childhood onset GLUT1 deficiency syndrome 2

Summary

childhood onset GLUT1 deficiency syndrome 2 (MONDO:0012805) is a disease caused by SLC2A1 (GenCC Strong), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SLC2A1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 207
• Phenotypes (HPO): 17
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		50	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

17 HPO clinical features (Orphanet curated; top 17 by frequency):

HPO ID	Term	Frequency
HP:0001266	Choreoathetosis	Very frequent (80-99%)
HP:0001332	Dystonia	Very frequent (80-99%)
HP:0007166	Paroxysmal dyskinesia	Very frequent (80-99%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001304	Torsion dystonia	Frequent (30-79%)
HP:0002121	Generalized non-motor (absence) seizure	Frequent (30-79%)
HP:0003401	Paresthesia	Frequent (30-79%)
HP:0004305	Involuntary movements	Frequent (30-79%)
HP:0006801	Hyperactive deep tendon reflexes	Frequent (30-79%)
HP:0000718	Aggressive behavior	Occasional (5-29%)
HP:0000737	Irritability	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001328	Specific learning disability	Occasional (5-29%)
HP:0002072	Chorea	Occasional (5-29%)
HP:0001256	Intellectual disability, mild	Very rare (<1-4%)
HP:0002061	Lower limb spasticity	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	childhood onset GLUT1 deficiency syndrome 2
Mondo ID	MONDO:0012805
MeSH	C564288
OMIM	612126
Orphanet	98811
DOID	DOID:0090045
SNOMED CT	724072002
UMLS	C1842534
MedGen	330866
GARD	0010541
Is cancer (heuristic)	no

Also known as: childhood onset GLUT1 deficiency syndrome 2 · childhood onset GLUT1 deficiency syndrome type 2 · dystonia 18 · DYT-SLC2A1 · DYT18 · GLUT1 deficiency syndrome 2 · GLUT1 deficiency syndrome 2, childhood onset · GLUT1 deficiency syndrome type 2 · GLUT1DS2 · paroxysmal exercise-induced dyskinesia with or without epilepsy and/or hemolytic Anaemia · paroxysmal exercise-induced dystonia · paroxysmal exertion-induced dystonia with or without epilepsy and/or hemolytic Anaemia · PED · ped · ped with or without epilepsy and/or hemolytic Anaemia · PxMD-SLC2A1

Data availability: 207 ClinVar variants · 3 GenCC gene-disease records.

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 › childhood onset GLUT1 deficiency syndrome 2

Related subtypes (1): encephalopathy due to GLUT1 deficiency

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

207 retrieved; paginated sample, class counts are floors:

67 uncertain significance, 34 likely benign, 25 benign/likely benign, 21 pathogenic, 21 conflicting classifications of pathogenicity, 19 benign, 11 pathogenic/likely pathogenic, 9 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1076377	NM_006516.4(SLC2A1):c.457C>T (p.Arg153Cys)	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
1328934	NM_006516.4(SLC2A1):c.1043_1044insT (p.Ile349fs)	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
16115	NM_006516.4(SLC2A1):c.101A>T (p.Asn34Ile)	SLC2A1	Pathogenic	no assertion criteria provided
16116	NM_006516.4(SLC2A1):c.283_284delinsAT (p.Ser95Ile)	SLC2A1	Pathogenic	no assertion criteria provided
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
1803945	NM_006516.4(SLC2A1):c.16A>T (p.Lys6Ter)	SLC2A1	Pathogenic	criteria provided, single submitter
1810596	NM_006516.4(SLC2A1):c.742_743del (p.Arg249fs)	SLC2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
198842	NM_006516.4(SLC2A1):c.997C>T (p.Arg333Trp)	SLC2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
202196	NM_006516.4(SLC2A1):c.724C>T (p.Gln242Ter)	SLC2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
207193	NM_006516.4(SLC2A1):c.667C>T (p.Arg223Trp)	SLC2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
207196	NM_006516.4(SLC2A1):c.988C>T (p.Arg330Ter)	SLC2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
207225	NM_006516.4(SLC2A1):c.19-2A>G	SLC2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
280046	NM_006516.4(SLC2A1):c.1199G>A (p.Arg400His)	SLC2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29723	NM_006516.4(SLC2A1):c.876_878dup (p.Tyr293_Ser294insTyr)	SLC2A1	Pathogenic	no assertion criteria provided
3777183	NM_006516.4(SLC2A1):c.1078C>T (p.Gln360Ter)	SLC2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
379258	NM_006516.4(SLC2A1):c.493G>A (p.Val165Ile)	SLC2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
419011	NM_006516.4(SLC2A1):c.505_507del (p.Leu169del)	SLC2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
433186	NM_006516.4(SLC2A1):c.844_855del (p.Gln282_Ser285del)	SLC2A1	Pathogenic	criteria provided, single submitter
448897	NM_006516.4(SLC2A1):c.998G>A (p.Arg333Gln)	SLC2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
619980	NM_006516.4(SLC2A1):c.161dup (p.Ser55fs)	SLC2A1	Pathogenic	criteria provided, single submitter
662199	NM_006516.4(SLC2A1):c.101A>G (p.Asn34Ser)	SLC2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
812757	NM_006516.4(SLC2A1):c.736_739del (p.Glu246fs)	SLC2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
96708	NM_006516.4(SLC2A1):c.1372C>T (p.Arg458Trp)	SLC2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 32 · Orphanet: 13 · 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
PRRT2	Supportive	Autosomal dominant	childhood onset GLUT1 deficiency syndrome 2	18

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
PRRT2	Orphanet:306	Self-limited infantile epilepsy
PRRT2	Orphanet:36387	Genetic epilepsy with febrile seizure plus
PRRT2	Orphanet:569	Familial or sporadic hemiplegic migraine
PRRT2	Orphanet:98809	Paroxysmal kinesigenic dyskinesia
PRRT2	Orphanet:98810	Paroxysmal non-kinesigenic dyskinesia
PRRT2	Orphanet:98811	Paroxysmal exertion-induced dyskinesia

Cohort genes → proteins

2 cohort genes, 2 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
PRRT2	HGNC:30500	ENSG00000167371	Q7Z6L0	Proline-rich transmembrane protein 2	gencc

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.
PRRT2	Proline-rich transmembrane protein 2	As a component of the outer core of AMPAR complex, may be involved in synaptic transmission in the central nervous system.

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
PRRT2	Other/Unknown	no		CD225/Dispanin_fam, CD225/Dispanin

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	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
PRRT2	202	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC2A1	5,711
PRRT2	1,545

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC2A1	P11166	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PRRT2	Q7Z6L0	51.86

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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of short-term synaptic potentiation	1	8426.0×	0.002	PRRT2
negative regulation of SNARE complex assembly	1	4213.0×	0.002	PRRT2
regulation of calcium-dependent activation of synaptic vesicle fusion	1	2808.7×	0.002	PRRT2
response to Thyroglobulin triiodothyronine	1	2808.7×	0.002	SLC2A1
long-chain fatty acid import across plasma membrane	1	2106.5×	0.002	SLC2A1
GDP-L-fucose salvage	1	2106.5×	0.002	SLC2A1
D-glucose import across plasma membrane	1	1404.3×	0.002	SLC2A1
synaptic vesicle fusion to presynaptic active zone membrane	1	842.6×	0.003	PRRT2
L-ascorbic acid metabolic process	1	766.0×	0.003	SLC2A1
dehydroascorbic acid transport	1	601.9×	0.004	SLC2A1
cellular hyperosmotic response	1	601.9×	0.004	SLC2A1
neuromuscular process controlling posture	1	526.6×	0.004	PRRT2
D-glucose transmembrane transport	1	468.1×	0.004	SLC2A1
obsolete D-glucose import	1	421.3×	0.004	SLC2A1
photoreceptor cell maintenance	1	179.3×	0.009	SLC2A1
cellular response to glucose starvation	1	168.5×	0.009	SLC2A1
response to insulin	1	115.4×	0.012	SLC2A1
cellular response to mechanical stimulus	1	108.0×	0.012	SLC2A1
female pregnancy	1	105.3×	0.012	SLC2A1
cerebral cortex development	1	102.8×	0.012	SLC2A1
transport across blood-brain barrier	1	89.6×	0.013	SLC2A1
central nervous system development	1	57.7×	0.018	SLC2A1
protein-containing complex assembly	1	56.9×	0.018	SLC2A1
response to hypoxia	1	47.9×	0.021	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
PRRT2	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: 1; 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	PRRT2

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)
PRRT2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04112862	EARLY_PHASE1	COMPLETED	Sodium Lactate Infusion in GLUT1DS Patients