Clinical Guidance

Milder manifestations (e.g., intermittent epilepsy, dyskinesias, and ataxia) of Glut1DS are associated with 25%-35% reduction in Glut1 transporter function . More severe manifestations in infantile- and childhood-onset Glut1DS are associated with greater reductions (perhaps 40%-75%) in Glut1 transporter function . The following classes of SLC2A1 pathogenic variants associated with these phenotypes :

• Missense variants. Predominantly mild or moderate clinical phenotype

• Splice site and nonsense variants and insertions, deletions, and exon deletions. Almost exclusively moderate or severe clinical phenotype

• Complete gene deletions. Severe clinical phenotype

Source: GeneReviews — "Glucose Transporter Type 1 Deficiency Syndrome"

Penetrance

Penetrance in Glut1DS inherited in an autosomal dominant manner is complete. If an asymptomatic or minimally symptomatic parent of a fully symptomatic child is identified by genetic testing, one should investigate the possibility that the parent is mosaic for the SLC2A1 pathogenic variant. Mosaicism blunts the clinical severity of the condition.

Source: GeneReviews — "Glucose Transporter Type 1 Deficiency Syndrome"

Diagnostic Criteria

An international consensus statement on the standard of care for glucose transporter type 1 deficiency syndrome (Glut1DS) diagnosis and management has been published (full text).

Suggestive Findings

Glut1DS should be suspected in probands with the following clinical features by age, laboratory findings, and family history .

Clinical Features by Age

Infancy to early childhood (age 4 years). Most frequently between ages one to six months; less often after age two years

Source: GeneReviews — "Glucose Transporter Type 1 Deficiency Syndrome"

Differential Diagnosis

A few individuals have a severe clinical phenotype and laboratory signature of glucose transporter type 1 deficiency syndrome (Glut1DS) – low cerebrospinal fluid glucose and lactate, normal red blood cell glucose uptake assay – but no identifiable pathogenic variants in SLC2A1; thus, a different, as-yet-unidentified gene should be considered [DC De Vivo U Monani, personal experience]. The differential diagnosis of Glut1DS includes a range of metabolic and neurologic disorders, including those listed in .

Table 3.

Glucose Transporter Type 1 Deficiency Syndrome: Differential Diagnosis

Feature | Disorders of Interest in the Differential Diagnosis of Glut1DS

Neuroglycopenia/hypoglycorrhachia | Conditions causing chronic or intermittent hypoglycemia:

Source: GeneReviews — "Glucose Transporter Type 1 Deficiency Syndrome"

Management Guidelines

An international consensus statement on the standard of care for glucose transporter type 1 deficiency syndrome (Glut1DS) diagnosis and management has been published (full text).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Glut1DS, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Glucose Transporter Type 1 Deficiency Syndrome: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Neurologic

| Neurologic eval | • To incl brain MRI if not performed at time of diagnosis

• Consider FDG-PET in select persons; typically used in research settings, but has distinctive findings.

• Eval for movement disorders incl ataxia, dystonia, choreoathetosis, paroxysmal dyskinesias

• Preprandial postprandial EEG to characterize seizure types distinguish seizures from non-seizure paroxysmal behaviors

Ataxia

| Orthopedics/ physical medicine rehab/ PT OT eval | To incl assessment of:

• Gross motor fine motor skills

Clinical Guidance

Barbiturates. Generally, children with infantile-onset seizures are treated with phenobarbital, the most used ASM in this age group. In vitro studies indicate that barbiturates aggravate the glucose transporter type 1 (Glut1) transport defect in erythrocytes of individuals with Glut1DS . On occasion, parents have reported that phenobarbital did not improve their child's seizure control or may have worsened their child's clinical condition. Valproic acid. Although studies suggest that valproic acid effects in vitro are mixed and the clinical consequences of valproic acid usage in individuals with Glut1DS cannot be predicted , the authors do not feel that these mixed in vitro data minimize the clinical concerns and recommend avoiding this drug as a treatment of seizures in the setting of KDTs. Acetazolamide, topiramate, and zonisamide inhibit carbonic anhydrase and may potentiate metabolic acidosis. They can also cause kidney stones. Methylxanthines (e.g., caffeine), which are known to inhibit transport of glucose by Glut1 , have been reported to worsen the clinical findings in individuals with Glut1DS . Thus, it is advisable for affected individuals to avoid coffee and other caffeinated beverages.

Source: GeneReviews — "Glucose Transporter Type 1 Deficiency Syndrome"

Therapies Under Investigation

Triheptanoin. This odd-carbon medium-chain triglyceride consists of three seven-carbon fatty acids on a glycerol backbone. Open-label studies suggested possible benefit of triheptanoin as a treatment for seizures and movement disorders in Glut1DS. However, in a randomized, double-blind trial of triheptanoin for treatment of drug-resistant epilepsy in Glut1DS, triheptanoin did not significantly reduce seizure frequency in individuals with Glut1DS who were not on KDTs . Similarly, triheptanoin did not show benefit vs placebo for the treatment of paroxysmal movement disorders in Glut1DS . Both studies used safflower oil as the placebo. Diazoxide blocks the release of insulin from the beta cells in the pancreas and has been used for decades as a treatment for genetic hyperinsulinism.

Source: GeneReviews — "Glucose Transporter Type 1 Deficiency Syndrome"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended. Table 6. Glucose Transporter Type 1 Deficiency Syndrome: Recommended Surveillance

Source: GeneReviews — "Glucose Transporter Type 1 Deficiency Syndrome"