Neurodegenerative syndrome due to cerebral folate transport deficiency

Summary

Neurodegenerative syndrome due to cerebral folate transport deficiency (MONDO:0013110) is a disease caused by FOLR1 (GenCC Definitive), with 3 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: FOLR1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 232
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	neurodegenerative syndrome due to cerebral folate transport deficiency
Mondo ID	MONDO:0013110
MeSH	C567791
OMIM	613068
Orphanet	217382
DOID	DOID:0050719
ICD-11	1158040363
SNOMED CT	711403001
UMLS	C2751584
MedGen	442763
GARD	0010594
Is cancer (heuristic)	no

Also known as: cerebral folate deficiency syndrome · cerebral folate transport deficiency · neurodegenerative syndrome due to cerebral folate transport deficiency

Data availability: 232 ClinVar variants · 5 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 vitamin metabolic disorder › neurodegenerative syndrome due to cerebral folate transport deficiency

Related subtypes (4): familial isolated deficiency of vitamin E, disorders of vitamin D metabolism, inborn disorder of cobalamin metabolism and transport, cerebral folate 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

232 retrieved; paginated sample, class counts are floors:

98 uncertain significance, 85 likely benign, 20 conflicting classifications of pathogenicity, 19 pathogenic, 6 likely pathogenic, 3 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1322929	NM_016729.3(FOLR1):c.258G>A (p.Trp86Ter)	FOLR1	Pathogenic	criteria provided, single submitter
1459015	NC_000011.9:g.(?71903218)(71903405_?)del	FOLR1	Pathogenic	criteria provided, single submitter
1459749	NM_016729.3(FOLR1):c.330_333dup (p.Asn112fs)	FOLR1	Pathogenic	criteria provided, single submitter
16255	NM_016729.3(FOLR1):c.352C>T (p.Gln118Ter)	FOLR1	Pathogenic	criteria provided, multiple submitters, no conflicts
16256	NM_016729.3(FOLR1):c.525C>A (p.Cys175Ter)	FOLR1	Pathogenic	criteria provided, single submitter
1685824	NM_016729.3(FOLR1):c.373C>T (p.Arg125Cys)	FOLR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2024511	NM_016729.3(FOLR1):c.321C>A (p.Tyr107Ter)	FOLR1	Pathogenic	criteria provided, single submitter
2426313	NC_000011.9:g.(?71903218)(72019668_?)del	FOLR1	Pathogenic	criteria provided, single submitter
3244663	NC_000011.9:g.(?71906295)(71907221_?)del	FOLR1	Pathogenic	criteria provided, single submitter
470723	NM_016729.3(FOLR1):c.257G>A (p.Trp86Ter)	FOLR1	Pathogenic	criteria provided, single submitter
929424	NM_016729.3(FOLR1):c.197G>A (p.Cys66Tyr)	FOLR1	Pathogenic	criteria provided, single submitter
1068582	NM_016729.3(FOLR1):c.584_587del (p.His195fs)	FOLR1-AS1	Pathogenic	criteria provided, single submitter
1073567	NM_016729.3(FOLR1):c.428G>A (p.Trp143Ter)	FOLR1-AS1	Pathogenic	criteria provided, single submitter
16257	NM_016729.3(FOLR1):c.130_147dup (p.Lys44_Pro49dup)	FOLR1-AS1	Pathogenic	no assertion criteria provided
1676682	NM_016729.3(FOLR1):c.621_622delinsT (p.Arg208fs)	FOLR1-AS1	Pathogenic	criteria provided, single submitter
2835572	NM_016729.3(FOLR1):c.181_182del (p.Arg61fs)	FOLR1-AS1	Pathogenic	criteria provided, single submitter
3714352	NM_016729.3(FOLR1):c.496_514del (p.Phe166fs)	FOLR1-AS1	Pathogenic	criteria provided, single submitter
3775416	NM_016729.3(FOLR1):c.327C>A (p.Cys109Ter)	FOLR1-AS1	Pathogenic	criteria provided, single submitter
4724036	NM_016729.3(FOLR1):c.421C>T (p.Gln141Ter)	FOLR1-AS1	Pathogenic	criteria provided, single submitter
639442	NM_016729.3(FOLR1):c.465_466delinsTG (p.Trp156Gly)	FOLR1-AS1	Pathogenic	criteria provided, single submitter
3892365	NM_016729.3(FOLR1):c.172C>T (p.Arg58Ter)	FOLR1	Likely pathogenic	criteria provided, single submitter
429907	NM_016729.3(FOLR1):c.610C>T (p.Arg204Ter)	FOLR1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067993	NM_016729.3(FOLR1):c.358-2A>G	FOLR1-AS1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3573997	NM_016729.3(FOLR1):c.466T>G (p.Trp156Gly)	FOLR1-AS1	Likely pathogenic	criteria provided, single submitter
3776059	NM_016729.3(FOLR1):c.466dup (p.Trp156fs)	FOLR1-AS1	Likely pathogenic	criteria provided, single submitter
937986	NM_016729.3(FOLR1):c.590A>G (p.Tyr197Cys)	FOLR1-AS1	Likely pathogenic	criteria provided, single submitter
195316	NM_016729.3(FOLR1):c.157T>C (p.Leu53=)	FOLR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
196475	NM_016729.3(FOLR1):c.215A>G (p.Gln72Arg)	FOLR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
197830	NM_016729.3(FOLR1):c.719C>T (p.Ala240Val)	FOLR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
205460	NM_016729.3(FOLR1):c.508G>A (p.Ala170Thr)	FOLR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
FOLR1	Definitive	Autosomal recessive	neurodegenerative syndrome due to cerebral folate transport deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FOLR1	Orphanet:217382	Neurodegenerative syndrome due to cerebral folate transport deficiency

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FOLR1	HGNC:3791	ENSG00000110195	P15328	Folate receptor alpha	gencc,clinvar
FAM86C1P	HGNC:25561	ENSG00000158483	Q9NVL1	Putative protein FAM86C1P	clinvar
FOLR1-AS1	HGNC:58347	ENSG00000204971		FOLR1 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FOLR1	Folate receptor alpha	Binds to folate and reduced folic acid derivatives and mediates delivery of 5-methyltetrahydrofolate and folate analogs into the interior of cells.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.0

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
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FOLR1	Other/Unknown	no		Folate_rcpt, Folate_rcpt-like
FAM86C1P	Other/Unknown	no		FAM86_N
FOLR1-AS1	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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
primordial germ cell in gonad	2
parotid gland	1
right lung	1
right uterine tube	1
smooth muscle tissue	1
stromal cell of endometrium	1
male germ line stem cell (sensu Vertebrata) in testis	1
spleen	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FOLR1	193	broad	marker	right uterine tube, parotid gland, right lung
FAM86C1P	134	ubiquitous	yes	primordial germ cell in gonad, stromal cell of endometrium, smooth muscle tissue
FOLR1-AS1	98		yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, spleen

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FOLR1	1,625
FAM86C1P	310
FOLR1-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FOLR1	P15328	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FAM86C1P	Q9NVL1	49.70

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 3 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
Cargo concentration in the ER	1	335.9×	0.009	FOLR1
COPII-mediated vesicle transport	1	163.1×	0.009	FOLR1
COPI-mediated anterograde transport	1	109.8×	0.009	FOLR1

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
neural crest cell migration involved in heart formation	1	8426.0×	0.001	FOLR1
cellular response to folic acid	1	8426.0×	0.001	FOLR1
anterior neural tube closure	1	2106.5×	0.002	FOLR1
folic acid transport	1	1404.3×	0.002	FOLR1
tetrahydrofolate biosynthetic process	1	1404.3×	0.002	FOLR1
cardiac neural crest cell migration involved in outflow tract morphogenesis	1	1203.7×	0.002	FOLR1
pharyngeal arch artery morphogenesis	1	842.6×	0.003	FOLR1
axon regeneration	1	561.7×	0.003	FOLR1
sperm-egg recognition	1	561.7×	0.003	FOLR1
folic acid metabolic process	1	561.7×	0.003	FOLR1
regulation of transforming growth factor beta receptor signaling pathway	1	401.2×	0.004	FOLR1
fusion of sperm to egg plasma membrane involved in single fertilization	1	280.9×	0.005	FOLR1
regulation of canonical Wnt signaling pathway	1	271.8×	0.005	FOLR1
heart looping	1	133.8×	0.009	FOLR1
receptor-mediated endocytosis	1	110.9×	0.010	FOLR1
methylation	1	85.1×	0.012	FAM86C1P
cell adhesion	1	18.7×	0.053	FOLR1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 1 of 3 evidence-associated genes (33%) 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
FOLR1	PRALATREXATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FOLR1	4	4
FAM86C1P	0	0
FOLR1-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PRALATREXATE	4	FOLR1
RALTITREXED	4	FOLR1
PEMETREXED	4	FOLR1
METHOTREXATE	4	FOLR1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
FOLR1	34	Binding:34

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

4 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)
PRALATREXATE	4	FOLR1
RALTITREXED	4	FOLR1
PEMETREXED	4	FOLR1
METHOTREXATE	4	FOLR1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	FOLR1
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	2	FAM86C1P, FOLR1-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FAM86C1P	0	—
FOLR1-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening