagnostics

Comments: EEG should be performed at least 3 months prior to initiating the KD, then after achieving a stable level of ketosis, and subsequently every 6 months.

Comments: video-EEG monitoring should be performed if standard (routine) EEG is not feasible, at least 3 months prior to initiating the KD, then after achieving a stable level of ketosis, and subsequently every 6 months.

In patients with Glut1 deficiency, the interictal EEG is usually normal. EEG findings most commonly reveal multifocal spike-wave discharges, polyspike-wave discharges, and bilaterally synchronous discharges.

In infants, regional slowing and epileptiform discharges are more frequently recorded. In children aged two years and older, generalized 2.5–4 Hz spike-wave discharges are observed [27, 31, 74].

Any seizure type may be observed, with generalized tonic or clonic seizures, absence seizures, focal seizures, myoclonic seizures, and atonic seizures being the most common.

An important pathognomonic sign of the disease is the regression of epileptic seizures and abnormal EEG changes following food intake.

Comments: Magnetic resonance imaging is performed to rule out structural brain anomalies and neurometabolic disorders. Neuroimaging in patients with Glut1 deficiency syndrome mostly reveals no pathological findings. In some cases, the following have been described: hyperintense signal from U-fibers, enlargement of Virchow-Robin perivascular spaces, and delayed myelination [71, 74].

Comments: Ultrasound of the abdominal organs and kidneys is performed to rule out structural anomalies, determine the condition of internal organs before starting a ketogenic diet, and for subsequent monitoring. The examination is performed before initiating the KD, at 3 months, and thereafter once every 6 months [69, 72].

Comments: the examination is performed before initiating the KD, at 3 months, and thereafter once every 6 months.

2.5 Other Procedures

The frequency of examinations is detailed in Appendix G3.

Specialist consultations may be provided to patients at various stages of medical care, including during the disease diagnosis period.

Comments: All patients with Glut1 deficiency syndrome undergo initial and follow-up consultations (examinations) with a pediatrician/general practitioner/family physician during diagnosis and follow-up to assess the general condition and effectiveness of therapy, and to participate in prescribing and implementing treatment and rehabilitation measures.

All patients with Glut1 deficiency syndrome undergo initial and follow-up consultations (examinations, evaluations) with a suitably trained neurologist and geneticist to establish the diagnosis, clarify the severity of central nervous system (CNS) involvement, and determine the tactics of treatment and rehabilitation measures [18].

All patients with Glut1 deficiency syndrome undergo initial and follow-up consultations (examinations, evaluations) with a nutritionist/dietitian to prescribe the ketogenic diet and subsequently, if necessary, to adjust diet therapy and monitor compliance [3, 22, 79].

Patients with suspected Glut1 deficiency syndrome undergo a consultation (examination) with a geneticist to establish the diagnosis; patients with a confirmed diagnosis of Glut1 deficiency syndrome and families with relatives affected by Glut1 deficiency syndrome undergo it for family planning [18].

If the patient has suspected/confirmed visual system pathology, initial and follow-up consultations (examinations) with an ophthalmologist are performed [3, 62, 63].

If the patient has suspected/confirmed cardiovascular system pathology, initial and follow-up consultations (examinations) with a cardiologist/pediatric cardiologist are performed [56].

To plan an individual rehabilitation program for psychological and pedagogical support for patients and their families, initial and follow-up consultations (testing, evaluation) with a medical psychologist and a speech and language therapist/defectologist are performed [3, 80].

Consultations with a physical therapy doctor, gastroenterologist, nephrologist, anesthesiologist-resuscitologist, palliative care physician, pediatric/general dentist, and other specialists are performed as indicated.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

Management of Glut1 deficiency syndrome includes both pathogenetic treatment—dietary therapy—and symptomatic therapy aimed at reducing secondary complications. The management of patients with Glut1 deficiency syndrome requires a multidisciplinary approach involving neurologists, geneticists, gastroenterologists, and other specialists with experience in treating this rare disease.

3.1 Pathogenetic treatment

Currently, the only effective treatment for patients with Glut1 deficiency syndrome is the ketogenic diet (KD).

Comments: On a KD, metabolism shifts toward fat breakdown, and the brain begins to use alternative energy sources—ketone bodies (β-hydroxybutyrate, acetoacetate).

Ketone bodies enter the brain via facilitated diffusion using monocarboxylate transporter 1 (MCT1) and provide alternative energy metabolism in the central nervous system.

In most cases, KD is well tolerated and helps reduce the main clinical manifestations of the disease by providing control over epileptic seizures, reducing epileptiform activity on EEG, and improving speech, cognitive, and motor functions. However, seizures may persist even while following a KD, and when the seizure syndrome is controlled, patients sometimes exhibit neuropsychological deficits [54].

Neurological outcome largely depends on the age at which treatment is initiated: patients who begin receiving effective treatment at an earlier age have a more favorable prognosis [39].

Specialized infant formulas for medical dietary management of drug-resistant epilepsy and other conditions where KD is indicated can be used to feed severely ill patients from one year of age orally and/or via a nasogastric tube or gastrostomy. Products and oils used in the KD are presented in Appendix G16.

3.1.1 Recommendations for Ketogenic Diet Therapy

The KD is a high-fat, sharply carbohydrate-restricted diet with a controlled amount of protein, which promotes the induction and maintenance of a state of ketosis in the body.

To achieve a therapeutic effect, blood ketone levels must reach the range of 2–6 mmol/L. Patients with Glut1 deficiency syndrome, especially in the first years of life, need to maintain a high level of ketone bodies at the upper limit of the recommended therapeutic corridor (at least 4 mmol/L) to achieve a clinical effect. Therefore, the initial variant of dietary therapy for them is the classical KD.

In the classical KD, the fat component is represented by natural animal fats and vegetable oils. The traditional ketogenic ratio (mass ratio of fats to proteins and carbohydrates) for the classical KD is 4:1 or 3:1. However, the exact value is determined individually in each case, taking into account the level of ketonemia. Appendix G11 presents the preparatory, initial, and maintenance stages of KD treatment in young children.

It is possible to include medium-chain triglycerides (MCTs) in the ketogenic diet, which can provide a higher level of ketonemia while simultaneously reducing the workload on the enzyme systems of the gastrointestinal tract (GIT). At the same time, MCT diets are less well tolerated by young children. A comparative characteristic of KDs used in the treatment of GLUT1 deficiency is presented in Appendix G6. Appendix G5 shows the macronutrient ratios for various KD options calculated for a 1200 kcal diet.

Comments: MAD does not require strict monitoring of food intake. However, the classical KD should be used as the initial option for Glut1 deficiency syndrome.

Comments: The classical KD should be maintained for as long as possible, as it can provide an optimal level of blood ketone bodies. MAD can be offered to adolescents and adults as an alternative to the classical KD if long-term tolerability issues arise. The low glycemic index treatment (LGIT) cannot provide sustained ketonemia and is not used in the treatment of Glut1 deficiency syndrome.

The organization of the KD for Glut1 deficiency syndrome is carried out in accordance with general requirements for ketogenic dietary therapy [69]. The prescription of the KD must be preceded by a comprehensive examination, including the assessment of the patient's neurological, somatic, and nutritional status using anthropometric, laboratory, and instrumental studies, as well as an analysis of pharmacotherapy. Based on the examination results, a decision is made to initiate dietary therapy, and an individualized treatment plan and ketogenic menu are developed [72].

Indications and contraindications for prescribing the KD are presented in Appendix G4.

According to recent studies, the range of applied KD ratios is 2–4.5:1. The ketogenic ratio is determined individually for each patient, taking into account the characteristics of their ketogenesis and tolerability [2, 14, 24, 26, 32, 50].

Comments: The energy value of the ketogenic diet is calculated individually for each patient, taking into account age, physical activity level, and metabolic characteristics.

When using a KD, calorie intake is often restricted to 80–90% of the daily norm for the healthy population; however, there is no proven efficacy for such a calculation, and most experts prefer not to restrict calorie intake [69].

To determine energy requirements, one can refer to the average daily physiological energy requirements for healthy children according to FAO/WHO/UNU 2001 (WHO Technical Report Series 17-24okt 2001), presented in Appendices G7 and G10.

For children with a significant restriction of physical activity, energy requirements are calculated individually using the Schofield equation [82] (Appendix G15).

It is possible to evenly divide the calculated number of calories throughout the day, or organize main meals and snacks with lower energy value and, accordingly, fewer carbohydrates.

Adequate calorie intake is indicated by the rate of weight gain and the level of ketone bodies.

Excessive energy intake is associated with high weight gain and reduced ketosis, whereas inadequate calorie intake can cause delayed physical development and excessive ketonemia.

The energy value of the diet is adjusted throughout the dietary therapy, taking into account the dynamics of weight and height parameters [72].

Physical development is assessed taking into account the ideal weight-for-age and weight-for-height ratios.

Anthropometric measurements are performed weekly for infants, once every two weeks for children aged 1–2 years, and monthly for children aged 3 years and older.

Comments: The protein content in the diet should not fall below the safe level of intake. To calculate protein requirements for patients with GLUT1 deficiency, use the RDA (Recommended Dietary Allowances) values presented in Appendices G8 and G10 [18, 58].

In the classical KD, protein accounts for an average of 5–15% of total caloric intake. In MAD, the amount of protein is quite high, making up to 30% of the energy value.

In case of growth retardation, the protein intake level is adjusted upward to achieve adequate growth rates.

Comments: The classical KD is based predominantly on long-chain triglycerides (LCT) and uses natural animal fats and vegetable oils as fat sources. At least 60% of fats should come from vegetable oils. Depending on individual tolerance and ketogenesis characteristics, the ketogenic ratio can vary significantly from 2:1 to 4.5:1, with the proportion of energy from fat intake correspondingly accounting for 70–90%.

In the MCT diet, 30–60% of fats are represented by medium-chain triglycerides. MCTs have the ability to stimulate ketogenesis, allowing for lower ketogenic ratio values (down to 1:1) and, accordingly, a higher amount of carbohydrates. At the same time, in younger age groups, the MCT diet is often accompanied by gastrointestinal intolerance symptoms, which is why it is not prescribed to infants in their first year of life and toddlers. Special fat modules as well as coconut oil (45% of whose fats are MCTs) are used as sources of MCTs. The inclusion of special modules is more justified given the high content of saturated fats in coconut oil. Differences in clinical efficacy between the classical KD and the MCT diet have not been established [5]. If MCTs need to be included in the diet, they should be used with all meals to reduce potential side effects [72].

MCT oil is also used as a component of the classical KD to enhance ketogenesis, reduce gastrointestinal strain, and stimulate bowel motility. The total amount of MCTs that does not cause tolerance issues in early childhood does not exceed 10–25% of the daily caloric intake [39].

For MAD, the amount of fat accounts to 60–65% of the energy value.

Comments: In the classical KD, the amount of carbohydrates is calculated after determining the total amount of proteins and fats and subtracting the required amount of protein. When calculating the amount of carbohydrates, all possible sources are taken into account, including those present in pharmaceutical preparations. The amount of carbohydrates is calculated for each meal based on its contribution to the total energy value.

For MAD, the allowable daily amount of carbohydrates is 10–15% of the energy value. A gradual attainment of the required amount of carbohydrates in the diet is recommended, starting from 10 grams per day.

The use of sweeteners in regulated amounts is permitted [39].

The amount of carbohydrates is calculated for each meal based on its contribution to the total energy value of the diet. An even distribution throughout the day may be proposed, or main meals can be organized with the introduction of an additional snack of lower energy value and, accordingly, a smaller amount of carbohydrates.

Comments: whenever possible, such drugs should be replaced with alternative options without carbohydrate content.

Comments: Considering that KD has a diuretic effect, it is necessary to ensure sufficient fluid intake to prevent dehydration and related metabolic complications, primarily renal complications (nephrolithiasis), as well as gastrointestinal motility disorders (constipation).

With good tolerance to the ketogenic diet, normal fluid requirements are calculated based on daily caloric intake (fluid volume/day = at least kcal/day, i.e., 1000 kcal/day — at least 1 L of fluid per day).

In case of increased fluid losses (hyperthermia, vomiting, diarrhea, etc.), the amount must be adjusted.

The required amount of fluid intake depending on age and weight is presented in Appendix G9.

Comments: The initiation of KD in children of the first 3 years of life is carried out exclusively in a hospital. MAD can be initiated in an outpatient setting.

The introduction of the ketogenic diet is carried out in various ways. To quickly achieve the therapeutic level of ketone bodies, a short fasting period (not exceeding 6 hours) can be used, followed by a fractionated (over 2–3 days) introduction of the ketogenic diet, starting with ½ of the required energy value. It is also possible to introduce the KD by replacing 1 meal per day with a ketogenic one every 1–2 days. More rarely, a progressive increase in the ketogenic ratio of the diet from 1:1 (or 2:1) until the required level of ketonemia is reached is used. The ratio is changed depending on the child's condition and well-being every 3–4 days or weekly. The disadvantages of the latter option include reaching the therapeutic corridor of ketone bodies outside the hospital, which is undesirable given the possibility of individual adverse reactions to ketosis.

3.2 Symptomatic Therapy — Antiepileptic Drugs

Antiepileptic drugs (AEDs) are generally ineffective or provide minor improvement in the absence of ketogenic diet treatment. Some AEDs may have relative contraindications when prescribed as adjunctive therapy in children on a ketogenic diet.

Comments: The prescription of AEDs is advisable when the pathogenetic therapy—the ketogenic diet—is insufficiently effective.

The use of certain antiepileptic drugs is associated with an increased frequency of KD side effects and/or a decrease in its efficacy.

The use of carbonic anhydrase inhibitors—acetazolamide**, topiramate**, sulthiame—can significantly increase acidosis. Topiramate**, acetazolamide**, and zonisamide increase the risk of urolithiasis. A decrease in diet therapy efficacy has been noted against the background of lamotrigine use. The use of valproic acid** increases the risk of hepatotoxicity [26].

3.3 Concomitant Therapy During Ketogenic Diet

Vitamins and mineral supplements

Comments: The KD diet is not physiological and complete; therefore, it needs to be supplemented with multivitamins and mineral supplements in a carbohydrate-free form.

Due to the restriction of fruits, vegetables, grains, and calcium-rich foods in the diet, patients on a KD are prescribed carbohydrate-free multivitamin and mineral supplements. Given that foods used in KD typically contain insufficient amounts of vitamin D and calcium, and children with pharmacoresistant epilepsy are at risk of vitamin D deficiency even before starting KD therapy, the addition of vitamin D and its analogues in accordance with the recommended age norm is indicated. Some experts agreed on prescribing increased doses of vitamin D and its analogues exceeding RDA recommendations [69].

Comments: Young children, patients receiving valproic acid** pharmacotherapy, those with low body weight, and those following a ketogenic diet long-term are at an increased risk of developing secondary carnitine deficiency. Carnitine deficiency may manifest as fatigue and muscle weakness, but it rarely leads to hepatic or cardiovascular dysfunction. Given the necessity of long-term adherence to a ketogenic diet in Glut1 deficiency syndrome, these patients are at risk for secondary carnitine deficiency and require supplementation at a dosage of 50–100 mg/kg/day [107].

Comments: it is necessary to consider the increased risk of megaloblastic anemia associated with the use of this group of drugs due to reduced folic acid absorption [69].

3.4 Pre-Ketogenic Diet Evaluations

The necessary examinations prior to initiating a ketogenic diet are described in Appendix G3. The recommended clinical monitoring during the ketogenic diet is presented in Appendices G12 and G13.

3.4.1 Initial Laboratory Investigations for Ketogenic Diet

Comments: this includes assessing total hemoglobin, red blood cells, white blood cells, platelets, differential white blood cell count (leukocyte formula), and erythrocyte sedimentation rate. Atypical clinical presentations are rarely accompanied by hemolytic anemia. The test is performed during follow-up monitoring; the frequency is determined individually.

Comments: visual inspection of urine is required (color, transparency), determination of urine hydrogen ion concentration (pH), specific gravity (relative density), urine protein, urine glucose, ketone bodies, bile pigments, blood bilirubin, hemoglobin, nitrites, and microscopic examination of the urine sediment (epithelium, leukocytes, erythrocytes, salt crystals, bacteria, mucus). The test is performed at diagnosis and subsequently during follow-up monitoring; the frequency is determined individually.

Comments: a ketogenic diet is prescribed for Glut1 deficiency syndrome, and the condition of internal organs must be assessed upon initiation and during adherence to the diet. It is necessary to test for total blood protein, blood albumin, blood urea, blood creatinine, blood triglycerides, blood cholesterol, low-density lipoprotein cholesterol, blood lipoproteins, alkaline phosphatase activity, total blood bilirubin, free and conjugated blood bilirubin, blood 25-OH vitamin D, blood glucose, aspartate aminotransferase activity, alanine aminotransferase activity, blood amylase activity, blood sodium, blood potassium, total blood calcium, and total serum magnesium.

Comments: a ketogenic diet is prescribed for Glut1 deficiency syndrome; upon introducing the diet and throughout its maintenance, the condition of internal organs must be evaluated.

Comments: A ketogenic diet is prescribed for Glut1 deficiency syndrome; the condition of internal organs must be assessed during its introduction and throughout the course of adherence.

Comments: Ketones can be measured in the blood (most informative) or in urine. At the initial stage of the diet, measuring blood ketones using an IVD home-use blood glucose/ketone monitoring system is recommended, as this method is more accurate and not subject to urine dilution effects or the influence of potential fluid balance fluctuations that may occur in infants during their first months of life. Blood ketones should be measured twice daily using a finger-prick or heel-prick sample. The target blood ketone level (β-hydroxybutyrate) on the ketogenic diet is 2–6 mmol/L, and the target urine level (acetoacetate) is 8–16 mmol/L [70].

To evaluate the efficacy of the ketogenic diet, regular self-monitoring of blood ketone levels is required twice daily using an IVD home-use blood glucose/ketone monitoring system (device, lancets, test strips). Test strips must be compatible with the ketone meter.

Comments: To evaluate the efficacy of the ketogenic diet, regular self-monitoring of blood glucose levels is required twice daily using an IVD home-use blood glucose/ketone monitoring system (device, lancets, test strips). Test strips must be compatible with the glucose meter.

Comments: during the ketogenic diet initiation phase, these parameters are evaluated every 1–3 days, and subsequently as clinically indicated once ketosis is stable.

3.4.2 Instrumental Investigations Prior to Ketogenic Diet Therapy

Comments: EEG should be performed at least 3 months prior to initiating the KD, then after achieving a stable level of ketosis, and subsequently every 6 months.

Comments: video-EEG monitoring should be performed if standard (routine) EEG is not feasible, at least 3 months prior to initiating the KD, then after achieving a stable level of ketosis, and subsequently every 6 months.

In patients with Glut1 deficiency, the interictal EEG is usually normal. EEG findings most commonly reveal multifocal spike-wave discharges, polyspike-wave discharges, and bilaterally synchronous discharges.

Focal slowing and epileptiform discharges are more frequently recorded in infants. In children aged two years and older, generalized 2.5–4 Hz spike-wave discharges are observed [27, 31, 74].

Any seizure type may be observed, with generalized tonic or clonic seizures, absence seizures, focal seizures, myoclonic seizures, and atonic seizures being the most common.

An important pathognomonic sign of the disease is the regression of epileptic seizures and abnormal EEG changes following food intake.

Comments: Combined endotracheal anesthesia or combined inhalation anesthesia as indicated; use of propofol** in children older than 1 month of age should be approached with caution (see subsection 3.6) [75]. Magnetic resonance imaging is performed to rule out structural brain anomalies and neurometabolic disorders. In most cases, neuroimaging in patients with Glut1 deficiency syndrome reveals no pathological changes. In some cases, the following have been described: high signal intensity from U-fibers, enlarged Virchow-Robin perivascular spaces, and delayed myelination [71, 74].

Comments: if necessary, a comprehensive ultrasound examination of the abdominal organs and kidneys is also performed to rule out structural anomalies, assess the condition of internal organs before starting the ketogenic diet, and for subsequent monitoring. The examination is performed before starting the KD, at 3 months, and subsequently every 6 months (more frequently as indicated) [69, 72].

Comments: the examination is performed before starting the KD, at 3 and 6 months, and subsequently every 6 months.

3.5 Management of Side Effects and Complications of the Ketogenic Diet

A table of potential side effects of the ketogenic diet, along with their prevention and management, is provided in Appendix G14.

Comments: The onset of shortness of breath, tachycardia, increasing drowsiness or confusion, and repeated vomiting may indicate hyperketonemia (diagnosed when blood ketone levels exceed 6 mmol/L). The management involves administering 5 g of carbohydrates and re-monitoring blood ketone bodies in 15–20 minutes. If necessary, carbohydrate intake should be repeated.

Comments: Ketone levels should be measured 15–20 minutes after treatment; if no effect is achieved, repeat the treatment.

If blood glucose drops below 3 mmol/L, a physician must be contacted. Give the child 2–5 g of carbohydrates (50 ml of fruit juice or 100 ml of milk).

If episodes of excessive ketosis occur frequently, recalculation of the keto ratio should be considered.

Comments: Check blood glucose levels 15–20 minutes after treatment; if no effect is achieved, repeat the treatment.

If oral carbohydrate intake is not possible, or if the patient is having seizures or is unconscious, intravenous administration of a 10% dextrose solution** at a dose of 5 ml/kg is recommended [77].

If hypoglycemia occurs frequently, consider recalculating the keto ratio.

Comments: blood ketone levels are also tested. If metabolic acidosis is associated with hypoglycemia or excessive ketosis, sodium bicarbonate** therapy is generally not required. Correcting blood glucose and ketone levels is sufficient.

Comments: sodium bicarbonate** solutions (ATX code — B05XA), potassium chloride + sodium bicarbonate + sodium chloride are used to correct dehydration and intoxication. Sodium bicarbonate** is used as an 8.4% and 4.2% solution for convenience in recalculating to mmol of NaHCO. Its dosage (mmol) is determined by the formula: (-BE) × body weight (kg) × 0.3. In addition, patients are advised to consume alkaline drinks — a soda solution at ½–1 teaspoon per 200 ml of water, and alkaline mineral waters.

Depending on the severity of the condition, monitor blood acid-base balance, sodium, and potassium levels every 6–12 hours.

Consider reducing the dose or discontinuing carbonic anhydrase inhibitors (topiramate**, zonisamide, and acetazolamide**) if they were previously prescribed.

3.6 Interaction of the ketogenic diet with medications.

Comments: If such medications must be prescribed, it is recommended to account for the amount of carbohydrates they contain when calculating the allowable carbohydrate intake to ensure adequate ketonemia.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Specific rehabilitation is not required for patients with Glut1 deficiency syndrome. Rehabilitation measures may include sessions with a medical psychologist, stays in specialized sanatoriums, as well as clinical and psychological adaptation, social rehabilitation involving specialists and social workers, and general medical massage courses. It is important to prevent complications and promote school and occupational integration and peer socialization.

Comments: Patients with Glut1 deficiency syndrome exhibit psychomotor and speech developmental delays and behavioral disorders that require comprehensive monitoring and therapy by medical psychologists, defectologists, physical and rehabilitation medicine physicians / medical rehabilitation physicians, or professionals performing these functions.

Psychological and pedagogical rehabilitation of adolescents. They face problems related to puberty, which is accompanied by a desire for independence, oppositional behavior, and susceptibility to peer influence. This is a period of frequent refusals by adolescent patients to follow diet therapy or consume specialized nutrition products, as well as a high risk of losing metabolic control and complete cessation of medical supervision [97].

5. Prevention and Dispensary Observation

5.1 Prevention

Comments: Patients with Glut1 deficiency syndrome are indicated for medical genetic counseling to determine the genetic prognosis for the family.

In most cases, the disease is caused by a heterozygous mutation in the SLC2A1 gene, predominantly arising de novo. Less commonly (in approximately 10% of reported cases), inheritance is autosomal dominant, with a mild form of the disease possible in a parent with an identified pathogenic SLC2A1 mutation. A possible explanation for the milder phenotype may be reduced activity of the protein product due to tissue mosaicism [2]. There are also reports of rare autosomal recessive inheritance of the disease.

Comments: contraindications are determined individually.

Glut1 deficiency syndrome is not a contraindication to vaccination with other vaccines.

5.2 Dispensary monitoring

Monitoring the dynamics of baseline evaluation parameters:

— for infants in the first year of life: at 1–1.5 months after starting the ketogenic diet, then at 3 months, 6 months, 12 months, and subsequently every 6–12 months.

— for children over 2 years of age: at 3 months, 6 months, 12 months, and subsequently every 6–12 months [69, 72].

Comments: Atypical clinical variants may rarely be accompanied by hemolytic anemia. Testing is performed during follow-up monitoring, and the frequency is determined individually.

Comments: visual inspection of urine (color, transparency), determination of urine pH, determination of specific gravity (relative density), determination of urine protein, urine glucose testing, detection of ketone bodies in urine, bile pigments in urine, urine bilirubin testing, detection of hemoglobin in urine, urine nitrite testing, and microscopic examination of urine sediment (epithelial cells, leukocytes, erythrocytes, salt crystals, bacteria, mucus) are required. Testing is performed at diagnosis and subsequently during follow-up monitoring; the frequency is determined individually.

Comments: Patients with Glut1 deficiency syndrome are prescribed a ketogenic diet. Upon introduction of the diet and during its adherence, the condition of internal organs must be assessed. The following tests must be performed: total protein in blood, albumin in blood, blood urea, blood creatinine, triglycerides in blood, cholesterol in blood, low-density lipoprotein cholesterol, blood lipoproteins, alkaline phosphatase activity in blood, total bilirubin in blood, free and conjugated bilirubin in blood, 25-OH vitamin D in blood, blood glucose, aspartate aminotransferase activity in blood, alanine aminotransferase activity in blood, amylase activity in blood, blood sodium, blood potassium, total calcium in blood, and total magnesium in blood serum.

Comments: Ketones can be measured in the blood (most informative) or in urine. At the initial stage of the diet, measuring blood ketones using an IVD home-use blood glucose/ketone monitoring system is recommended, as this method is more accurate and not subject to urine dilution effects or the influence of potential fluid balance fluctuations that may occur in infants during their first months of life. Blood ketones should be measured twice daily using a finger-prick or heel-prick sample. The target blood ketone level (β-hydroxybutyrate) on the ketogenic diet is 2–6 mmol/L, and the target urine level (acetoacetate) is 8–16 mmol/L [70].

To evaluate the efficacy of the ketogenic diet, regular self-monitoring of blood ketone levels is required twice daily using an IVD home-use blood glucose/ketone monitoring system (device, lancets, test strips). Test strips must be compatible with the ketone meter.

Comments: To evaluate the efficacy of the ketogenic diet, regular self-monitoring of blood glucose levels is required twice daily using an IVD home-use blood glucose/ketone monitoring system (device, lancets, test strips). Test strips must be compatible with the glucose meter.

Comments: EEG should be performed at least 3 months prior to initiating the KD, then after achieving a stable level of ketosis, and subsequently every 6 months.

Comments: video-EEG monitoring should be performed if standard (routine) EEG is not feasible, at least 3 months prior to initiating the KD, then after achieving a stable level of ketosis, and subsequently every 6 months.

In patients with Glut1 deficiency, the interictal EEG is usually normal. EEG findings most commonly reveal multifocal spike-wave discharges, polyspike-wave discharges, and bilaterally synchronous discharges.

Regional slowing and epileptiform discharges are more frequently recorded in infants. In children aged two years and older, generalized 2.5–4 Hz spike-wave discharges are observed [27, 31, 74].

Any seizure type may be observed, with generalized tonic or clonic seizures, absence seizures, focal seizures, myoclonic seizures, and atonic seizures being the most common.

An important pathognomonic sign of the disease is the regression of epileptic seizures and abnormal EEG changes following food intake.

Comments: Magnetic resonance imaging is performed to rule out structural brain anomalies and neurometabolic disorders. Neuroimaging in patients with Glut1 deficiency syndrome mostly reveals no pathological findings. In some cases, the following have been described: hyperintense signal from U-fibers, enlargement of Virchow-Robin perivascular spaces, and delayed myelination [71, 74].

Comments: if necessary, a comprehensive abdominal ultrasound is also performed. Ultrasound of the abdominal organs and kidneys is performed to exclude structural anomalies, determine the state of internal organs before starting the ketogenic diet, and for subsequent monitoring. The study is performed before introducing the ketogenic diet, at 3 months, and subsequently every 6 months (more frequently as clinically indicated) [69, 72].

Comments: The study is performed before introducing the ketogenic diet, at 3 months, and subsequently every 6 months.

Comments: initial and follow-up consultations are indicated with a medical geneticist, ophthalmologist, neurologist, dietitian, gastroenterologist, endocrinologist, cardiologist, pediatric cardiologist, nephrologist, pediatrician/general practitioner/family physician, as well as other specialists for patients with Glut1 deficiency syndrome on a ketogenic diet who have impairments in the functions of corresponding organs and systems

6. Organization of Medical Care

Patients with Glut1 deficiency, depending on necessity, may receive medical care of any type, under any conditions, and in any forms provided for by the legislation of the Russian Federation.

The management of patients with Glut1 deficiency is usually carried out by a neurologist, dietitian, gastroenterologist, pediatrician/general practitioner, as well as other medical specialists experienced in managing patients with Glut deficiency.

Hospitalization is most frequently carried out in the neurology department.

The necessary specialist examinations, laboratory and instrumental evaluations, and their recommended frequency are presented in Section 5.2

Indications for elective hospitalization:

- Provision of diagnostics and treatment requiring round-the-clock medical observation;

- A condition requiring active treatment and round-the-clock medical observation;

- A condition requiring high-tech treatment methods;

- The need for various types of expert evaluations or examinations in a medical organization when they cannot be performed on an outpatient basis and require dynamic observation (including issuing a conclusion by a federal medical board).

Indications for urgent/emergency hospitalization:

- Acute diseases;

- Exacerbations of chronic diseases;

- Poisonings and injuries, conditions requiring intensive care and transfer to intensive care units or critical care units, and other life-threatening acute conditions, as well as round-the-clock medical observation and specialized examinations and treatments.

7. Additional Information

Drugs to avoid:

Barbiturates and their derivatives. Typically, children with infantile seizures are treated with phenobarbital**, the most commonly used antiepileptic drug in this age group. In vitro studies show that barbiturates and their derivatives exacerbate the Glut1 transport defect in red blood cells of individuals with Glut1 deficiency syndrome [36]. Parents have occasionally reported that phenobarbital** failed to improve seizure control or possibly worsened the child's clinical condition.

Xanthine derivatives (e.g., caffeine), which are known to inhibit glucose transport via Glut1 [86], have also been reported to worsen the clinical condition of patients with Glut1 deficiency syndrome [87]. Therefore, patients are advised to avoid coffee and other caffeinated beverages.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Sergey O. Ayvazyan — Cand. of Sci. (Med.), Leading Researcher, Associate Professor, Head of the Resistant Forms of Epilepsy Research Group, Research Department, Research and Practical Center for Specialized Medical Care for Children named after V.F. Voino-Yasenetsky, Moscow Healthcare Department; Nevromed Medical Center, Moscow

2. Inga V. Anisimova — Cand. of Sci. (Med.), Head of the Medical Care Organization Department, Geneticist, Research Centre for Medical Genetics named after Academician N.P. Bochkov, Member of the Association of Medical Geneticists

3. Baranov Aleksandr Aleksandrovich - Academician of the RAS, Professor, Doctor of Medical Sciences; Honorary President of the Union of Pediatricians of Russia, Advisor to the Head of the Research Institute of Pediatrics and Child Health of the National Medical Research Center No. 2 of the Petrovsky National Research Centre of Surgery, Professor of the Department of Pediatrics and Pediatric Rheumatology of the Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University), Chief freelance pediatric specialist of the Ministry of Health of Russia

4. Elena D. Belousova — Dr. of Sci. (Med.), Professor, Honored Doctor of the Russian Federation, Head of the Department of Psychoneurology and Epileptology, Veltischev Research and Clinical Institute of Pediatrics, Pirogov Russian National Research Medical University of the Ministry of Health of Russia

5. Nato D. Vashakmadze — Dr. of Sci. (Med.), Head of the Department of Orphan Diseases and Prevention of Disabling Conditions, Research Institute of Pediatrics and Child Health, National Medical Research Center for Surgery named after Academician B.V. Petrovsky, Professor at the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Ministry of Health of Russia, Member of the Union of Pedatricians of Russia

6. Elena A. Vishnyova — Dr. of Sci. (Med.), Professor of the RAS, Deputy Head for Research at the Research Institute of Pediatrics and Child Health, National Medical Research Center for Surgery named after Academician B.V. Petrovsky of the Ministry of Science and Higher Education, Professor at the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Ministry of Health of Russia, Member of the Union of Pediatricians of Russia

7. Svetlana S. Zhilina — Cand. of Sci. (Med.), Associate Professor, Leading Researcher of the Genetic Research Group, Geneticist, Research and Practical Center for Specialized Medical Care for Children named after V.F. Voino-Yasenetsky, Moscow Healthcare Department; Pirogov Russian National Research Medical University of the Ministry of Health of Russia

8. Nataliya V. Zhurkova — Cand. of Sci. (Med.), Leading Researcher, Research Institute of Pediatrics and Child Health, National Medical Research Center for Surgery named after Academician B.V. Petrovsky, Member of the Union of Pediatricians of Russia, Member of the Association of Medical Geneticists

9. Vera V. Zarubina — Geneticist, Medical Genetics Department, Morozov Children's City Clinical Hospital, Moscow Healthcare Department

10. Ekaterina Yu. Zakharova — Dr. of Sci. (Med.), Head of the Laboratory of Inherited Metabolic Diseases, Research Centre for Medical Genetics named after Academician N.P. Bochkov, Member of the Russian Society of Medical Geneticists, Member of the Society for the Study of Inborn Errors of Metabolism (SSIEM)

11. Tatyana V. Kozhanova — Cand. of Sci. (Med.), Associate Professor, Leading Researcher of the Genetic Research Group, Laboratory Geneticist, Research and Practical Center for Specialized Medical Care for Children named after V.F. Voino-Yasenetsky, Moscow Healthcare Department; Pirogov Russian National Research Medical University of the Ministry of Health of Russia

12. Lyudmila M. Kuzenkova — Dr. of Sci. (Med.), Head of the Department of Psychoneurology and Psychosomatic Pathology, National Medical Research Center for Children's Health of the Ministry of Health of Russia, Member of the Union of Pediatricians of Russia

13. Sergey I. Kutsev — Academician of the RAS, Dr. of Sci. (Med.), Director of the Research Centre for Medical Genetics named after Academician N.P. Bochkov, President of the Association of Medical Geneticists (AMG)

14. Ekaterina G. Lukyanova — Neurologist, Research and Practical Center for Specialized Medical Care for Children named after V.F. Voino-Yasenetsky, Moscow Healthcare Department

15. Svetlana V. Mikhailova — Dr. of Sci. (Med.), Head of Department, Russian Children's Clinical Hospital of the Ministry of Health of Russia

16. Leyla S. Namazova-Baranova — Academician of the RAS, Professor, Dr. of Sci. (Med.), President of the Union of Pediatricians of Russia; Past-President of EPA/UNEPSA; Head of the Research Institute of Pediatrics and Child Health, National Medical Research Center for Surgery named after Academician B.V. Petrovsky, Head of the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Ministry of Health of Russia, Chief freelance pediatric specialist in preventive medicine of the Ministry of Health of Russia

17. Sergey S. Nikitin — Dr. of Sci. (Med.), Professor, Chairman of the Society of Neuromuscular Disease Specialists

18. Karina V. Osipova — Cand. of Sci. (Med.), Head of Psychoneurological Department No. 1, Research and Practical Center for Specialized Medical Care for Children named after V.F. Voino-Yasenetsky, Moscow Healthcare Department; Nevromed Medical Center, Moscow

19. Tatyana V. Podkletnova — Cand. of Sci. (Med.), Senior Researcher, Laboratory of Rare Inherited Diseases in Children, National Medical Research Center for Children's Health of the Ministry of Health of Russia, Member of the Union of Pediatricians of Russia

20. Ekaterina A. Pyryeva — Cand. of Sci. (Med.), Nutritionist, Head of the Laboratory of Age-Related Nutrition, Federal Research Center of Nutrition, Biotechnology and Food Safety

21. Svetlana A. Repina — Cand. of Sci. (Med.), Geneticist, Research Centre for Medical Genetics named after Academician N.P. Bochkov, Member of the Russian Society of Medical Geneticists, Member of the Association of Medical Geneticists

22. Valeriya V. Sviridova — Geneticist, Medical Care Organization Department, Research Centre for Medical Genetics, Junior Researcher, Laboratory of Mutagenesis, Research Centre for Medical Genetics

23. Liliya R. Selimzyanova, Cand. of Sci. (Med.), Leading Researcher, Research Institute of Pediatrics and Child Health, Academician B.V. Petrovsky National Research Center of Surgery, Sechenov First Moscow State Medical University (Sechenov University) of the Russian Ministry of Health, Associate Professor at the Department of Faculty Pediatrics, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Member of the Union of Pediatricians of Russia

24. Olga Ya. Smirnova, Medical Geneticist, Senior Researcher, Department of Standardization and Study of Evidence-Based Medicine Fundamentals, Research Institute of Pediatrics and Child Health, Academician B.V. Petrovsky National Research Center of Surgery, Member of the Union of Pediatricians of Russia

25. Andrey N. Surkov, Dr. of Sci. (Med.), Head of the Pediatric Gastroenterology Department (Inpatient Unit for Children), Head of the Department of Scientific Foundations of Pediatric Gastroenterology, Hepatology and Metabolic Disorders, Research Institute of Pediatrics and Child Health, Academician B.V. Petrovsky National Research Center of Surgery, Professor at the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health.

26. Tatyana N. Sorvacheva — Dr. of Sci. (Med.), Head of the Department of Dietology and Nutrition, Russian Medical Academy of Continuous Professional Education

27. Liliya M. Sushko — Neurologist, Research and Practical Center for Specialized Medical Care for Children named after V.F. Voyno-Yasenetsky, Moscow Healthcare Department

28. Dmitry M. Subbotin — Medical Geneticist, Medical Genetic Research Center, Member of the Association of Medical Geneticists

29. Rustem F. Tepayev, Dr. of Sci. (Med.), Professor at the Department of Pediatrics with a Course in Pediatric Rheumatology, Sechenov First Moscow State Medical University (Sechenov University) of the Russian Ministry of Health, Head of the Anesthesiology and Intensive Care Unit, Bashlyaeva Children's City Clinical Hospital, Moscow Healthcare Department

30. Marina V. Fedoseenko, Cand. of Sci. (Med.), Head of the Department for the Development of Scientific Approaches to Immunization of Patients with Health Deviations and Chronic Diseases, Leading Researcher, Pediatrician, Research Institute of Pediatrics and Child Health, Academician B.V. Petrovsky National Research Center of Surgery, Associate Professor at the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Member of the Union of Pediatricians of Russia

The authors declare no financial support or conflicts of interest that need to be disclosed.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Medical geneticists;

2. Dietitians;

3. Laboratory geneticists;

4. Neurologists;

5. General practitioners (family physicians);

6. Pediatricians;

7. General practitioners;

8. Functional diagnostics physicians;

9. Psychiatrists;

10. Pediatric psychiatrists;

11. Medical psychologists;

12. Residents;

13. . Medical students.

Table 1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Scale for assessing levels of reliable evidence (LRE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, rehabilitation interventions)

Table 3. Grade of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines

The mechanism for updating clinical guidelines provides for their systematic revision — at least once every three years, as well as upon the emergence of new evidence-based medicine data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or when justified additions/comments to previously approved clinical guidelines are available, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

1. Federal Law No. 323-FZ of November 21, 2011, "On the Fundamentals of Healthcare Protection in the Russian Federation".

2. Decree of the Government of the Russian Federation No. 890 dated July 30, 1994, "On State Support for the Development of the Medical Industry and Improvement of the Provision of Medicines and Medical Devices to the Population and Healthcare Institutions" (with amendments and additions).

3. Order of the Ministry of Health of the Russian Federation No. 274n dated April 21, 2022, "On Approval of the Procedure for Providing Medical Care to Patients with Congenital and (or) Hereditary Diseases."

4. Government Decree No. 403 of April 26, 2012, "On the Procedure for Maintaining the Federal Register of Persons Suffering from Life-Threatening and Chronically Progressive Rare Orphan Diseases Leading to a Reduction in Citizens' Life Expectancy or Disability, and Its Regional Segment".

5. Order of the Ministry of Health of the Russian Federation No. 834n of December 15, 2014, "On Approval of Unified Forms of Medical Documentation Used by Medical Organizations Providing Outpatient Medical Care and Procedures for Their Completion".

6. Order of the Ministry of Health of the Russian Federation No. 1177n dated December 20, 2012, "On Approval of the Procedure for Giving Informed Voluntary Consent to Medical Intervention and Refusal of Medical Intervention for Certain Types of Medical Interventions, Forms of Informed Voluntary Consent to Medical Intervention and Forms of Refusal of Medical Intervention."

7. Order of the Ministry of Health of the Russian Federation No. 1094n dated November 24, 2021, "On Approval of the Procedure for Prescribing Medicinal Products, Prescription Form Templates for Medicinal Products, the Procedure for Issuing, Recording, and Storing Said Forms, Templates of Prescription Forms Containing Prescriptions for Narcotic Drugs or Psychotropic Substances, the Procedure for Their Manufacture, Distribution, Registration, Recording, and Storing, as Well as the Rules for Issuing Prescription Forms, Including in the Form of Electronic Documents"

8. Order of the Ministry of Health of the Russian Federation No. 302n dated May 16, 2019, "On Approval of the Procedure for Minors Undergoing Dispensary Observation, Including During the Period of Education and Upbringing in Educational Organizations"

9. Directive of the Government of the Russian Federation No. 3053-r dated December 31, 2018 "On Approval of Lists of Medical Devices Implanted into the Human Body When Providing Medical Care within the Framework of the State Guarantee Program for Free Medical Care to Citizens and Dispensed by Prescription for Medical Devices Upon Provision of a Set of Social Services"

10. Order of the Ministry of Health of the Russian Federation No. 354n dated June 6, 2013, "On the Procedure for Conducting Pathological Autopsies" (registered by the Ministry of Justice of the Russian Federation on December 16, 2013, registration No. 30612).

Information on medicinal products: https://grls.rosminzdrav.ru/

Key regulatory legal acts governing the provision of palliative medical care:

1. Federal Law No. 18-FZ dated March 6, 2019, "On Amendments to the Federal Law 'On the Basics of Protecting the Health of Citizens in the Russian Federation' Regarding the Provision of Palliative Medical Care."

2. Order of the Russian Ministry of Health No. 345n, Russian Ministry of Labor No. 372n dated May 31, 2019, "On approval of the Regulations on the organization of palliative medical care, including the procedure for interaction between medical organizations, social service organizations, and public associations, and other non-profit organizations operating in the field of health protection."

3. Order of the Russian Ministry of Health No. 348n dated May 31, 2019, "On approval of the list of medical devices intended to maintain human organs and body systems, provided for home use."

4. Order of the Russian Ministry of Health No. 505n dated July 10, 2019, "On approval of the Procedure for the transfer by a medical organization to a patient (their legal representative) of medical devices intended to maintain the functions of human organs and body systems for home use in the provision of palliative medical care."

5. Order of the Ministry of Health of the Russian Federation No. 831 dated October 3, 2019, "On Approval of the Departmental Target Program 'Development of the Palliative Medical Care Delivery System'." Other regulatory legal documents used in the development of the clinical guidelines:

6. International Statistical Classification of Diseases and Related Health Problems (ICD-10);

7. Order of the Ministry of Health of the Russian Federation No. 1183n dated December 20, 2012 "On approval of the nomenclature of positions of medical and pharmaceutical workers".

8. Order of the Ministry of Health of the Russian Federation No. 541n dated July 23, 2010. "Unified Qualification Handbook of Positions of Managers, Specialists, and Employees, Section: Qualification Characteristics of Positions of Healthcare Workers."

9. Federal Law No. 489-FZ dated December 25, 2018, "On Amendments to Article 40 of the Federal Law 'On Compulsory Medical Insurance in the Russian Federation' and the Federal Law 'On the Fundamentals of Public Health Protection in the Russian Federation' regarding Clinical Guidelines".

10. Order of the Ministry of Health of the Russian Federation No. 103n dated February 28, 2019, "On Approval of the Procedure and Timeframes for the Development and Revision of Clinical Guidelines, Their Template Form, and Requirements for Their Structure, Composition, and Scientific Validity of Information Included in Clinical Guidelines".

11. Order of the Russian Ministry of Health No. 804n dated October 13, 2017, "On approval of the nomenclature of medical services."

12. Order of the Ministry of Labor and Social Protection of the Russian Federation No. 585n dated August 27, 2019, "On Classifications and Criteria Used in Carrying Out Medical and Social Expertise of Citizens by Federal State Institutions of Medical and Social Expertise";

13. Order of the Ministry of Health and Social Development of the Russian Federation dated August 9, 2005, No. 494, "On the procedure for the use of medicinal products in patients for vital indications"

14. Information letter of the Russian Ministry of Health on the possibility of procuring a medicinal product by its trade name (https://www.rosminzdrav.ru/news/2019/12/18/13043-minzdrav-podgotovil-informatsionnoe-pismo-po-vozmozhnosti-zakupki-lekarstvennogo-preparata-po-torgovomu-naimenovaniyu);

15. List of specialized therapeutic nutrition products for disabled children for 2023, Order of the Government of the Russian Federation No. 3551-r dated December 11, 2023

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

What is Glut1 deficiency syndrome?

Glut1 deficiency syndrome (glucose transporter type 1 deficiency syndrome) is a rare genetic disorder primarily affecting the central nervous system. The cause of the disease is a defect in the SLC2A1 gene, which encodes the glucose transporter protein type 1 (Glut1) responsible for transporting glucose from the blood into the brain. As a result of the genetic defect, protein function is impaired, depriving the brain of its main source of energy. In children, more than 85% of all glucose is consumed specifically by the nervous system. While blood glucose levels remain normal, impaired function of the glucose transporter into the central nervous system leads to decreased glucose concentration in the cerebrospinal fluid. This results in starvation of brain cells and, consequently, the development of neurological symptoms — seizures, movement disorders, speech impairments, and other manifestations. The disease was first described by De Vivo in 1991.

How does Glut1 deficiency syndrome manifest?

The disease is characterized by the development of metabolic encephalopathy accompanied by epileptic seizures, psychomotor retardation, coordination impairment (ataxia), muscle tone changes (dystonia), acquired microcephaly (decreased rate of head circumference growth), and other neurological manifestations. However, the clinical manifestations of the disease are variable and may differ even within the same family.

How is Glut1 deficiency syndrome diagnosed?

The diagnosis is established based on the clinical picture and laboratory test results. The diagnostic criterion for the disease is a decrease in cerebrospinal fluid glucose below the threshold level in the presence of a normal blood glucose level. A definitive diagnosis is made following genetic testing — DNA diagnostics.

How is Glut1 deficiency syndrome inherited?

The disease is inherited in an autosomal dominant manner (Fig. B1.1), meaning a single mutation is sufficient for the disease to manifest. In most patients with Glut1 deficiency syndrome, mutations arise de novo, i.e., for the first time (not inherited from parents). Less commonly, the disease may be transmitted from an affected parent who is a carrier of the pathogenic mutation and has a milder form of the disease. The risk of transmitting the damaged gene from an affected parent to offspring is 50% for each pregnancy. The risk is equal for males and females.

Figure B1.1 Autosomal dominant inheritance pattern.

How are patients with Glut1 deficiency syndrome treated?

Currently, the only effective therapy for patients with Glut1 deficiency syndrome is a ketogenic diet — a high-fat, low-carbohydrate diet.

The therapeutic effect of the ketogenic diet lies in the fact that our brain can use not only glucose but also ketone bodies (3-hydroxybutyrate, acetoacetate) for energy. These are water-soluble compounds synthesized in liver cells from fatty acids (which fats are composed of) when carbohydrates are insufficient. Ketone bodies are able to cross into the brain via another transporter protein, supplying the brain with the necessary amount of energy for metabolism, thereby preventing further damage and helping to reduce clinical manifestations of the disease, control seizures, and improve motor, speech, and cognitive functions.

To constantly maintain the required blood ketone concentration, the patient's daily diet is enriched with fats. To shift metabolism towards fat breakdown and energy production via ketone bodies, carbohydrate intake is restricted.

The diet has certain side effects and specific features, but with the right approach and calculations, it is well tolerated. Initiation of ketosis is performed strictly under medical supervision. The physician will help select the appropriate dietary fat ratio while monitoring blood ketone levels and the function of other organs.

Prognosis of Glut1 deficiency syndrome

The prognosis depends on the type of disease, age of onset, and initiation of therapy. With early diagnosis and timely therapy, the prognosis is generally favorable; patients can expect a full life, differing only in lifestyle and diet.

Where in Russia can one get diagnosed and treated for Glut1 deficiency syndrome?

There are many centers in Russia that perform molecular genetic diagnostic tests. Medical genetics centers exist in each region where patients can consult a geneticist and order molecular studies. The ketogenic diet is prescribed by a neurologist, dietician, gastroenterologist, or pediatrician with training in dietetics.

Learn more

There are many organizations worldwide that can help you find answers to any other questions related to Glut1 deficiency syndrome:

International Glut1 Deficiency Family Association https://www.g1dfoundation.org

Russian Epilepsy Portal https://epilepsyinfo.ru

International Rare Diseases Portal www.orpha.net

EURORDIS, the European organization representing patients with rare diseases www.eurordis.org

Appendix B2. Example of an emergency guide for patients on a ketogenic diet

Attention! The patient is on a ketogenic diet.

Ketogenic diet (KD) is a high-fat, low-carbohydrate diet under medical supervision. It is one of the treatment methods for certain drug-resistant epilepsies. It is tailored individually for each child, so the instructions for calorie intake and the ratio of proteins, fats, and carbohydrates are specific to each child.

Target ketone levels while following the ketogenic diet:

IN THE BLOOD — 2–5 MMOL/L (acceptable value up to 6 if feeling well),

IN THE URINE — 8–16 MMOL/L.

A drop in blood ketone levels may lead to the return or intensification of seizures.

The diet has certain side effects and specific features, but is usually well tolerated. Many types of malaise can be treated on an outpatient basis. A patient on a KD usually requires inpatient monitoring if they present with the following complaints:

· Vomiting and diarrhea (usually caused by gastroenteritis)

· Febrile fever

· Increased frequency of epileptic seizures.

ASSISTANCE:

4 key factors when seeking medical help:

1. Determining the cause of illness (in case of signs of sepsis, vomiting with blood or bile, hospitalization is required)

2. Assessing the degree of dehydration

3. Detecting ketoacidosis (assessing acid-base balance and blood gases (testing blood hydrogen ion levels (pH), blood buffer substances), blood glucose, blood sodium, total blood calcium, blood potassium, blood chlorides, blood lactic acid; weakness, nausea, fruity (ketone) breath odor, tachycardia, tachypnea)

4. Determining deviation from the usual ketonemia level — patients and their parents should know the child's usual ketonemia level when feeling well:

· If ketonemia is over 5 mmol/l and there are no clinical signs of ketosis, observation is required,

· Ketonemia below 2 mmol/l is NOT dangerous, but undesirable.

PROVISION OF CARE:

I. Dehydration

1. For mild dehydration:

Oral rehydration:

Increasing intake of regular fluids — water, unsweetened tea.

Do not! Consume sugary drinks, juices, milk.

Keto-fluids are permitted.

If the patient refuses to drink — monitor the level of dehydration and adjust treatment if necessary.

2. Moderate dehydration, but the child drinks willingly, no vomiting

Oral rehydration; oral rehydration salt preparations can be used — Dextrose + Potassium chloride + Sodium chloride + Sodium citrate** – containing 1 and 1.5 g of dextrose** per 100 ml of solution, respectively

Rehydration is more important than lowering the target ketosis level!

3. Moderate dehydration, but the child refuses to drink

In the absence of vomiting, rehydration via a nasogastric tube is possible — Dextrose + Potassium chloride + Sodium chloride + Sodium citrate** + (Keto-fluids in the absence of hyperketosis).

4. Severe dehydration

Any child with severe dehydration requires intravenous administration of 0.9% sodium chloride solution** 10–20 ml/kg, after which other solutions may be administered if necessary.

There is NO need to administer a dextrose solution** if glycemia is above 2.6 mmol/l.

II. Hypoglycemia

Glucose level below 2.6 mmol/l:

Check ketone levels. If they are within the required range and the patient is neurologically stable, allow hypoglycemia. If neurological symptoms occur, administer oral carbohydrates.

2–5 g of carbohydrates:

· 20–50 ml of fruit juice

· 1 teaspoon of sugar, jam, honey, or syrup (can be mixed with water or tea)

· 5 g (1 teaspoon) #dextrose** powder in 100 ml of water [100]

· 10% dextrose solution** can be used (10 ml – 1 g of dextrose**)

Glucose level above 2.6 mmol/l, but symptoms of hypoglycemia are present:

The child is lethargic, has decreased muscle tone, is pale, lethargic, has a lowered body temperature, cold and clammy sweat, cyanosis. Begin treatment for hypoglycemia via the same route. Measure glucose level 15–20 minutes after treatment starts; if no results, repeat treatment. For unconscious patients and/or those with seizures (if oral glucose intake is impossible) — intravenous administration of 10% dextrose** at a dose of 5 ml/kg. If hypoglycemia episodes recur — inform the dietician, as the keto-ratio may need adjustment.

III. Ketosis ↑↑

Perform an assessment of acid-base balance and blood gases. If pH is normal, continue the KD. If pH ↓ (uncompensated acidosis ↑) — decrease the KD ratio or administer a carbohydrate solution (e.g., 20–50 ml of fruit juice).

Treatment of hyperketonemia. Addition of extra carbohydrates to the diet or via intravenous infusion:

· 20–50 ml of fruit juice

· 1 teaspoon of sugar, jam, honey, or syrup (can be mixed with water or tea)

· Re-evaluation of blood ketones 120 minutes after carbohydrate intake

· If ketonemia is ≥ 6 mmol/L and/or symptoms of acidosis are present, give the child an additional 30 ml of juice/tea with sugar

· If the second carbohydrate portion has no effect, intravenous administration of a 5% dextrose solution** is required

· Monitor ketone levels every 6 hours

· Glycemia monitoring is not necessary. Required values are above 2.6 mmol/L.

CONCLUSION:

· With high ketosis and good general well-being — observation

· With high ketosis and general weakness — additional examination and treatment of comorbid conditions

· High ketosis and acidosis — intravenous administration of 5% dextrose solution** and 0.9% sodium chloride solution**

· High ketosis and hypoglycemia — standard treatment for hypoglycemia.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. Symptoms observed in Glut1 deficiency syndrome

Figure 1 Symptoms observed in Glut1 deficiency syndrome by age [39]

Figure 2 Neurological manifestations in Glut1 deficiency syndrome [45]

Appendix G2. Genotype-Phenotype Correlation in Glut1 Deficiency Syndrome

A correlation was noted between the specific pathogenic variant type of the SLC2A1 gene and clinical severity [18].

Fifty-three patients were clinically divided into four groups according to the Columbia Neurological Score (CNS) [18]:

• Minimal (70–76 points)

• Mild (60–69 points)

• Moderate (50–59 points)

• Severe (40–49 points)

Comparison of heterozygous pathogenic variant types in the SLC2A1 gene among the four groups revealed the following:

• Missense variants were predominantly found in mild and moderate neurological impairment.

• Splice-site variants, nonsense variants, insertions, and exon deletions were almost always found in moderate-to-severe neurological impairment.

• Complete gene deletions were observed in severe cases.

A significant inverse correlation (R ² = 0.94) was observed between the mean values of erythrocyte 3-O-methyl-D-glucose uptake and clinical severity determined by the Columbia Neurological Score. Thus, erythrocyte glucose uptake serves as an indicator of the functional effect of the pathogenic variant.

A multitude of pathogenic variants have been identified [18, 69]. Several mutation hotspots and gene regions were discovered:

• Three individuals (each from different families) have a mild clinical phenotype (determined by the CNS scale) and the heterozygous p.Arg333Trp pathogenic missense variant.

• Twelve individuals have a heterozygous pathogenic missense variant at amino acid residue arginine 126.

• Five had a mild phenotype: three members of one family with the p.Arg126His pathogenic variant and two members of one family with the p.Arg126Cys pathogenic variant.

• Five with a classic phenotype or non-epileptic phenotype had the p.Arg126Cys pathogenic variant.

• Two monozygotic twin brothers with paroxysmal choreoathetosis with spasticity were heterozygous for the p.Arg126Cys pathogenic variant.

• A significant portion (5/21) of pathogenic variants is located in the vulnerable region of the Glut1 protein, which includes the fourth transmembrane domain encoded by exon 4, indicating a critical functional impairment associated with structural changes in this protein region

• Three individuals were heterozygotes for the p.Thr295Met pathogenic variant:

• Classic early-onset phenotype including monthly seizures starting in infancy, developmental delay, ataxia, microcephaly, and language deficit;

• Hypoglycorrhachia and low-normal lactate concentrations in the cerebrospinal fluid;

• Normal 3-OMG (3-O-methyl-d-glucose) influx into erythrocytes.

Mutagenesis studies show that p.Thr295Met specifically affects glucose flux by impairing efflux rather than influx. These findings explain the seemingly paradoxical findings of Glut1 deficiency syndrome with hypoglycorrhachia and "normal" erythrocyte glucose uptake [68].

Appendix G3. Required Evaluations Prior to KD Initiation

Patient examination before initiating the ketogenic diet:

• Characteristics of seizures (Type, frequency)

• Comorbidities

• Regular medications taken at the time of examination

• Eating habits

• Intolerance to specific foods

• Assessment of somatic status

• Assessment of neurological status

• Anthropometric measurements (body weight, height, head circumference)

Required examinations prior to KD initiation

Appendix G4. Ketogenic Diet: Indications and Contraindications

Appendix G5. Macronutrient ratios for various KD variants, calculated for a 1200 kcal diet

Appendix G6. Comparison of various KD variants used in Glut1 deficiency

Appendix G7. Average Daily Physiological Energy Requirements for Children

Average daily physiological energy requirements for children according to FAO/WHO/UNU 2001

Energy requirements of infants receiving ketogenic diet, based on RDA^a

Note: ^a Based on the average for Australia, France, Germany, the Netherlands, the UK, and the USA.

Appendix G8. Recommended daily protein intake in patients receiving ketogenic diet

Based on RDA values

Based on RDA or WHO/FAO values

Note: a — Based on the average for Australia, France, Germany, the Netherlands, the UK, and the USA; b — WHO 2007: safe level for growth +1.96 SD; c — FAO 2013.

Appendix G9. Recommended Daily Fluid Intake

Recommended daily fluid intake based on RDA^a

Note: a — Based on the average for Australia, France, Germany, the Netherlands, the UK, and the USA.

Appendix G10. Safe levels of protein intake and energy requirements in children and adults, as well as during pregnancy and lactation (selected from FAO/WHO/UNU recommendations for a healthy population)

Appendix G11. Preparatory, initial, and maintenance stages of treatment based on ketogenic diet in infants and young children

Appendix G12. Recommended clinical monitoring during the ketogenic diet

Appendix G13. Recommended Laboratory Monitoring During Dietotherapy

Appendix G14. Side effects of the KD, their prevention and management

Appendix G15. Schofield Formulas for Basal Metabolic Rate Calculation by Body Weight in Children

^{Note: *BMR — basal metabolic rate, **BW — body weight (kg).}

Appendix G16. Foods and Oils Used in the KD