encephalopathy due to GLUT1 deficiency

Summary

encephalopathy due to GLUT1 deficiency (MONDO:0011724) is a disease caused by SLC2A1 (GenCC Definitive), with 2 cohort genes and 25 clinical trials. Top therapeutic interventions include triheptanoin and l-fucose.

At a glance

• Prevalence: 1-9 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SLC2A1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 346
• Phenotypes (HPO): 33
• Clinical trials: 25

Clinical features

Epidemiology

Prevalence records

4 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.538	Worldwide	Validated
Point prevalence	1-9 / 1 000 000	0.26	Norway	Validated
Point prevalence	1-9 / 100 000	1.11	Australia	Validated
Point prevalence	1-9 / 100 000	1.2	Denmark	Validated

Signs & symptoms

Clinical features (HPO)

33 HPO clinical features (Orphanet curated; top 33 by frequency):

HPO ID	Term	Frequency
HP:0000253	Progressive microcephaly	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001251	Ataxia	Very frequent (80-99%)
HP:0001257	Spasticity	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001298	Encephalopathy	Very frequent (80-99%)
HP:0001332	Dystonia	Very frequent (80-99%)
HP:0001877	Abnormal erythrocyte morphology	Very frequent (80-99%)
HP:0002133	Status epilepticus	Very frequent (80-99%)
HP:0002353	EEG abnormality	Very frequent (80-99%)
HP:0011972	Hypoglycorrhachia	Very frequent (80-99%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0000961	Cyanosis	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001254	Lethargy	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001266	Choreoathetosis	Frequent (30-79%)
HP:0001269	Hemiparesis	Frequent (30-79%)
HP:0001276	Hypertonia	Frequent (30-79%)
HP:0001289	Confusion	Frequent (30-79%)
HP:0002072	Chorea	Frequent (30-79%)
HP:0002315	Headache	Frequent (30-79%)
HP:0003470	Paralysis	Frequent (30-79%)
HP:0003552	Muscle stiffness	Frequent (30-79%)
HP:0007034	Generalized hyperreflexia	Frequent (30-79%)
HP:0007308	Extrapyramidal dyskinesia	Frequent (30-79%)
HP:0007704	Paroxysmal involuntary eye movements	Frequent (30-79%)
HP:0100660	Dyskinesia	Frequent (30-79%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0001336	Myoclonus	Occasional (5-29%)
HP:0002186	Apraxia	Occasional (5-29%)
HP:0002360	Sleep abnormality	Occasional (5-29%)
HP:0002871	Central apnea	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	encephalopathy due to GLUT1 deficiency
Mondo ID	MONDO:0011724
MeSH	C536830
OMIM	606777
Orphanet	71277
DOID	DOID:0070561
ICD-11	1231079185
UMLS	C4551966
MedGen	1645412
GARD	0009265
NORD	1188
Is cancer (heuristic)	no

Also known as: De Vivo disease · encephalopathy due to GLUT1 deficiency · G1D · glucose transport defect, blood-brain barrier · glucose TRANSPORT defect, blood-brain barrier GLUT1 deficiency syndrome 1, autosomal recessive, included · glucose transporter Protein syndrome · glucose transporter protein syndrome · glucose transporter type 1 deficiency · Glucose Transporter Type 1 Deficiency Syndrome · glucose transporter type 1 deficiency syndrome · glucose transporter type1 (glut-1) deficiency · glut-1 deficiency syndrome · GLUT1 deficiency syndrome · GLUT1 deficiency syndrome 1 · GLUT1 deficiency syndrome 1, infantile onset, severe · GLUT1 deficiency syndrome type 1 · GLUT1 DS · GLUT1-DS · GLUT1DS1

Data availability: 346 ClinVar variants · 4 GenCC gene-disease records · 12 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn carbohydrate metabolic disorder › GLUT1 deficiency syndrome › encephalopathy due to GLUT1 deficiency

Related subtypes (1): childhood onset GLUT1 deficiency syndrome 2

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

346 retrieved; paginated sample, class counts are floors:

101 uncertain significance, 70 pathogenic, 39 conflicting classifications of pathogenicity, 34 likely benign, 30 benign, 26 pathogenic/likely pathogenic, 26 benign/likely benign, 20 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
16105	NC_000001.11:g.(?42925375)(42959176_?)del	LOC129930367	Pathogenic	no assertion criteria provided
1027418	NM_006516.4(SLC2A1):c.985G>A (p.Glu329Lys)	SLC2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1027520	NM_006516.4(SLC2A1):c.136C>T (p.Gln46Ter)	SLC2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1048756	NM_006516.4(SLC2A1):c.275+1del	SLC2A1	Pathogenic	no assertion criteria provided
1069398	NM_006516.4(SLC2A1):c.558G>A (p.Trp186Ter)	SLC2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1073271	NM_006516.4(SLC2A1):c.634del (p.Arg212fs)	SLC2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1189059	NM_006516.4(SLC2A1):c.399C>A (p.Cys133Ter)	SLC2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1254825	NM_006516.4(SLC2A1):c.275+1G>C	SLC2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1326270	NM_006516.4(SLC2A1):c.1350_1351del (p.Phe450fs)	SLC2A1	Pathogenic	no assertion criteria provided
1335936	NM_006516.4(SLC2A1):c.739G>T (p.Glu247Ter)	SLC2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
159921	NM_006516.4(SLC2A1):c.100A>G (p.Asn34Asp)	SLC2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
159922	NM_006516.4(SLC2A1):c.1089del (p.Pro362_Trp363insTer)	SLC2A1	Pathogenic	criteria provided, single submitter
159924	NC_000001.11:g.42943313_42943322del	SLC2A1	Pathogenic	criteria provided, single submitter
159928	NM_006516.4(SLC2A1):c.748C>T (p.Gln250Ter)	SLC2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
159930	NM_006516.4(SLC2A1):c.847C>T (p.Gln283Ter)	SLC2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
16106	NM_006516.4(SLC2A1):c.1366A>T (p.Lys456Ter)	SLC2A1	Pathogenic	no assertion criteria provided
16107	NM_006516.4(SLC2A1):c.1347C>A (p.Tyr449Ter)	SLC2A1	Pathogenic	no assertion criteria provided
16109	NM_006516.4(SLC2A1):c.377G>T (p.Arg126Leu)	SLC2A1	Pathogenic	no assertion criteria provided
16110	NM_006516.4(SLC2A1):c.272G>A (p.Gly91Asp)	SLC2A1	Pathogenic	no assertion criteria provided
16111	NM_006516.4(SLC2A1):c.377G>A (p.Arg126His)	SLC2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16112	NM_006516.4(SLC2A1):c.843_854del (p.Gln282_Ser285del)	SLC2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16113	NM_006516.4(SLC2A1):c.940G>A (p.Gly314Ser)	SLC2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
16114	NM_006516.4(SLC2A1):c.823G>A (p.Ala275Thr)	SLC2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16117	NM_006516.4(SLC2A1):c.277C>T (p.Arg93Trp)	SLC2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
16118	NM_006516.4(SLC2A1):c.376C>T (p.Arg126Cys)	SLC2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16119	NM_006516.4(SLC2A1):c.274C>T (p.Arg92Trp)	SLC2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1686203	NM_006516.4(SLC2A1):c.115-2A>C	SLC2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1698134	NM_006516.4(SLC2A1):c.115-2A>G	SLC2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1699946	NM_006516.4(SLC2A1):c.679+1G>A	SLC2A1	Pathogenic	criteria provided, single submitter
1804053	NM_006516.4(SLC2A1):c.500del (p.Gly167fs)	SLC2A1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 7 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
SLC2A1	Definitive	Autosomal dominant	encephalopathy due to GLUT1 deficiency	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC2A1	Orphanet:168577	Hereditary cryohydrocytosis with reduced stomatin
SLC2A1	Orphanet:1942	Epilepsy with myoclonic-atonic seizures
SLC2A1	Orphanet:2131	Alternating hemiplegia of childhood
SLC2A1	Orphanet:53583	Paroxysmal dystonic choreathetosis with episodic ataxia and spasticity
SLC2A1	Orphanet:71277	Classic glucose transporter type 1 deficiency syndrome
SLC2A1	Orphanet:86911	Epilepsy with myoclonic absences
SLC2A1	Orphanet:98811	Paroxysmal exertion-induced dyskinesia

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC2A1	HGNC:11005	ENSG00000117394	P11166	Solute carrier family 2, facilitated glucose transporter member 1	gencc,clinvar
SLC2A1-DT	HGNC:44187	ENSG00000227533		SLC2A1 divergent transcript	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC2A1	Solute carrier family 2, facilitated glucose transporter member 1	Facilitative glucose transporter, which is responsible for constitutive or basal glucose uptake.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transporter	1	38.9×	0.051
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC2A1	Transporter	yes		Glu_transpt_1, Sugar/inositol_transpt, MFS_sugar_transport-like
SLC2A1-DT	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
skin of abdomen	1
sural nerve	1
tibial nerve	1
lateral globus pallidus	1
sperm	1
vena cava	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC2A1	250	ubiquitous	marker	tibial nerve, sural nerve, skin of abdomen
SLC2A1-DT	168	ubiquitous	yes	sperm, vena cava, lateral globus pallidus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC2A1	5,711
SLC2A1-DT	0

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC2A1	P11166	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 2 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective SLC2A1 causes GLUT1 deficiency syndrome 1 (GLUT1DS1)	1	11420.0×	4e-04	SLC2A1
Lactose synthesis	1	3806.7×	7e-04	SLC2A1
Vitamin C (ascorbate) metabolism	1	1427.5×	0.001	SLC2A1
Cellular hexose transport	1	543.8×	0.002	SLC2A1
Regulation of insulin secretion	1	219.6×	0.005	SLC2A1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to Thyroglobulin triiodothyronine	1	5617.3×	0.002	SLC2A1
long-chain fatty acid import across plasma membrane	1	4213.0×	0.002	SLC2A1
GDP-L-fucose salvage	1	4213.0×	0.002	SLC2A1
D-glucose import across plasma membrane	1	2808.7×	0.002	SLC2A1
L-ascorbic acid metabolic process	1	1532.0×	0.002	SLC2A1
dehydroascorbic acid transport	1	1203.7×	0.002	SLC2A1
cellular hyperosmotic response	1	1203.7×	0.002	SLC2A1
D-glucose transmembrane transport	1	936.2×	0.003	SLC2A1
obsolete D-glucose import	1	842.6×	0.003	SLC2A1
photoreceptor cell maintenance	1	358.6×	0.005	SLC2A1
cellular response to glucose starvation	1	337.0×	0.005	SLC2A1
response to insulin	1	230.8×	0.006	SLC2A1
cellular response to mechanical stimulus	1	216.1×	0.006	SLC2A1
female pregnancy	1	210.7×	0.006	SLC2A1
cerebral cortex development	1	205.5×	0.006	SLC2A1
transport across blood-brain barrier	1	179.3×	0.007	SLC2A1
central nervous system development	1	115.4×	0.009	SLC2A1
protein-containing complex assembly	1	113.9×	0.009	SLC2A1
response to hypoxia	1	95.8×	0.010	SLC2A1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SLC2A1	EMETINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC2A1	7	4
SLC2A1-DT	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
EMETINE	4	SLC2A1
GOSSYPOL	3	SLC2A1
CYCLOHEXIMIDE	2	SLC2A1
GENISTEIN	2	SLC2A1
COLFORSIN	2	SLC2A1
KAEMPFEROL	1	SLC2A1
PD-0166285	1	SLC2A1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
SLC2A1	158	Binding:130, ADMET:24, Functional:4

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
SLC2A1	158

Pharmacogenomics

Cohort genes with a PharmGKB record: 0; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

7 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
EMETINE	4	SLC2A1
GOSSYPOL	3	SLC2A1
CYCLOHEXIMIDE	2	SLC2A1
GENISTEIN	2	SLC2A1
COLFORSIN	2	SLC2A1
KAEMPFEROL	1	SLC2A1
PD-0166285	1	SLC2A1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SLC2A1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SLC2A1-DT

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SLC2A1-DT	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 25.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	13
PHASE2	7
PHASE1	2
PHASE3	1
PHASE1/PHASE2	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02960217	PHASE3	TERMINATED	Crossover Study to Assess the Efficacy and Safety of UX007 in the Treatment of Movement Disorders Associated With Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)
NCT07432490	PHASE2	RECRUITING	A Phase II Study With Exploratory Outcomes of Fucose Supplementation in GLUT1 Deficiency Syndrome
NCT01993186	PHASE2	COMPLETED	Phase 2 Study of Triheptanoin (UX007) for the Treatment of Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS)
NCT02000960	PHASE2	UNKNOWN	Pilot Study of Triheptanoin in Patients With Glucose Transporter 1 Deficiency Syndrome
NCT02014883	PHASE2	COMPLETED	Phase II Open Label Study Using Triheptanoin in Patients With Glucose Type 1 Transporter Deficiency GLUT1-DS
NCT02021526	PHASE1/PHASE2	WITHDRAWN	Triheptanoin (C7 Oil), a Food Supplement, for Glucose Transporter Type I Deficiency (G1D)
NCT02599961	PHASE2	TERMINATED	Study to Assess the Long Term Safety and Efficacy of UX007 in Participants With Glucose Type 1 Deficiency Syndrome (Glut1 DS)
NCT03181399	PHASE2	COMPLETED	Diet Treatment Glucose Transporter Type 1 Deficiency (G1D)
NCT03301532	PHASE2	COMPLETED	Compatibility of C7 With Ketogenic Diet in Patients Diagnosed With G1D
NCT02018315	PHASE1	COMPLETED	Treatment Development for Glucose Transporter Type I Deficiency Syndrome (G1D)
NCT03041363	PHASE1	COMPLETED	Treatment Development of Triheptanoin (G1D)
NCT04112862	EARLY_PHASE1	COMPLETED	Sodium Lactate Infusion in GLUT1DS Patients
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT05085704	Not specified	RECRUITING	Brain Metabolism Observed at 7 Tesla
NCT05887739	Not specified	ACTIVE_NOT_RECRUITING	Harmonic Ratio in Patients With GLUT1 Deficiency Syndrome
NCT02013583	Not specified	COMPLETED	The Glucose Transporter Type I Deficiency (G1D) Registry
NCT02018302	Not specified	NO_LONGER_AVAILABLE	Post Study Continuation of C7 for G1D
NCT02915211	Not specified	COMPLETED	Evaluation of Keyo in Children With Epilepsy
NCT03202108	Not specified	WITHDRAWN	Evaluation of Krio in Children and Adults With Epilepsy
NCT03722212	Not specified	COMPLETED	Early Diagnosis of the GLUT1 Deficiency Syndrome With a Blood Based Test
NCT04137692	Not specified	SUSPENDED	Red Blood Cell Exchange Transfusion as a Novel Treatment for GLUT1 Deficiency Syndrome
NCT04399954	Not specified	COMPLETED	Evaluation of Ketoflo
NCT04646850	Not specified	UNKNOWN	Long-term Treatment With the Ketogenic Diet in Epilepsy
NCT05234411	Not specified	UNKNOWN	Ketonemia Through Menstrual Cycle
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
TRIHEPTANOIN	4	10
L-FUCOSE	3	1
CHEMBL1230861	0	1