FOLR1-Related Cerebral Folate Transport Deficiency

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Inheritance

1

Autosomal recessive inheritance HP:0000007

FOLR1-CFTD results from biallelic pathogenic FOLR1 variants; both parents are typically asymptomatic heterozygous carriers.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:38224559 SUPPORT Human Clinical

"FOLR1-CFTD is inherited in an autosomal recessive manner."

GeneReviews states the autosomal recessive mode of inheritance.

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Discussions and Knowledge Gaps

1

What determines the degree and reversibility of neurologic recovery after folinic acid treatment in FOLR1-CFTD, and why do some deficits (particularly established hypomyelination and cognitive impairment) fail to reverse when treatment is started late despite normalization of CSF folate?

KNOWLEDGE GAP OPEN gap_folr1_treatment_response_determinants

Attached to

pathophysiology#Hypomyelination and Neurodegeneration treatments#High-dose folinic acid (leucovorin)

FOLR1-CFTD is a treatable disorder in which folinic acid can restore CSF folate and drive clinical improvement, yet clinical severity does not correlate cleanly with residual FRalpha function, and later-treated individuals may retain irreversible deficits. The determinants of treatment response, the therapeutic window relative to the postnatal myelination period, and whether irreversible deficits reflect a fixed developmental myelination defect versus ongoing correctable metabolic dysfunction remain unresolved, and are central to the case for early or newborn-screening-based diagnosis.

Show evidence (1 reference)

PMID:22586289 SUPPORT Human Clinical

"different clinical severities do not necessarily correlate with residual function of folate receptor alpha mutants and indicate that additional factors contribute to the clinical phenotype in cerebral folate transport deficiency."

Documents that clinical severity is not explained by residual FRalpha function alone, motivating the open question about response determinants.

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Pathophysiology

5

FOLR1 Biallelic Loss of Function and Folate Receptor Alpha Deficiency

Biallelic loss-of-function variants in FOLR1 abolish functional folate receptor alpha (FRalpha), a GPI-anchored high-affinity folate-binding receptor highly expressed at the apical surface of choroid-plexus epithelium. Missense variants are expressed but mislocalize away from the cell surface, eliminating cellular folate binding, so both truncating and missense alleles converge on functional FRalpha loss at the blood-CSF barrier.

choroid plexus epithelial cell CL:0000706

folic acid receptor activity GO:0061714 ↓ DECREASED

choroid plexus UBERON:0001886

Downstream

Impaired Folate Transport Across the Blood-CSF Barrier and Low CSF 5-MTHF

Show evidence (2 references)

PMID:19732866 SUPPORT Human Clinical

"We identified an inherited brain-specific folate transport defect that is caused by mutations in the folate receptor 1 (FOLR1) gene coding for folate receptor alpha (FRalpha)."

Establishes biallelic FOLR1 defect and loss of FRalpha as the molecular cause of this brain-specific folate transport disorder.

PMID:22586289 SUPPORT In Vitro

"Heterologous expression of the missense mutations, including previously described mutants, revealed minor decrease in protein expression but loss of cell surface localization, mistargeting to intracellular compartments and thus absence of cellular binding of folic acid."

Shows FOLR1 missense variants abolish surface FRalpha and folate binding, the functional loss modeled by this trigger node.

Impaired Folate Transport Across the Blood-CSF Barrier and Low CSF 5-MTHF

FRalpha-mediated transcytosis moves 5-methyltetrahydrofolate from blood across the choroid-plexus epithelium into the cerebrospinal fluid. Loss of FRalpha blocks this blood-CSF folate transport, producing a severe isolated reduction of CSF 5-MTHF while serum/systemic folate remains normal, the biochemical hallmark of cerebral folate deficiency.

choroid plexus epithelial cell CL:0000706

folate transmembrane transport GO:0098838 ↓ DECREASED

Downstream

Deficient Exosomal Folate Delivery into Brain Parenchyma

Show evidence (2 references)

PMID:23828504 SUPPORT In Vitro

"we identify folate receptor-α-positive intralumenal vesicles within multivesicular bodies and demonstrate the directional cotransport of human folate receptor-α, and labelled folate from the basolateral to the apical membrane in rat choroid plexus cells."

Demonstrates FRalpha-dependent directional basolateral-to-apical (transcytotic) folate transport across choroid-plexus cells, the step abolished by FRalpha loss.

PMID:19732866 SUPPORT Human Clinical

"Three patients carrying FOLR1 mutations developed progressive movement disturbance, psychomotor decline, and epilepsy and showed severely reduced folate concentrations in the cerebrospinal fluid (CSF)."

Documents severely reduced CSF folate in patients with FOLR1 variants.

Deficient Exosomal Folate Delivery into Brain Parenchyma

Beyond transcytosis into the CSF, folate receptor alpha is shed on FRalpha-positive exosomes that shuttle 5-methyltetrahydrofolate from the choroid plexus across the CSF into the brain parenchyma, where the exosomes are internalized by astrocytes and neurons. Loss of FRalpha eliminates these FRalpha-positive CSF exosomes, removing this second delivery step so that folate captured at the choroid plexus fails to reach parenchymal brain cells.

choroid plexus epithelial cell CL:0000706

exosomal secretion GO:1990182 ↓ DECREASED

choroid plexus UBERON:0001886

Downstream

Deficient CNS One-Carbon Metabolism

Show evidence (2 references)

PMID:23828504 SUPPORT Human Clinical

"Loss of folate receptor-α-expressing cerebrospinal fluid exosomes correlates with severely reduced 5-methyltetrahydrofolate concentration, corroborating the importance of the folate receptor-α-mediated folate transport in the cerebrospinal fluid."

Loss of FRalpha-positive CSF exosomes tracks with severely reduced CSF 5-MTHF, evidencing the exosomal folate-delivery step lost in FOLR1-CFTD.

PMID:23828504 SUPPORT Model Organism

"Intraventricular injections of folate receptor-α-positive and -negative exosomes into mouse brains demonstrate folate receptor-α-dependent delivery of exosomes into the brain parenchyma."

In vivo mouse experiments show FRalpha-dependent exosomal delivery into brain parenchyma, the delivery step abolished when FRalpha is lost.

Deficient CNS One-Carbon Metabolism

Low CNS folate starves brain one-carbon metabolism, impairing the folate-dependent methylation cycle (S-adenosylmethionine-dependent methylation of DNA, proteins, phospholipids, and myelin components) and monoamine neurotransmitter metabolism. MR spectroscopy in patients shows combined white-matter choline and inositol depletion, reflecting disturbed membrane and myelin-lipid methylation.

neuron CL:0000540

one-carbon metabolic process GO:0006730 ↓ DECREASED methylation GO:0032259 ↓ DECREASED

Downstream

Hypomyelination and Neurodegeneration

Show evidence (1 reference)

PMID:19732866 SUPPORT Human Clinical

"Brain magnetic resonance imaging (MRI) demonstrated profound hypomyelination, and MR-based in vivo metabolite analysis indicated a combined depletion of white-matter choline and inositol."

White-matter choline and inositol depletion reflects disturbed folate-dependent one-carbon/methylation metabolism in the brain.

Hypomyelination and Neurodegeneration

Sustained CNS folate and methylation deficiency during the period of postnatal myelination causes profound cerebral hypomyelination and progressive neurodegeneration with cerebellar atrophy. Clinically this drives the late-infantile onset syndrome of seizures, psychomotor regression, ataxia, and movement disorder that can progress to immobility if untreated.

oligodendrocyte CL:0000128

myelination GO:0042552 ↓ DECREASED

brain UBERON:0000955

Show evidence (2 references)

PMID:22586289 SUPPORT Human Clinical

"We identified nucleotide alterations in the folate receptor 1 gene in 10 individuals who shared developmental regression, ataxia, profound cerebral hypomyelination and cerebellar atrophy."

Links FOLR1 loss to the shared clinical-radiologic outcome of regression, ataxia, hypomyelination, and cerebellar atrophy.

PMID:38224559 SUPPORT Human Clinical

"Individuals with untreated FOLR1-CFTD have very low cerebrospinal fluid (CSF) levels and progressive neurologic deterioration with developmental delays and progressive cognitive impairment, behavioral issues, seizures, and movement disorders that may progress to immobility."

Describes the progressive neurodegenerative outcome of untreated disease.

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Pathograph

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Phenotypes

13

Head and Neck 1

Acquired microcephaly Secondary microcephaly HP:0005484

Show evidence (1 reference)

PMID:40218241 SUPPORT Human Clinical

"FOLR1-related CFD should be considered in cases with febrile convulsions, developmental delay, ataxia, autism spectrum disorder, acquired microcephaly, and MRI findings of white matter involvement and cerebellar atrophy."

Case series lists acquired microcephaly among the recognized features.

Nervous System 12

Seizures HP:0001250

Show evidence (3 references)

PMID:38224559 SUPPORT Human Clinical

"progressive neurologic deterioration with developmental delays and progressive cognitive impairment, behavioral issues, seizures, and movement disorders that may progress to immobility."

GeneReviews lists seizures among the neurologic manifestations.

PMID:40218241 SUPPORT Human Clinical

"with ataxia, choreoathetoid movements, and myoclonic epilepsy generally resistant to treatment."

Case series characterizes the epilepsy as myoclonic and generally treatment-resistant.

PMID:40218241 SUPPORT Human Clinical

"The diagnosis most commonly made before the definitive diagnosis was epilepsy, and the first seizure occurred at a mean of 5.2 years."

Case series documents epilepsy as the common initial diagnosis with a mean first-seizure age in childhood.

Developmental regression HP:0002376

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:22586289 SUPPORT Human Clinical

"10 individuals who shared developmental regression, ataxia, profound cerebral hypomyelination and cerebellar atrophy."

Developmental regression is a shared feature of the FOLR1 patient cohort.

Ataxia HP:0001251

Show evidence (1 reference)

PMID:22586289 SUPPORT Human Clinical

"10 individuals who shared developmental regression, ataxia, profound cerebral hypomyelination and cerebellar atrophy."

Ataxia is a shared feature of the FOLR1 patient cohort.

Movement disorder Abnormality of movement HP:0100022

Show evidence (1 reference)

PMID:19732866 SUPPORT Human Clinical

"Three patients carrying FOLR1 mutations developed progressive movement disturbance, psychomotor decline, and epilepsy"

Progressive movement disturbance is part of the presenting phenotype.

CNS hypomyelination HP:0003429

Show evidence (1 reference)

PMID:19732866 SUPPORT Human Clinical

"Brain magnetic resonance imaging (MRI) demonstrated profound hypomyelination"

MRI documents profound hypomyelination in affected patients.

Cerebellar atrophy HP:0001272

Show evidence (1 reference)

PMID:22586289 SUPPORT Human Clinical

"profound cerebral hypomyelination and cerebellar atrophy."

Cerebellar atrophy is a shared imaging feature of the FOLR1 cohort.

Cognitive impairment HP:0100543

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:38224559 SUPPORT Human Clinical

"progressive neurologic deterioration with developmental delays and progressive cognitive impairment"

GeneReviews describes progressive cognitive impairment.

Autism spectrum disorder HP:0000717

Show evidence (1 reference)

PMID:40218241 SUPPORT Human Clinical

"FOLR1-related CFD should be considered in cases with febrile convulsions, developmental delay, ataxia, autism spectrum disorder, acquired microcephaly, and MRI findings of white matter involvement and cerebellar atrophy."

Case series lists autism spectrum disorder among the recognized features.

Febrile seizures Febrile seizure (within the age range of 3 months to 6 years) HP:0002373

Show evidence (1 reference)

PMID:40218241 SUPPORT Human Clinical

"The most frequently seen first complaints were febrile convulsions and attention deficit-hyperactivity-learning difficulties."

Case series reports febrile convulsions as one of the most frequent first complaints.

Choreoathetosis HP:0001266

Show evidence (1 reference)

PMID:40218241 SUPPORT Human Clinical

"with ataxia, choreoathetoid movements, and myoclonic epilepsy generally resistant to treatment."

Case series describes choreoathetoid movements as a characteristic feature.

Attention deficit hyperactivity disorder HP:0007018

Show evidence (1 reference)

PMID:40218241 SUPPORT Human Clinical

"The most frequently seen first complaints were febrile convulsions and attention deficit-hyperactivity-learning difficulties."

Case series reports attention deficit-hyperactivity-learning difficulties among the most frequent first complaints.

Cerebral atrophy HP:0002059

Show evidence (1 reference)

PMID:40218241 SUPPORT Human Clinical

"white matter involvement, cerebellar atrophy and cerebral atrophy were determined most often."

Case series reports cerebral atrophy as one of the most frequent imaging findings.

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Genetic Associations

1

FOLR1 loss-of-function variants (Disease-causing)

Gene: FOLR1 hgnc:3791 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:19732866 SUPPORT Human Clinical

"caused by mutations in the folate receptor 1 (FOLR1) gene coding for folate receptor alpha (FRalpha)."

FOLR1 is the causative gene encoding folate receptor alpha.

PMID:22586289 SUPPORT In Vitro

"These results explain the functional loss of folate receptor alpha for all detected folate receptor 1 mutations."

Functional studies show all detected FOLR1 variants cause loss of FRalpha function.

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Medical Actions

3

High-dose folinic acid (leucovorin)

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: folinic acid CHEBI:15640

Disease-specific therapy is high-dose folinic acid (5-formyltetrahydrofolate, also called leucovorin), which bypasses the FRalpha transport block and restores CSF folate into the normal range. Oral high-dose therapy is usually sufficient (a reported oral dose is 5.2 mg/kg/day), with intramuscular or intermittent intravenous dosing as alternatives, and CSF folate is monitored to confirm adequacy. Benefit is greatest when started early; presymptomatic treatment of affected sibs can prevent or markedly mitigate disease. Plain folic acid is avoided because it binds FRalpha tightly and may interfere with any residual receptor function.

Mechanism Target:

BYPASSES Impaired Folate Transport Across the Blood-CSF Barrier and Low CSF 5-MTHF — Folinic acid (5-formyltetrahydrofolate) is a reduced folate that enters the CNS independently of folate receptor alpha, bypassing the blocked FRalpha-mediated blood-CSF folate transport step and restoring CSF folate.

Target Phenotypes: Seizure HP:0001250 CNS hypomyelination HP:0003429 Ataxia HP:0001251

Show evidence (5 references)

PMID:38224559 SUPPORT Human Clinical

"Treatment with 5-formyltetrahydrofolate (5-formylTHF; also known as folinic acid or leucovorin) can result in substantial improvement in neurologic findings, particularly when started at a young age."

GeneReviews establishes folinic acid as the disease-specific therapy with early-treatment benefit.

PMID:38224559 SUPPORT Human Clinical

"Folic acid is not used to treat FOLR1-CFTD because folic acid binds tightly to FOLR1, possibly interfering with FOLR1 function, which is a concern when treating individuals who may have residual FOLR1 activity."

Captures the folic-acid caveat: plain folic acid is avoided in favor of folinic acid.

PMID:19732866 SUPPORT Human Clinical

"restored by folinic acid therapy and preceded clinical improvements."

Original description shows folinic acid restores CSF folate ahead of clinical improvement.

+ 2 more references

CSF folate surveillance monitoring

Category: Monitoring Action: CSF folate monitoring Ontology label: Diagnostic Procedure NCIT:C18020

For individuals on 5-formyltetrahydrofolate therapy, CSF folate is monitored to confirm an adequate therapeutic dose: repeat CSF folate after treatment initiation, repeat with clinical change (developmental regression, new neurologic findings, seizures) or adherence concerns, and, optimally and if feasible, yearly CSF folate levels until age five years.

Show evidence (1 reference)

PMID:38224559 SUPPORT Human Clinical

"optimally and if feasible, yearly CSF folate levels until age five years."

GeneReviews surveillance protocol recommends periodic CSF folate monitoring, including yearly levels until age five.

Evaluation of relatives at risk

Category: Screening Action: molecular genetic testing Ontology label: Molecular Analysis NCIT:C19770

Because presymptomatic treatment can prevent or mitigate disease, the genetic status of all sibs of a proband should be clarified to identify as early as possible those who would benefit from prompt initiation of 5-formyltetrahydrofolate; newborns at risk are evaluated for the familial FOLR1 variants if not tested prenatally.

Show evidence (1 reference)

PMID:38224559 SUPPORT Human Clinical

"Clarification of the genetic status of all sibs of a proband is recommended to identify as early as possible those sibs who would benefit from prompt initiation of treatment with 5-formylTHF."

GeneReviews recommends clarifying at-risk sibs' genetic status to enable early presymptomatic treatment.

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Biochemical Markers

1

Cerebrospinal fluid 5-methyltetrahydrofolate (5-MTHF) (DECREASED)

Context: Severely reduced CSF 5-MTHF in the setting of normal serum/systemic folate is the defining biochemical signature of cerebral folate deficiency and the key diagnostic finding in FOLR1-CFTD. Because the defect is brain-specific (a blood-CSF transport block rather than a systemic folate deficiency), peripheral folate indices are typically normal, so the diagnosis requires direct CSF folate measurement by lumbar puncture.

Show evidence (2 references)

PMID:22586289 SUPPORT Human Clinical

"We screened 72 children with low 5-methyltetrahydrofolate concentrations in the cerebrospinal fluid and neurological symptoms that developed after infancy."

Low CSF 5-MTHF is the biochemical entry criterion for the FOLR1 cohort.

PMID:19732866 SUPPORT Human Clinical

"We identified an inherited brain-specific folate transport defect"

The brain-specific nature of the defect explains low CSF folate with normal systemic folate.

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Diagnosis

2

Cerebrospinal fluid 5-MTHF measurement

Lumbar puncture with measurement of CSF 5-methyltetrahydrofolate is the biochemical screening test; a severely low CSF 5-MTHF with normal peripheral folate raises the diagnosis of cerebral folate deficiency and prompts FOLR1 testing.

diagnostic procedure NCIT:C18020

Markers: CSF 5-methyltetrahydrofolate

Results: Severely reduced CSF 5-MTHF with normal serum folate indicates cerebral folate deficiency.

Show evidence (1 reference)

PMID:22586289 SUPPORT Human Clinical

"children with low 5-methyltetrahydrofolate concentrations in the cerebrospinal fluid"

CSF 5-MTHF measurement is the biochemical screen used to ascertain cases.

FOLR1 molecular genetic testing

Confirmatory diagnosis rests on identifying biallelic pathogenic FOLR1 variants by molecular genetic testing.

molecular genetic testing NCIT:C19770

Markers: FOLR1 biallelic pathogenic variants

Results: Two pathogenic FOLR1 alleles confirm the diagnosis.

Show evidence (1 reference)

PMID:38224559 SUPPORT Human Clinical

"The diagnosis of FOLR1-CFTD is established in a proband with biallelic FOLR1 pathogenic variants identified by molecular genetic testing."

GeneReviews defines the molecular diagnostic criterion.

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Progression

3

Late-infantile onset and progressive neurodegeneration

Age: Typically after the first year of life

After a relatively normal early infancy, affected children develop progressive movement disturbance, psychomotor regression, ataxia, and epilepsy with a late-infantile onset.

Show evidence (1 reference)

PMID:22586289 SUPPORT Human Clinical

"This genetic defect gives rise to a progressive neurological disorder with late infantile onset."

Establishes the late-infantile onset and progressive course.

Response to folinic acid therapy

Age: After treatment initiation

FOLR1-CFTD is treatable and its course can be reversed or stabilized: folinic acid restores CSF folate and biochemical markers and can precede and drive substantial clinical improvement, with the greatest benefit when treatment starts early. Because of the asymptomatic early period, diagnosis is often delayed and treatment started after symptom onset may be less effective.

Show evidence (3 references)

PMID:19732866 SUPPORT Human Clinical

"CSF folate concentrations, as well as glial choline and inositol depletion, were restored by folinic acid therapy and preceded clinical improvements."

Documents biochemical and clinical improvement with folinic acid.

PMID:38224559 SUPPORT Human Clinical

"Treatment with 5-formyltetrahydrofolate (5-formylTHF; also known as folinic acid or leucovorin) can result in substantial improvement in neurologic findings, particularly when started at a young age."

GeneReviews states treatment can substantially improve neurologic findings, especially when started early.

PMID:40218241 SUPPORT Human Clinical

"Due to an asymptomatic early period, CFD diagnosis may be delayed, and treatment after symptom onset may be less effective."

Case series notes delayed diagnosis and reduced efficacy of treatment started after symptom onset, underscoring the reversibility window.

Long-term survival despite neurologic disability

Age: Untreated natural history

Despite the incapacitating neurologic findings of untreated disease, affected individuals can survive well into adulthood, a clinically important and counterintuitive prognosis for a disorder classified as neurodegenerative.

Show evidence (1 reference)

PMID:38224559 SUPPORT Human Clinical

"Despite these incapacitating neurologic findings, untreated individuals can live well into adulthood."

GeneReviews notes untreated individuals can live well into adulthood.

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Prevalence

1

Worldwide

Cases In Literature Ultra Rare

Ultra-rare, with only a small number of affected individuals reported worldwide since the disorder was first delineated in 2009; the true prevalence is unknown and the condition is likely underdiagnosed because of its treatable, initially asymptomatic course.

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Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from FOLR1-Related Cerebral Folate Transport Deficiency:

Hereditary folate malabsorption (SLC46A1/PCFT deficiency)

Overlapping Features Hereditary folate malabsorption is caused by biallelic SLC46A1 (proton-coupled folate transporter, PCFT) variants and causes systemic folate deficiency with megaloblastic anemia in addition to low CSF folate, distinguishing it from the brain-specific, hematologically normal FOLR1-CFTD. It is distinguished by molecular testing.

Distinguishing Features

Systemic folate deficiency and megaloblastic anemia favor SLC46A1/PCFT hereditary folate malabsorption.
Normal systemic folate with isolated low CSF folate favors FOLR1-CFTD.

Show evidence (1 reference)

PMID:19732866 SUPPORT Human Clinical

"At least five distinct inherited disorders of folate transport and metabolism are presently known, all of which cause systemic folate deficiency."

Contrasts the systemic folate-deficiency disorders with the brain-specific FOLR1 defect.

Dihydrofolate reductase (DHFR) deficiency

Overlapping Features DHFR deficiency is a distinct autosomal recessive inborn error of folate metabolism (different gene, DHFR) that also lowers CSF folate but characteristically causes megaloblastic anemia; it is distinguished by gene testing.

Distinguishing Features

Megaloblastic anemia with a DHFR variant favors DHFR deficiency.
A biallelic FOLR1 variant with normal hematology favors FOLR1-CFTD.

Show evidence (1 reference)

PMID:21310276 SUPPORT Human Clinical

"We describe three individuals from two families with a recessive inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency due to a germline missense mutation in DHFR, resulting in..."

DHFR deficiency lowers cerebral folate but is distinguished from FOLR1-CFTD by megaloblastic anemia/pancytopenia and a DHFR mutation.

Folate receptor alpha autoantibody cerebral folate deficiency

Overlapping Features Acquired cerebral folate deficiency due to blocking autoantibodies against folate receptor alpha produces a biochemically similar low CSF 5-MTHF but is not caused by FOLR1 variants and is diagnosed by autoantibody testing rather than molecular genetics.

Distinguishing Features

FRalpha blocking autoantibodies with normal FOLR1 sequence favor autoantibody-mediated cerebral folate deficiency.
Biallelic pathogenic FOLR1 variants favor FOLR1-CFTD.

Show evidence (2 references)

PMID:15888699 SUPPORT Human Clinical

"Serum from 25 of the 28 patients and 0 of 28 control subjects contained high-affinity blocking autoantibodies against membrane-bound folate receptors that are present on the choroid plexus."

Blocking autoantibodies against choroid-plexus folate receptors define the acquired autoantibody-mediated mimic that has normal FOLR1.

PMID:15888699 SUPPORT Human Clinical

"Cerebral folate deficiency is a disorder in which autoantibodies can prevent the transfer of folate from the plasma to the cerebrospinal fluid."

Establishes the autoantibody mechanism blocking blood-to-CSF folate transfer, biochemically mimicking FOLR1-CFTD without an FOLR1 variant.

{ }

Source YAML

click to show

name: FOLR1-Related Cerebral Folate Transport Deficiency
category: Mendelian
creation_date: '2026-07-25T00:00:00Z'
synonyms:
- Cerebral folate transport deficiency
- Neurodegeneration due to cerebral folate transport deficiency
- FOLR1-CFTD
- Cerebral folate deficiency, FOLR1-related
description: >-
  FOLR1-related cerebral folate transport deficiency is an autosomal recessive,
  treatable metabolic epilepsy caused by biallelic loss-of-function variants in
  FOLR1, which encodes folate receptor alpha (FRalpha). FRalpha mediates folate
  transport across the choroid-plexus blood-cerebrospinal-fluid barrier, so its
  loss produces an isolated brain-specific folate deficiency: cerebrospinal-fluid
  5-methyltetrahydrofolate (5-MTHF) is severely reduced despite normal systemic
  folate status. Low CNS folate impairs one-carbon metabolism, methylation, and
  myelin synthesis, causing late-infantile onset seizures, psychomotor
  regression, ataxia, movement disorder, and profound hypomyelination with
  cerebellar atrophy on MRI. Crucially the disorder is treatable: high-dose
  folinic acid (5-formyltetrahydrofolate, leucovorin) restores CSF folate and can
  substantially improve or stabilize neurologic findings, particularly when
  started early. Plain folic acid is avoided because it binds FRalpha tightly and
  may interfere with residual receptor function.
disease_term:
  preferred_term: FOLR1-related cerebral folate transport deficiency
  term:
    id: MONDO:0013110
    label: neurodegenerative syndrome due to cerebral folate transport deficiency
references:
- reference: PMID:38224559
  title: "FOLR1-Related Cerebral Folate Transport Deficiency."
  tags:
  - GeneReviews
parents:
- Metabolic Disease
- Inborn Error of Metabolism
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    FOLR1-CFTD results from biallelic pathogenic FOLR1 variants; both parents are
    typically asymptomatic heterozygous carriers.
  evidence:
  - reference: PMID:38224559
    reference_title: "FOLR1-Related Cerebral Folate Transport Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      FOLR1-CFTD is inherited in an autosomal recessive manner.
    explanation: >-
      GeneReviews states the autosomal recessive mode of inheritance.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Ultra-rare, with only a small number of affected individuals reported
    worldwide since the disorder was first delineated in 2009; the true
    prevalence is unknown and the condition is likely underdiagnosed because of
    its treatable, initially asymptomatic course.
pathophysiology:
- name: FOLR1 Biallelic Loss of Function and Folate Receptor Alpha Deficiency
  description: >-
    Biallelic loss-of-function variants in FOLR1 abolish functional folate
    receptor alpha (FRalpha), a GPI-anchored high-affinity folate-binding
    receptor highly expressed at the apical surface of choroid-plexus epithelium.
    Missense variants are expressed but mislocalize away from the cell surface,
    eliminating cellular folate binding, so both truncating and missense alleles
    converge on functional FRalpha loss at the blood-CSF barrier.
  role: trigger
  cell_types:
  - preferred_term: choroid plexus epithelial cell
    term:
      id: CL:0000706
      label: choroid plexus epithelial cell
  molecular_functions:
  - preferred_term: folic acid receptor activity
    term:
      id: GO:0061714
      label: folic acid receptor activity
    modifier: DECREASED
  locations:
  - preferred_term: choroid plexus
    term:
      id: UBERON:0001886
      label: choroid plexus
  evidence:
  - reference: PMID:19732866
    reference_title: "Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified an inherited brain-specific folate transport defect that is
      caused by mutations in the folate receptor 1 (FOLR1) gene coding for folate
      receptor alpha (FRalpha).
    explanation: >-
      Establishes biallelic FOLR1 defect and loss of FRalpha as the molecular
      cause of this brain-specific folate transport disorder.
  - reference: PMID:22586289
    reference_title: "Molecular characterization of folate receptor 1 mutations delineates cerebral folate transport deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Heterologous expression of the missense mutations, including previously
      described mutants, revealed minor decrease in protein expression but loss of
      cell surface localization, mistargeting to intracellular compartments and
      thus absence of cellular binding of folic acid.
    explanation: >-
      Shows FOLR1 missense variants abolish surface FRalpha and folate binding,
      the functional loss modeled by this trigger node.
  downstream:
  - target: Impaired Folate Transport Across the Blood-CSF Barrier and Low CSF 5-MTHF
    causal_link_type: DIRECT
- name: Impaired Folate Transport Across the Blood-CSF Barrier and Low CSF 5-MTHF
  description: >-
    FRalpha-mediated transcytosis moves 5-methyltetrahydrofolate from blood
    across the choroid-plexus epithelium into the cerebrospinal fluid. Loss of
    FRalpha blocks this blood-CSF folate transport, producing a severe isolated
    reduction of CSF 5-MTHF while serum/systemic folate remains normal, the
    biochemical hallmark of cerebral folate deficiency.
  role: intermediate
  cell_types:
  - preferred_term: choroid plexus epithelial cell
    term:
      id: CL:0000706
      label: choroid plexus epithelial cell
  biological_processes:
  - preferred_term: folate transmembrane transport
    term:
      id: GO:0098838
      label: folate transmembrane transport
    modifier: DECREASED
  evidence:
  - reference: PMID:23828504
    reference_title: "Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we identify folate receptor-α-positive intralumenal vesicles within
      multivesicular bodies and demonstrate the directional cotransport of human
      folate receptor-α, and labelled folate from the basolateral to the apical
      membrane in rat choroid plexus cells.
    explanation: >-
      Demonstrates FRalpha-dependent directional basolateral-to-apical
      (transcytotic) folate transport across choroid-plexus cells, the step
      abolished by FRalpha loss.
  - reference: PMID:19732866
    reference_title: "Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three patients carrying FOLR1 mutations developed progressive movement
      disturbance, psychomotor decline, and epilepsy and showed severely reduced
      folate concentrations in the cerebrospinal fluid (CSF).
    explanation: >-
      Documents severely reduced CSF folate in patients with FOLR1 variants.
  downstream:
  - target: Deficient Exosomal Folate Delivery into Brain Parenchyma
    causal_link_type: DIRECT
- name: Deficient Exosomal Folate Delivery into Brain Parenchyma
  description: >-
    Beyond transcytosis into the CSF, folate receptor alpha is shed on
    FRalpha-positive exosomes that shuttle 5-methyltetrahydrofolate from the
    choroid plexus across the CSF into the brain parenchyma, where the exosomes
    are internalized by astrocytes and neurons. Loss of FRalpha eliminates these
    FRalpha-positive CSF exosomes, removing this second delivery step so that
    folate captured at the choroid plexus fails to reach parenchymal brain cells.
  role: intermediate
  cell_types:
  - preferred_term: choroid plexus epithelial cell
    term:
      id: CL:0000706
      label: choroid plexus epithelial cell
  biological_processes:
  - preferred_term: exosomal secretion
    term:
      id: GO:1990182
      label: exosomal secretion
    modifier: DECREASED
  locations:
  - preferred_term: choroid plexus
    term:
      id: UBERON:0001886
      label: choroid plexus
  evidence:
  - reference: PMID:23828504
    reference_title: "Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Loss of folate receptor-α-expressing cerebrospinal fluid exosomes
      correlates with severely reduced 5-methyltetrahydrofolate concentration,
      corroborating the importance of the folate receptor-α-mediated folate
      transport in the cerebrospinal fluid.
    explanation: >-
      Loss of FRalpha-positive CSF exosomes tracks with severely reduced CSF
      5-MTHF, evidencing the exosomal folate-delivery step lost in FOLR1-CFTD.
  - reference: PMID:23828504
    reference_title: "Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Intraventricular injections of folate receptor-α-positive and -negative
      exosomes into mouse brains demonstrate folate receptor-α-dependent delivery
      of exosomes into the brain parenchyma.
    explanation: >-
      In vivo mouse experiments show FRalpha-dependent exosomal delivery into
      brain parenchyma, the delivery step abolished when FRalpha is lost.
  downstream:
  - target: Deficient CNS One-Carbon Metabolism
    causal_link_type: DIRECT
- name: Deficient CNS One-Carbon Metabolism
  description: >-
    Low CNS folate starves brain one-carbon metabolism, impairing the
    folate-dependent methylation cycle (S-adenosylmethionine-dependent
    methylation of DNA, proteins, phospholipids, and myelin components) and
    monoamine neurotransmitter metabolism. MR spectroscopy in patients shows
    combined white-matter choline and inositol depletion, reflecting disturbed
    membrane and myelin-lipid methylation.
  role: intermediate
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: one-carbon metabolic process
    term:
      id: GO:0006730
      label: one-carbon metabolic process
    modifier: DECREASED
  - preferred_term: methylation
    term:
      id: GO:0032259
      label: methylation
    modifier: DECREASED
  evidence:
  - reference: PMID:19732866
    reference_title: "Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain magnetic resonance imaging (MRI) demonstrated profound
      hypomyelination, and MR-based in vivo metabolite analysis indicated a
      combined depletion of white-matter choline and inositol.
    explanation: >-
      White-matter choline and inositol depletion reflects disturbed
      folate-dependent one-carbon/methylation metabolism in the brain.
  downstream:
  - target: Hypomyelination and Neurodegeneration
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Deficient methylation and myelin-lipid synthesis in the developing brain.
- name: Hypomyelination and Neurodegeneration
  description: >-
    Sustained CNS folate and methylation deficiency during the period of
    postnatal myelination causes profound cerebral hypomyelination and
    progressive neurodegeneration with cerebellar atrophy. Clinically this drives
    the late-infantile onset syndrome of seizures, psychomotor regression,
    ataxia, and movement disorder that can progress to immobility if untreated.
  role: outcome
  cell_types:
  - preferred_term: oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  biological_processes:
  - preferred_term: myelination
    term:
      id: GO:0042552
      label: myelination
    modifier: DECREASED
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:22586289
    reference_title: "Molecular characterization of folate receptor 1 mutations delineates cerebral folate transport deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified nucleotide alterations in the folate receptor 1 gene in 10
      individuals who shared developmental regression, ataxia, profound cerebral
      hypomyelination and cerebellar atrophy.
    explanation: >-
      Links FOLR1 loss to the shared clinical-radiologic outcome of regression,
      ataxia, hypomyelination, and cerebellar atrophy.
  - reference: PMID:38224559
    reference_title: "FOLR1-Related Cerebral Folate Transport Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individuals with untreated FOLR1-CFTD have very low cerebrospinal fluid
      (CSF) levels and progressive neurologic deterioration with developmental
      delays and progressive cognitive impairment, behavioral issues, seizures,
      and movement disorders that may progress to immobility.
    explanation: >-
      Describes the progressive neurodegenerative outcome of untreated disease.
phenotypes:
- name: Seizures
  category: Clinical
  description: >-
    Epilepsy is a core, frequently presenting feature; myoclonic epilepsy that is
    generally resistant to treatment and other seizure types occur, and epilepsy
    is often the initial diagnosis before the underlying folate transport defect
    is recognized.
  diagnostic: true
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:38224559
    reference_title: "FOLR1-Related Cerebral Folate Transport Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      progressive neurologic deterioration with developmental delays and
      progressive cognitive impairment, behavioral issues, seizures, and movement
      disorders that may progress to immobility.
    explanation: >-
      GeneReviews lists seizures among the neurologic manifestations.
  - reference: PMID:40218241
    reference_title: "A Clinical and Genetic Evaluation of Cases with Folate Receptor α Gene Mutation: A Case Series from Türkiye."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      with ataxia, choreoathetoid movements, and myoclonic epilepsy generally
      resistant to treatment.
    explanation: >-
      Case series characterizes the epilepsy as myoclonic and generally
      treatment-resistant.
  - reference: PMID:40218241
    reference_title: "A Clinical and Genetic Evaluation of Cases with Folate Receptor α Gene Mutation: A Case Series from Türkiye."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis most commonly made before the definitive diagnosis was
      epilepsy, and the first seizure occurred at a mean of 5.2 years.
    explanation: >-
      Case series documents epilepsy as the common initial diagnosis with a mean
      first-seizure age in childhood.
- name: Developmental regression
  category: Clinical
  description: >-
    Psychomotor regression with loss of previously acquired skills following an
    initial period of relatively normal development.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:22586289
    reference_title: "Molecular characterization of folate receptor 1 mutations delineates cerebral folate transport deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      10 individuals who shared developmental regression, ataxia, profound
      cerebral hypomyelination and cerebellar atrophy.
    explanation: >-
      Developmental regression is a shared feature of the FOLR1 patient cohort.
- name: Ataxia
  category: Clinical
  description: >-
    Cerebellar ataxia, corresponding to the cerebellar atrophy seen on imaging.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:22586289
    reference_title: "Molecular characterization of folate receptor 1 mutations delineates cerebral folate transport deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      10 individuals who shared developmental regression, ataxia, profound
      cerebral hypomyelination and cerebellar atrophy.
    explanation: >-
      Ataxia is a shared feature of the FOLR1 patient cohort.
- name: Movement disorder
  category: Clinical
  description: >-
    Progressive movement disturbance, part of the presenting neurologic picture
    and potentially progressing to immobility if untreated.
  phenotype_term:
    preferred_term: Movement disorder
    term:
      id: HP:0100022
      label: Abnormality of movement
  evidence:
  - reference: PMID:19732866
    reference_title: "Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three patients carrying FOLR1 mutations developed progressive movement
      disturbance, psychomotor decline, and epilepsy
    explanation: >-
      Progressive movement disturbance is part of the presenting phenotype.
- name: CNS hypomyelination
  category: Radiologic
  description: >-
    Profound cerebral hypomyelination on brain MRI is a characteristic imaging
    feature reflecting the folate-dependent myelination defect.
  diagnostic: true
  phenotype_term:
    preferred_term: CNS hypomyelination
    term:
      id: HP:0003429
      label: CNS hypomyelination
  evidence:
  - reference: PMID:19732866
    reference_title: "Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain magnetic resonance imaging (MRI) demonstrated profound
      hypomyelination
    explanation: >-
      MRI documents profound hypomyelination in affected patients.
- name: Cerebellar atrophy
  category: Radiologic
  description: >-
    Cerebellar atrophy on neuroimaging accompanies the cerebral hypomyelination.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: PMID:22586289
    reference_title: "Molecular characterization of folate receptor 1 mutations delineates cerebral folate transport deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      profound cerebral hypomyelination and cerebellar atrophy.
    explanation: >-
      Cerebellar atrophy is a shared imaging feature of the FOLR1 cohort.
- name: Acquired microcephaly
  category: Clinical
  description: >-
    Acquired (postnatal, secondary) microcephaly reflecting the progressive
    encephalopathy and impaired postnatal brain growth.
  phenotype_term:
    preferred_term: Acquired microcephaly
    term:
      id: HP:0005484
      label: Secondary microcephaly
  evidence:
  - reference: PMID:40218241
    reference_title: "A Clinical and Genetic Evaluation of Cases with Folate Receptor α Gene Mutation: A Case Series from Türkiye."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      FOLR1-related CFD should be considered in cases with febrile convulsions,
      developmental delay, ataxia, autism spectrum disorder, acquired
      microcephaly, and MRI findings of white matter involvement and cerebellar
      atrophy.
    explanation: >-
      Case series lists acquired microcephaly among the recognized features.
- name: Cognitive impairment
  category: Clinical
  description: >-
    Progressive cognitive impairment and developmental delay accompany the
    neurodegenerative course.
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:38224559
    reference_title: "FOLR1-Related Cerebral Folate Transport Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      progressive neurologic deterioration with developmental delays and
      progressive cognitive impairment
    explanation: >-
      GeneReviews describes progressive cognitive impairment.
- name: Autism spectrum disorder
  category: Clinical
  description: >-
    Autism spectrum disorder is among the recognized clinical features and is a
    reason to consider FOLR1-related cerebral folate deficiency.
  phenotype_term:
    preferred_term: Autism spectrum disorder
    term:
      id: HP:0000717
      label: Autism
  evidence:
  - reference: PMID:40218241
    reference_title: "A Clinical and Genetic Evaluation of Cases with Folate Receptor α Gene Mutation: A Case Series from Türkiye."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      FOLR1-related CFD should be considered in cases with febrile convulsions,
      developmental delay, ataxia, autism spectrum disorder, acquired
      microcephaly, and MRI findings of white matter involvement and cerebellar
      atrophy.
    explanation: >-
      Case series lists autism spectrum disorder among the recognized features.
- name: Febrile seizures
  category: Clinical
  description: >-
    Febrile convulsions are a frequent early complaint, often among the first
    manifestations noticed before the underlying diagnosis is made.
  phenotype_term:
    preferred_term: Febrile seizures
    term:
      id: HP:0002373
      label: Febrile seizure (within the age range of 3 months to 6 years)
  evidence:
  - reference: PMID:40218241
    reference_title: "A Clinical and Genetic Evaluation of Cases with Folate Receptor α Gene Mutation: A Case Series from Türkiye."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most frequently seen first complaints were febrile convulsions and
      attention deficit-hyperactivity-learning difficulties.
    explanation: >-
      Case series reports febrile convulsions as one of the most frequent first
      complaints.
- name: Choreoathetosis
  category: Clinical
  description: >-
    Choreoathetoid movements are part of the characteristic movement-disorder
    picture of cerebral folate transporter deficiency.
  phenotype_term:
    preferred_term: Choreoathetosis
    term:
      id: HP:0001266
      label: Choreoathetosis
  evidence:
  - reference: PMID:40218241
    reference_title: "A Clinical and Genetic Evaluation of Cases with Folate Receptor α Gene Mutation: A Case Series from Türkiye."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      with ataxia, choreoathetoid movements, and myoclonic epilepsy generally
      resistant to treatment.
    explanation: >-
      Case series describes choreoathetoid movements as a characteristic feature.
- name: Attention deficit hyperactivity disorder
  category: Clinical
  description: >-
    Attention deficit-hyperactivity and learning difficulties are among the most
    frequent presenting complaints in the case series.
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: PMID:40218241
    reference_title: "A Clinical and Genetic Evaluation of Cases with Folate Receptor α Gene Mutation: A Case Series from Türkiye."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most frequently seen first complaints were febrile convulsions and
      attention deficit-hyperactivity-learning difficulties.
    explanation: >-
      Case series reports attention deficit-hyperactivity-learning difficulties
      among the most frequent first complaints.
- name: Cerebral atrophy
  category: Radiologic
  description: >-
    Cerebral atrophy on cranial imaging accompanies the white-matter involvement
    and cerebellar atrophy characteristic of the disorder.
  phenotype_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
  evidence:
  - reference: PMID:40218241
    reference_title: "A Clinical and Genetic Evaluation of Cases with Folate Receptor α Gene Mutation: A Case Series from Türkiye."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      white matter involvement, cerebellar atrophy and cerebral atrophy were
      determined most often.
    explanation: >-
      Case series reports cerebral atrophy as one of the most frequent imaging
      findings.
biochemical:
- name: Cerebrospinal fluid 5-methyltetrahydrofolate (5-MTHF)
  presence: DECREASED
  context: >-
    Severely reduced CSF 5-MTHF in the setting of normal serum/systemic folate is
    the defining biochemical signature of cerebral folate deficiency and the key
    diagnostic finding in FOLR1-CFTD. Because the defect is brain-specific (a
    blood-CSF transport block rather than a systemic folate deficiency),
    peripheral folate indices are typically normal, so the diagnosis requires
    direct CSF folate measurement by lumbar puncture.
  evidence:
  - reference: PMID:22586289
    reference_title: "Molecular characterization of folate receptor 1 mutations delineates cerebral folate transport deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We screened 72 children with low 5-methyltetrahydrofolate concentrations in
      the cerebrospinal fluid and neurological symptoms that developed after
      infancy.
    explanation: >-
      Low CSF 5-MTHF is the biochemical entry criterion for the FOLR1 cohort.
  - reference: PMID:19732866
    reference_title: "Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified an inherited brain-specific folate transport defect
    explanation: >-
      The brain-specific nature of the defect explains low CSF folate with normal
      systemic folate.
genetic:
- name: FOLR1 loss-of-function variants
  gene_term:
    preferred_term: FOLR1
    term:
      id: hgnc:3791
      label: FOLR1
  association: Disease-causing
  relationship_type: CAUSATIVE
  notes: >-
    Biallelic pathogenic FOLR1 variants (missense, splice-site, and other
    loss-of-function alleles) cause FOLR1-CFTD. Missense alleles are expressed but
    fail to reach the cell surface, so all characterized variants converge on
    functional loss of folate receptor alpha.
  evidence:
  - reference: PMID:19732866
    reference_title: "Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      caused by mutations in the folate receptor 1 (FOLR1) gene coding for folate
      receptor alpha (FRalpha).
    explanation: >-
      FOLR1 is the causative gene encoding folate receptor alpha.
  - reference: PMID:22586289
    reference_title: "Molecular characterization of folate receptor 1 mutations delineates cerebral folate transport deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These results explain the functional loss of folate receptor alpha for all
      detected folate receptor 1 mutations.
    explanation: >-
      Functional studies show all detected FOLR1 variants cause loss of FRalpha
      function.
diagnosis:
- name: Cerebrospinal fluid 5-MTHF measurement
  description: >-
    Lumbar puncture with measurement of CSF 5-methyltetrahydrofolate is the
    biochemical screening test; a severely low CSF 5-MTHF with normal peripheral
    folate raises the diagnosis of cerebral folate deficiency and prompts FOLR1
    testing.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  markers: CSF 5-methyltetrahydrofolate
  results: >-
    Severely reduced CSF 5-MTHF with normal serum folate indicates cerebral
    folate deficiency.
  evidence:
  - reference: PMID:22586289
    reference_title: "Molecular characterization of folate receptor 1 mutations delineates cerebral folate transport deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      children with low 5-methyltetrahydrofolate concentrations in the
      cerebrospinal fluid
    explanation: >-
      CSF 5-MTHF measurement is the biochemical screen used to ascertain cases.
- name: FOLR1 molecular genetic testing
  description: >-
    Confirmatory diagnosis rests on identifying biallelic pathogenic FOLR1
    variants by molecular genetic testing.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  markers: FOLR1 biallelic pathogenic variants
  results: >-
    Two pathogenic FOLR1 alleles confirm the diagnosis.
  evidence:
  - reference: PMID:38224559
    reference_title: "FOLR1-Related Cerebral Folate Transport Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of FOLR1-CFTD is established in a proband with biallelic FOLR1
      pathogenic variants identified by molecular genetic testing.
    explanation: >-
      GeneReviews defines the molecular diagnostic criterion.
differential_diagnoses:
- name: Hereditary folate malabsorption (SLC46A1/PCFT deficiency)
  description: >-
    Hereditary folate malabsorption is caused by biallelic SLC46A1 (proton-coupled
    folate transporter, PCFT) variants and causes systemic folate deficiency with
    megaloblastic anemia in addition to low CSF folate, distinguishing it from the
    brain-specific, hematologically normal FOLR1-CFTD. It is distinguished by
    molecular testing.
  distinguishing_features:
  - Systemic folate deficiency and megaloblastic anemia favor SLC46A1/PCFT hereditary folate malabsorption.
  - Normal systemic folate with isolated low CSF folate favors FOLR1-CFTD.
  evidence:
  - reference: PMID:19732866
    reference_title: "Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At least five distinct inherited disorders of folate transport and
      metabolism are presently known, all of which cause systemic folate
      deficiency.
    explanation: >-
      Contrasts the systemic folate-deficiency disorders with the brain-specific
      FOLR1 defect.
- name: Dihydrofolate reductase (DHFR) deficiency
  description: >-
    DHFR deficiency is a distinct autosomal recessive inborn error of folate
    metabolism (different gene, DHFR) that also lowers CSF folate but characteristically
    causes megaloblastic anemia; it is distinguished by gene testing.
  distinguishing_features:
  - Megaloblastic anemia with a DHFR variant favors DHFR deficiency.
  - A biallelic FOLR1 variant with normal hematology favors FOLR1-CFTD.
  evidence:
  - reference: PMID:21310276
    reference_title: "Identification and characterization of an inborn error of metabolism caused by dihydrofolate reductase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe three individuals from two families with a recessive inborn
      error of metabolism, characterized by megaloblastic anemia and/or
      pancytopenia, severe cerebral folate deficiency, and cerebral
      tetrahydrobiopterin deficiency due to a germline missense mutation in DHFR,
      resulting in profound enzyme deficiency.
    explanation: >-
      DHFR deficiency lowers cerebral folate but is distinguished from FOLR1-CFTD
      by megaloblastic anemia/pancytopenia and a DHFR mutation.
- name: Folate receptor alpha autoantibody cerebral folate deficiency
  description: >-
    Acquired cerebral folate deficiency due to blocking autoantibodies against
    folate receptor alpha produces a biochemically similar low CSF 5-MTHF but is
    not caused by FOLR1 variants and is diagnosed by autoantibody testing rather
    than molecular genetics.
  distinguishing_features:
  - FRalpha blocking autoantibodies with normal FOLR1 sequence favor autoantibody-mediated cerebral folate deficiency.
  - Biallelic pathogenic FOLR1 variants favor FOLR1-CFTD.
  evidence:
  - reference: PMID:15888699
    reference_title: "Autoantibodies to folate receptors in the cerebral folate deficiency syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Serum from 25 of the 28 patients and 0 of 28 control subjects contained
      high-affinity blocking autoantibodies against membrane-bound folate
      receptors that are present on the choroid plexus.
    explanation: >-
      Blocking autoantibodies against choroid-plexus folate receptors define the
      acquired autoantibody-mediated mimic that has normal FOLR1.
  - reference: PMID:15888699
    reference_title: "Autoantibodies to folate receptors in the cerebral folate deficiency syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cerebral folate deficiency is a disorder in which autoantibodies can prevent
      the transfer of folate from the plasma to the cerebrospinal fluid.
    explanation: >-
      Establishes the autoantibody mechanism blocking blood-to-CSF folate
      transfer, biochemically mimicking FOLR1-CFTD without an FOLR1 variant.
progression:
- phase: Late-infantile onset and progressive neurodegeneration
  age_range: Typically after the first year of life
  notes: >-
    After a relatively normal early infancy, affected children develop
    progressive movement disturbance, psychomotor regression, ataxia, and
    epilepsy with a late-infantile onset.
  evidence:
  - reference: PMID:22586289
    reference_title: "Molecular characterization of folate receptor 1 mutations delineates cerebral folate transport deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This genetic defect gives rise to a progressive neurological disorder with
      late infantile onset.
    explanation: >-
      Establishes the late-infantile onset and progressive course.
- phase: Response to folinic acid therapy
  age_range: After treatment initiation
  notes: >-
    FOLR1-CFTD is treatable and its course can be reversed or stabilized:
    folinic acid restores CSF folate and biochemical markers and can precede and
    drive substantial clinical improvement, with the greatest benefit when
    treatment starts early. Because of the asymptomatic early period, diagnosis
    is often delayed and treatment started after symptom onset may be less
    effective.
  evidence:
  - reference: PMID:19732866
    reference_title: "Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CSF folate concentrations, as well as glial choline and inositol depletion,
      were restored by folinic acid therapy and preceded clinical improvements.
    explanation: >-
      Documents biochemical and clinical improvement with folinic acid.
  - reference: PMID:38224559
    reference_title: "FOLR1-Related Cerebral Folate Transport Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment with 5-formyltetrahydrofolate (5-formylTHF; also known as folinic
      acid or leucovorin) can result in substantial improvement in neurologic
      findings, particularly when started at a young age.
    explanation: >-
      GeneReviews states treatment can substantially improve neurologic findings,
      especially when started early.
  - reference: PMID:40218241
    reference_title: "A Clinical and Genetic Evaluation of Cases with Folate Receptor α Gene Mutation: A Case Series from Türkiye."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Due to an asymptomatic early period, CFD diagnosis may be delayed, and
      treatment after symptom onset may be less effective.
    explanation: >-
      Case series notes delayed diagnosis and reduced efficacy of treatment
      started after symptom onset, underscoring the reversibility window.
- phase: Long-term survival despite neurologic disability
  age_range: Untreated natural history
  notes: >-
    Despite the incapacitating neurologic findings of untreated disease,
    affected individuals can survive well into adulthood, a clinically important
    and counterintuitive prognosis for a disorder classified as
    neurodegenerative.
  evidence:
  - reference: PMID:38224559
    reference_title: "FOLR1-Related Cerebral Folate Transport Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Despite these incapacitating neurologic findings, untreated individuals can
      live well into adulthood.
    explanation: >-
      GeneReviews notes untreated individuals can live well into adulthood.
treatments:
- name: High-dose folinic acid (leucovorin)
  description: >-
    Disease-specific therapy is high-dose folinic acid (5-formyltetrahydrofolate,
    also called leucovorin), which bypasses the FRalpha transport block and
    restores CSF folate into the normal range. Oral high-dose therapy is usually
    sufficient (a reported oral dose is 5.2 mg/kg/day), with intramuscular or
    intermittent intravenous dosing as alternatives, and CSF folate is monitored
    to confirm adequacy. Benefit is greatest when started early; presymptomatic
    treatment of affected sibs can prevent or markedly mitigate disease. Plain
    folic acid is avoided because it binds FRalpha tightly and may interfere with
    any residual receptor function.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: folinic acid
      term:
        id: CHEBI:15640
        label: 5-formyltetrahydrofolic acid
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  - preferred_term: CNS hypomyelination
    term:
      id: HP:0003429
      label: CNS hypomyelination
  - preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  target_mechanisms:
  - target: Impaired Folate Transport Across the Blood-CSF Barrier and Low CSF 5-MTHF
    treatment_effect: BYPASSES
    description: >-
      Folinic acid (5-formyltetrahydrofolate) is a reduced folate that enters the
      CNS independently of folate receptor alpha, bypassing the blocked
      FRalpha-mediated blood-CSF folate transport step and restoring CSF folate.
  evidence:
  - reference: PMID:38224559
    reference_title: "FOLR1-Related Cerebral Folate Transport Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment with 5-formyltetrahydrofolate (5-formylTHF; also known as folinic
      acid or leucovorin) can result in substantial improvement in neurologic
      findings, particularly when started at a young age.
    explanation: >-
      GeneReviews establishes folinic acid as the disease-specific therapy with
      early-treatment benefit.
  - reference: PMID:38224559
    reference_title: "FOLR1-Related Cerebral Folate Transport Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Folic acid is not used to treat FOLR1-CFTD because folic acid binds tightly
      to FOLR1, possibly interfering with FOLR1 function, which is a concern when
      treating individuals who may have residual FOLR1 activity.
    explanation: >-
      Captures the folic-acid caveat: plain folic acid is avoided in favor of
      folinic acid.
  - reference: PMID:19732866
    reference_title: "Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      restored by folinic acid therapy and preceded clinical improvements.
    explanation: >-
      Original description shows folinic acid restores CSF folate ahead of
      clinical improvement.
  - reference: PMID:40218241
    reference_title: "A Clinical and Genetic Evaluation of Cases with Folate Receptor α Gene Mutation: A Case Series from Türkiye."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment with folinic acid at a dose of 5.2 mg/kg/day of PO was started at
      the age of 9.8 years on average, and intravenous folinate was started at
      different doses.
    explanation: >-
      Case series reports a concrete oral folinic acid dose of 5.2 mg/kg/day.
  - reference: PMID:38224559
    reference_title: "FOLR1-Related Cerebral Folate Transport Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment of asymptomatic or mildly symptomatic younger sibs at the time of
      diagnosis of their older sibs can prevent or markedly mitigate the
      neurocognitive signs of this disorder.
    explanation: >-
      GeneReviews backs the presymptomatic-sib treatment claim: treating
      asymptomatic younger sibs can prevent or mitigate the disorder.
- name: CSF folate surveillance monitoring
  description: >-
    For individuals on 5-formyltetrahydrofolate therapy, CSF folate is monitored
    to confirm an adequate therapeutic dose: repeat CSF folate after treatment
    initiation, repeat with clinical change (developmental regression, new
    neurologic findings, seizures) or adherence concerns, and, optimally and if
    feasible, yearly CSF folate levels until age five years.
  action_category: MONITORING
  treatment_term:
    preferred_term: CSF folate monitoring
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  evidence:
  - reference: PMID:38224559
    reference_title: "FOLR1-Related Cerebral Folate Transport Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      optimally and if feasible, yearly CSF folate levels until age five years.
    explanation: >-
      GeneReviews surveillance protocol recommends periodic CSF folate
      monitoring, including yearly levels until age five.
- name: Evaluation of relatives at risk
  description: >-
    Because presymptomatic treatment can prevent or mitigate disease, the genetic
    status of all sibs of a proband should be clarified to identify as early as
    possible those who would benefit from prompt initiation of
    5-formyltetrahydrofolate; newborns at risk are evaluated for the familial
    FOLR1 variants if not tested prenatally.
  action_category: SCREENING
  treatment_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:38224559
    reference_title: "FOLR1-Related Cerebral Folate Transport Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clarification of the genetic status of all sibs of a proband is recommended
      to identify as early as possible those sibs who would benefit from prompt
      initiation of treatment with 5-formylTHF.
    explanation: >-
      GeneReviews recommends clarifying at-risk sibs' genetic status to enable
      early presymptomatic treatment.
discussions:
- discussion_id: gap_folr1_treatment_response_determinants
  prompt: >-
    What determines the degree and reversibility of neurologic recovery after
    folinic acid treatment in FOLR1-CFTD, and why do some deficits (particularly
    established hypomyelination and cognitive impairment) fail to reverse when
    treatment is started late despite normalization of CSF folate?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Hypomyelination and Neurodegeneration
  - treatments#High-dose folinic acid (leucovorin)
  rationale: >-
    FOLR1-CFTD is a treatable disorder in which folinic acid can restore CSF
    folate and drive clinical improvement, yet clinical severity does not
    correlate cleanly with residual FRalpha function, and later-treated
    individuals may retain irreversible deficits. The determinants of treatment
    response, the therapeutic window relative to the postnatal myelination
    period, and whether irreversible deficits reflect a fixed developmental
    myelination defect versus ongoing correctable metabolic dysfunction remain
    unresolved, and are central to the case for early or newborn-screening-based
    diagnosis.
  evidence:
  - reference: PMID:22586289
    reference_title: "Molecular characterization of folate receptor 1 mutations delineates cerebral folate transport deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      different clinical severities do not necessarily correlate with residual
      function of folate receptor alpha mutants and indicate that additional
      factors contribute to the clinical phenotype in cerebral folate transport
      deficiency.
    explanation: >-
      Documents that clinical severity is not explained by residual FRalpha
      function alone, motivating the open question about response determinants.

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PMID:38224559

FOLR1-Related Cerebral Folate Transport Deficiency.

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FOLR1-Related Cerebral Folate Transport Deficiency

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