Early onset or syndromic epilepsy

Gene: SLC2A1

Green List (high evidence)

Comment on mode of inheritance: There are numerous patients reported in literature with monoallelic SLC2A1 variants and GLUT1 deficiency syndrome (characterised by early-onset epileptic encephalopathy associated with hypoglycorrhachia, delayed development, acquired microcephaly, motor incoordination, and spasticity). There are only two probands reported to date with biallelic SLC2A1 variants and GLUT1 deficiency syndrome. While their heterozygous family members were reported as asymptomatic, GLUT1DS presents with variable and often mild symptoms. Hence, the mode of inheritance should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted on this panel, until more biallelic cases are reported.

Created: 8 Oct 2026, 1:21 p.m. | Last Modified: 8 Oct 2026, 1:21 p.m.

Panel Version: 9.87

PMID: 41561681 Previtali et al., 2026 - MONOALLELIC COHORT
Retrospective evaluation of 32 adults with genetically confirmed GLUT1DS from Italian medical centres. 17/32 variants in SLC2A1 were confirmed to be de novo, 10 inherited from a parent, and 5 of unknown inheritance. 24/32 patients had epilepsy, 26 had paroxysmal movement disorders. Fatigue was present in 12 individuals and migraine in 6. Psychomotor delay was observed in 15/32 subjects. Subsequently, 11/32 individuals received a diagnosis of intellectual disability. Mean age at symptom onset was 4 yrs. Brain MRI was unremarkable in most cases (15/20). Mostly missense variants detected.
Study highlights that "GLUT1DS presents with variable symptoms, often unrecognised or too mild to prompt clinical attention." Several adults in the study were diagnosed in adulthood - some asymptomatic and only following their child’s diagnosis.

BIALLELIC CASES:
PMID: 20687207 Rotstein et al., 2011
F1 - male proband seen at 3 yrs, with seizures, dev delay, progressive postnatal microcephaly, hypoglycorrhachia on CSF analysis. He had spasticity with distant lower limb dystonia. Parents and sister unaffected. He was found to carry comp het SLC2A1 (old name GLUT1) variants: c.945A>G, p.K256V (maternally inherited) and c.556G>T, p.R126L (de novo). The same patient as P13 in PMID: 10980529.
F2 - two affectes sisters, aged 6 and 2.5 yrs. Seems to be the same family as in PMID: 20221955.
Only SLC2A1 was analysed, method not described.

PMID: 20221955 Klepper et al., 2009
Report of a 6yo female patient from a consanguineous Arab family from Qatar, with moderate global developmental delay, epilepsy, ataxia, hypotonia, and hypoglycorrhachia (CSF glucose 36 mg/dL; CSF lactate 1.09 mmol/L; CSF/blood glucose ratio 0.44). Symptom onset was around 18 months of age, with frequent falls and an ataxic gait. She harboured a homozygous SLC2A1: c.1402C>T (p.Arg468Trp) variant - also homozygous in her younger sister who was asymptomatic. Unaffected parents were het for the variant. 3 hets reported in gnomAD v4.1.2, no hmz. Method: targeted sequencing of SLC2A1.

PMID: 10980529 Wang et al., 2000
Report of 15 children with infantile seizures, acquired microcephaly, low CSF/blood glucose ratio, and dev delay, harbouring SLC2A1 variants. Method: PCR sequencing of SLC2A1 only. 7 patients had het nonsense variants in SLC2A1, 3 had splicing variants, and 1 harboured a large deletion. 4 patients had missense variants, including Patient 13 with comp het SLC2A1 variants R126L and K256V
(K256V inherited from an asymptomatic mother).
Variants R126L (SLC2A1 c.377G>T (p.Arg126Leu)) & K256V (SLC2A1: c.766_767delinsGT (p.Lys256Val)) are not reported in gnomAD v4.1.2.

SLC2A1 association with AD GLUT1 deficiency syndrome is classified as Definitive in ClinGen (Intellectual Disability and Autism GCEP, Apr 2019). The gene is associated with several disease entities in OMIM: AD {Epilepsy, idiopathic generalized, susceptibility to, 12}, MIM:614847; AD Dystonia 9, MIM:601042; AD GLUT1 deficiency syndrome 2, childhood onset, MIM:612126; AD, AR GLUT1 deficiency syndrome 1, infantile onset, severe, MIM:606777; AD Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 (accessed 7th Oct 2026).

Created: 8 Oct 2026, 1:21 p.m. | Last Modified: 8 Oct 2026, 1:21 p.m.

Panel Version: 9.87

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
GLUT1 deficiency syndrome 2, childhood onset, OMIM:612126; childhood onset GLUT1 deficiency syndrome 2, MONDO:0012805; GLUT1 deficiency syndrome 1, infantile onset, severe, OMIM:606777; encephalopathy due to GLUT1 deficiency, MONDO:0011724; Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885

Publications

• 10980529
• 20221955
• 20687207
• 41561681

I don't know

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Green.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Green List (high evidence)

AD & AR GLUT1 deficiency syndrome, AD stomatin-deficient cryohydrocytosis & AD generalsied idiopathic epilepsy all of these have epilepsy as a feature of disease. Also AD Dystonia type 9 - of which seizures are sometimes observed.

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Dystonia 9,601042; GLUT1 deficiency syndrome 1, infantile onset, severe,606777; GLUT1 deficiency syndrome 2, childhood onset,612126; Stomatin-deficient cryohydrocytosis with neurologic defects,608885; {Epilepsy, idiopathic generalized, susceptibility to, 12},614847

Publications

• 20129935

Comment on mode of inheritance: GLUT1 deficiency syndrome 1, infantile onset, severe 606777 can be mono or biallelic, the other phenotypes associated with variants in the SLC2A1 gene are all monoallelic

Created: 4 Apr 2018, 3:49 p.m.

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Dystonia 9

Publications

• Weber et al (2011) Neurology 77: 959-964

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Dystonia 9

Publications

• Weber et al (2011) Neurology 77: 959-964

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Dystonia 9

Publications

• Weber et al (2011) Neurology 77: 959-964

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Dystonia 9

Publications

• Weber et al (2011) Neurology 77: 959-964

Variants in this GENE are reported as part of current diagnostic practice

Comment on list classification: ok

Created: 8 May 2016, 7:03 p.m.

Added the tag 'treatable' as a ketogenic diet can help ameloriate symptoms (PMID: 29303961).

Created: 19 Aug 2019, 9:58 a.m. | Last Modified: 19 Aug 2019, 9:58 a.m.

Panel Version: 1.254

Comment on mode of inheritance: Confirmed with reviewer that both is relevant (OMIM).

Created: 29 Jan 2016, 5:23 p.m.

Publications

• 29303961