Clinical characteristics.

SLC19A1 encodes the reduced folate carrier (RFC) protein that mediates transport of folates into mammalian cells. The clinical findings associated with SLC19A1-related folate transport deficiency (SLC19A1-FTD) depend on the degree of RFC functional loss. In untreated individuals with severe transport function loss, signs and symptoms may be present at or shortly after birth and can include poor growth, developmental delay (affecting motor, speech, and/or cognitive skills), seizures, recurrent infections (particularly pulmonary infections with unusual or opportunistic pathogens), oral mucositis, and diarrhea. Additionally, macrocytic anemia, sometimes accompanied by leukopenia and/or thrombocytopenia, may lead to oral and nasal bleeding. When the loss of function is modest, signs of the condition may be delayed and only emerge when dietary folate intake is insufficient. When the sole manifestations are hematologic, immunologic/infectious, and/or gastrointestinal, treatment with folate can completely reverse these signs and symptoms. Developmental and neurologic findings may improve with treatment depending on the extent and duration of impairment and adequacy of treatment.

Diagnosis/testing.

The diagnosis of SLC19A1-FTD is established in a proband with suggestive findings and biallelic pathogenic variants in SLC19A1 identified by molecular genetic testing.

Management.

Targeted therapies: Oral 5-formyl-tetrahydrofolate (THF) or 5-methylTHF at doses that lead to supranormal blood levels and result in normalization of systemic cellular folate levels will correct the hematologic, immunologic/infectious, and gastrointestinal manifestations of SLC19A1-FTD. Even higher blood levels are likely to be required to achieve cerebrospinal fluid (CSF) and intracerebral folate levels necessary for adequate delivery of folates into neural cells to address the cerebral consequences of this condition. Note: Folic acid is NOT recommended because it is a poor substrate for RFC and has a potential inhibitory effect at the choroid plexus due to tight binding to folate receptor alpha.

Supportive care: Depending on the severity of the deficiency, the time to diagnosis, and the adequacy of the cerebral folate concentrations achieved, cognitive and neurologic deficits may remain. There is no information on whether treatment with folate will reduce or eliminate seizures in those who have developed a seizure disorder. Supportive developmental therapies to address any motor or cognitive issues are appropriate.

Surveillance: Monitor developmental progress and educational needs at each visit. Neurologic examination every six months for at least five years, then as necessary. Consider periodic brain MRI, particularly if there are progressive developmental, cognitive, or neurologic signs. Once therapeutic serum folate concentrations are achieved, monitor serum folate, total homocysteine, and red blood cell folate concentrations every three months for two years and every six months thereafter, if stable. Monitor CSF folate concentration until levels are above the normal range for age, then monitor periodically thereafter for the first five years or if there are progressive developmental or neurologic signs or concerns about adherence. Monitor complete blood count; once corrected, assess every three months for two years, then every six months thereafter, if stable. Once immunoglobulins are normalized, levels need not be repeated as long as hematologic and metabolic parameters are normal and stable.

Agents/circumstances to avoid: Folic acid is not recommended for treatment of this condition. A variety of anionic compounds are potential inhibitors of RFC-mediated folate transport. If the pathogenic variant has residual function, sustained use of such agents, such as salicylates, at therapeutic blood levels should be avoided. Methotrexate should not be used to treat cancer or leukemia in individuals with SLC19A1-FTD. Pemetrexed, another folate analog, may retain therapeutic activity in the absence of RFC since it has different transport properties and mechanism of action.

Evaluation of relatives at risk: Clarification of the genetic status of newborn sibs and apparently asymptomatic younger and older sibs of a proband is recommended to identify as early as possible those who would benefit from prompt initiation of folate treatment. Molecular genetic testing of younger or older at-risk sibs who have not undergone prenatal testing should be performed immediately after birth. If genetic testing is not possible, complete blood count, serum and red blood cell folate concentrations, total homocysteine concentration, and serum immunoglobulin levels should be assessed in at-risk sibs immediately after birth or as soon as the diagnosis is confirmed in the proband.

Pregnancy management: Based upon available information, folic acid should not be taken by a pregnant women carrying a fetus with SLC19A1-FTD. The appropriate folate would be 5-methylTHF or 5-formylTHF. The natural folates found in foods are the physiologically reduced folates, mainly 5-methylTHF. The only folic acid present in food is the supplement added in very small amounts to grains and cereals and is not likely to be of concern.

Genetic counseling.

SLC19A1-FTD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a SLC19A1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the SLC19A1 pathogenic variant(s) have been identified in an affected family member, targeted heterozygote testing for at-risk relatives and prenatal/preimplantation genetic testing for SLC19A1-FTD are possible. Note that heterozygotes (carriers) are likely to be asymptomatic but may be at greater risk for clinical signs of folate deficiency when there is a decrease in folate intake.

Suggestive Findings

SLC19A1-FTD should be suspected in untreated probands with the following clinical, supportive laboratory, and imaging findings and family history.

Clinical findings

• Birth weight and head circumference that are in the lower ranges of the typical growth chart for age and sex
• Poor postnatal growth
• Developmental delay, including gross motor (gait), speech/language, and cognitive skills
• Seizures
• Recurrent infections, particularly respiratory
• Mucositis with oral lesions
• Diarrhea

Supportive laboratory findings

• Anemia, typically megaloblastic, that may be accompanied by leukopenia and/or thrombocytopenia
• Normal blood folate with low red blood cell folate
  Note: Serum folate should be normal if intake and intestinal absorption are normal; however, red blood cell folate will be depressed in affected individuals.
• Low cerebrospinal fluid (CSF) folate concentration
  Note: Normal CSF folate concentrations are higher in infants and toddlers and decrease with age.
• Elevated blood total homocysteine concentration
• Hypoimmunoglobulinemia

Imaging findings. Brain MRI demonstrating delayed myelination and cerebral and/or cerebellar calcifications

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of SLC19A1-FTD is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in SLC19A1 identified by molecular genetic testing (see Table 1).

Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic SLC19A1 variants of uncertain significance (or of one known SLC19A1 pathogenic variant and one SLC19A1 variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

SLC19A1 encodes the reduced folate carrier (RFC) protein that mediates transport of folates into mammalian cells. The clinical findings associated with SLC19A1-related folate transport deficiency (SLC19A1-FTD) depend on the degree of RFC functional loss associated with the pathogenic variants (see Molecular Genetics). With severe deficiency, signs may be present at or shortly after birth [Gök et al 2023, Shiraishi et al 2023]. With modest loss of function, clinical manifestations may be delayed and only emerge when dietary folate intake is insufficient [Svaton et al 2020]. When the sole manifestations are hematologic, immunologic/infectious, and/or gastrointestinal, treatment with folate can completely reverse these signs and symptoms. Developmental and neurologic findings may improve with treatment depending on the extent and duration of impairment and adequacy of treatment (see Management, Targeted Therapies).

To date, five individuals from three families have been identified with biallelic pathogenic variants in SLC19A1 [Svaton et al 2020, Gök et al 2023, Shiraishi et al 2023]. In addition, two sibs died at an early age prior to diagnosis [Gök et al 2023, Shiraishi et al 2023]. The following description of the phenotypic features associated with this condition in untreated individuals is based on these reports.

Hematologic findings. The initial laboratory abnormality recognized is macrocytic anemia that may be accompanied by leukopenia and/or thrombocytopenia; the latter may be associated with oral and nasal bleeding. Serum folate and B₁₂ are normal unless there are secondary deficiencies.

Infectious/immunodeficiency. Affected untreated individuals have immune deficiency due to low immunoglobulin levels. This results in recurrent infections, particularly respiratory, with unusual or opportunistic infections, such as Pneumocystis jirovecii or cytomegalovirus. There is also impaired stimulator of interferon genes protein (STING) activation, although its clinical role in the immunodeficiency and increased infections is unclear and probably minimal [Gök et al 2023, Shiraishi et al 2023].

Gastrointestinal. Affected untreated individuals typically have severe mucositis with mouth sores and chronic diarrhea contributing to poor nutrition.

Developmental delay (DD) and intellectual disability (ID). Signs of the condition may emerge during in utero development in those with severe pathogenic variants; this is suggested by the finding of low birth weight and small head circumference (in the lower percentiles on the typical growth chart for sex) at birth [Shiraishi et al 2023]. If left untreated, developmental and cognitive issues progress [Gök et al 2023, Shiraishi et al 2023]. Delays can be present in motor (gait), speech/language, and cognitive development.

Neurologic. Without adequate treatment, neurologic impairment may evolve to include seizures [Gök et al 2023, Shiraishi et al 2023].

Other. Curling gray hair was noted in two affected individuals.

Prognosis. The hematologic, immunologic/infectious, and gastrointestinal signs and symptoms associated with this condition typically correct with folate treatment. The developmental, cognitive, and neurologic consequences may be preventable or improve with treatment, particularly when the diagnosis is made, and treatment initiated, early in life.

Genotype-Phenotype Correlations

Biallelic c.1042G>A (p.Gly348Arg) pathogenic variants. This pathogenic variant has been reported in the homozygous state in four affected individuals and has been associated with early-onset severe anemia, mucositis, immune deficiency with frequent respiratory infections, and developmental, neurologic, and cognitive impairments [Gök et al 2023, Shiraishi et al 2023].

Biallelic c.634_636delTTC (p.Phe212del) pathogenic variants. This pathogenic variant in a conserved region of the large internal loop between the 6th and 7th helices (which is not predicted to have a major impact on function) has been reported in the homozygous state in a person with late-onset megaloblastic anemia who responded to oral folate supplementation (see Management, Targeted Therapies and Molecular Genetics) [Svaton et al 2020].

Prevalence

The prevalence of this condition is likely to be underestimated since pathogenic variants with only modest reduction in function may go undiagnosed unless there is secondary dietary folate deficiency and/or intestinal disease with folate malabsorption.

Note: Mice with total absence of RFC protein die in utero; unrecognized embryonic loss in humans is likely when there are biallelic pathogenic variants that result in complete loss of transport function [Zhao et al 2001, Gelineau-van Waes et al 2008].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with SLC19A1-FTD, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for SLC19A1-FTD.

Surveillance

To monitor existing manifestations, the individual's response to targeted therapy and supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Agents/Circumstances to Avoid

A variety of anionic compounds are potential inhibitors of RFC-mediated folate transport [Zhao & Goldman 2013]. If the pathogenic variant has residual function, sustained use of such agents, such as salicylates, at therapeutic blood levels should be avoided.

Folic acid is not recommended for treatment of this condition since it may interfere with physiologic folate transport into the CSF at the choroid plexus and it has a very low affinity for RFC.

RFC is also the major route of transport of the folate analog methotrexate into normal and malignant cells; therefore, methotrexate should not be used to treat cancer or leukemia in people with SLC19A1-FTD [Zhao & Goldman 2013]. Pemetrexed (another antineoplastic folate analog) retains transport and efficacy in the absence of RFC in cell systems even at physiologic pH, mediated by the SLC46A1-encoded proton-coupled folate transporter (PCFT), and hence can be utilized clinically for the treatment of cancers in individuals with impaired RFC function [Zhao et al 2008].

Evaluation of Relatives at Risk

Clarification of the genetic status of newborn sibs and apparently asymptomatic younger and older sibs of a proband is recommended to identify as early as possible those who would benefit from prompt initiation of folate treatment. There is very limited experience in the early treatment of this disorder; however, it is expected that the hematologic, gastrointestinal, and immunologic manifestations of SLC19A1-FTD will be prevented or rapidly reversed. Likewise, achieving adequate CSF folate concentrations should prevent or minimize developmental, neurologic, and cognitive manifestations.

Prenatal testing of a fetus at risk. Prenatal testing for the familial SLC19A1 pathogenic variants may be performed via amniocentesis or chorionic villus sampling to allow for early assessment and targeted treatment.

Newborn sibs and apparently asymptomatic younger and older sibs

• Molecular genetic testing of younger or older at-risk sibs who have not undergone prenatal testing should be performed immediately after birth.
• If genetic testing is not possible, complete blood count, serum and red blood cell folate concentrations, total homocysteine concentration, and serum immunoglobulin levels should be assessed in at-risk sibs immediately after birth or as soon as the diagnosis is confirmed in the proband.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Based upon available information, folic acid should not be taken by a pregnant woman carrying a fetus with SLC19A1-FTD. The appropriate folate would be 5-methyltetrahdrofolate (THF) or 5-formylTHF. The natural folates found in foods are the physiologically reduced folates, mainly 5-methylTHF. The only folic acid present in food is the supplement added in very small amounts to grains and cereals and is not likely to be of concern.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

SLC19A1-related folate transport deficiency (SLC19A1-FTD) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for an SLC19A1 pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an SLC19A1 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are likely to be asymptomatic but may be at greater risk for clinical signs of folate deficiency when there is a modest decrease in folate intake. No data on heterozygotes are currently available.

Sibs of a proband

• If both parents are known to be heterozygous for an SLC19A1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither of the familial SLC19A1 pathogenic variants.
• Clarification of the genetic status of all sibs of a proband is recommended in order to identify as early as possible those who inherited biallelic SLC19A1 pathogenic variants and would benefit from prompt initiation of treatment. There is very limited experience in the early treatment of this condition; however, it is expected that early treatment should prevent or fully reverse the hematologic, gastrointestinal, and immunologic consequences of SLC19A1-FTD and potentially prevent, mitigate, or reverse developmental, neurologic, and cognitive manifestations of the cerebral folate deficiency.
• Heterozygotes (carriers) are likely to be asymptomatic but may be at greater risk for clinical signs of folate deficiency when there is a decrease in folate intake or folate malabsorption. No data on heterozygotes are currently available.

Offspring of a proband. Unless an affected individual's reproductive partner also has SLC19A1-FTD or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in SLC19A1.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an SLC19A1 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the SLC19A1 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

Prenatal Testing and Preimplantation Genetic Testing

Once the SLC19A1 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

"Folates" refers to a family of B₉ vitamins that are interconvertible in a series of biochemical reactions within cells. Folic acid is the most frequently used form in vitamin preparations because it is chemically stable and inexpensive. Folic acid is not found in nature; as such it must be reduced by dihydrofolate reductase (for which it is a poor substrate) to tetrahydrofolate (THF), to which 1-carbon moieties are added at various oxidation states that then support essential biosynthetic reactions: DNA, RNA, amino acid biosynthesis, and a variety of methylation reactions.

The protein product of SLC19A1 is the reduced folate carrier (RFC) protein. RFC is required for transport of folates across the plasma membrane of mammalian cells and is therefore critical to sustaining folate-dependent metabolism. SLC19A1-related folate transport deficiency (SLC19A1-FTD) is caused by biallelic pathogenic variants in SLC19A1 that impair transport of folates into cells, resulting in systemic and central nervous system folate deficiency. Complete loss of RFC function is embryonic lethal in mice and would be expected to be similarly lethal in humans [Zhao et al 2001, Gelineau-van Waes et al 2008]. RFC is not required for intestinal folate absorption, a process mediated by the SLC46A1-encoded proton-coupled folate transporter (PCFT), so that in SLC19A1-FTD folate blood levels are normal in the absence of dietary deficiency or intestinal malabsorptive disease. Supranormal blood levels are required to compensate for the RFC functional defect, particularly if it is due to a decreased affinity of the transporter for folate. Alternatively, compensation by high folate blood levels may be due to less efficient transport mediated by another lower affinity/capacity transporter and/or passive diffusion. PCFT is present in most tissues and, while there is limited function at neutral pH, PCFT could represent an additional route of folate transport into cells if the folate blood level is sufficiently high.

RFC is also a low-affinity transporter of a variety of organic anions [Zhao & Goldman 2013] and is required for transport of 2',3'-cGAMP into cells, which mediates the extracellular activation of the stimulator of interferon genes protein (STING) pathway [Luteijn et al 2019, Ritchie et al 2019]. This defect persists after the provision of folate; however, the intracellular pathway for STING activation remains intact in the absence of RFC function. The clinical impact of the STING defect on systemic and cerebral immune competency is not known. However, the correction of the low immunoglobulin levels associated with the folate deficiency with the provision of folate appears to correct the infectious aspects of this disorder.

The role of the RFC protein in folate transport across the blood-brain barrier into the central nervous system is not understood. RFC is produced at the choroid plexus, but its role in transport of folate into the CSF is uncertain [Wang et al 2001]. Likely more important is its localization at the vascular blood-brain barrier, where blood flow is high and where folates and other nutrients are delivered directly to brain parenchyma [Alam et al 2020]. Once within the extracellular space of brain parenchyma, RFC is required for transport of folates across the plasma membrane into neural cells. The extent to which impaired RFC function results in impaired folate transport across the vascular blood-brain barrier and the dosing required to achieve sufficiently high folate concentration within the CSF and the cerebral excellular space to achieve adequate transport of folate into neural cells is unclear. To date, there is no data on CSF folate concentrations that must be achieved to prevent, mitigate, or reverse the developmental, neurologic, and cognitive manifestations of SLC19A1-FTD.

Mechanism of disease causation. Loss of function

Author Notes

Dr I David Goldman has a long-standing research interest in the mechanisms by which folates are absorbed in the intestine and are transported into and out of systemic tissues and the brain. His laboratory provided the first comprehensive characterization of the reduced folate carrier (RFC) protein, established RFC as an organic anion antiporter, and defined the role organic phosphates play in concentrative folate transport [Zhao & Goldman 2013]. Dr Goldman discovered the protein-coupled folate transporter (PCFT, encoded by SLC46A1) and established that loss of function of this transporter is the molecular basis for hereditary folate malabsorption [Qiu et al 2006, Zhao et al 2017]. He has studied the functional, structural, and clinical impact of SLC46A1 variants identified worldwide, associated with hereditary folate malabsorption [Zhao et al 2017, Zhan et al 2020]. Dr Goldman has also studied the mechanism of FOLR1-mediated transport of folates and antifolate drugs. Dr Goldman has a particular interest in clinical disorders that result in the loss of function of these transporters as well as characterization of the biochemical, molecular, and structural basis for the transport defects.

Faculty profile web page: www.einsteinmed.edu

Complete PubMed publications: www.pubmed.ncbi.nlm.nih.gov/

Dr Goldman is interested in hearing from clinicians treating, and families affected by, hereditary folate malabsorption, FOLR1-related cerebral folate transport deficiency, and SLC19A1-related folate transport deficiency. Also of interest are novel variants of these transporters of known or uncertain significance and their clinical presentations.

Acknowledgments

Dr Goldman's research has been supported by grants from the National Institutes of Health.

Revision History

• 14 August 2025 (ma) Review posted live
• 28 March 2024 (idg) Original submission

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