Clinical characteristics.

Hereditary folate malabsorption (HFM) is characterized by folate deficiency due to impaired intestinal folate absorption and impaired folate transport into the central nervous system. Findings include poor feeding and growth, diarrhea and/or oral mucositis, anemia and frequently pancytopenia, hypoimmunoglobulinemia, and other immunologic dysfunction resulting in infections, often Pneumocystis jirovecii pneumonia. Neurologic manifestations include developmental delays, cognitive and motor disorders, behavioral disorders, and seizures.

Diagnosis/testing.

The diagnosis of HFM is established in a proband with anemia, impaired absorption of an oral folate load, and very low cerebrospinal fluid (CSF) folate concentration (even after correction of the serum folate concentration); and/or biallelic pathogenic variants in SLC46A1, which encodes the proton-coupled folate transporter, identified on molecular genetic testing.

Management.

Targeted therapy: Early treatment with high-dose intramuscular or, if that is not possible, oral 5-formyltetrahydrofolate (5-formylTHF; also known as folinic acid or leucovorin) or, preferably, the active isomer of 5-formylTHF (levoleucovorin) readily corrects the systemic folate deficiency and, if the dose is sufficient, can achieve CSF folate concentrations that prevent or mitigate the neurologic consequences of HFM. Dosing is aimed at achieving CSF folate trough concentrations as close as possible to the normal range for the age of the affected individual (infants and children have higher CSF folate concentrations than adults).

Supportive care: Blood transfusion is rarely needed for severe anemia; in affected individuals with selective immunoglobulin (Ig) A deficiency, appropriate precautions for blood product transfusion should be taken. Pneumocystis jirovecii pneumonia is treated with trimethoprim-sulfamethoxazole. Developmental and educational services as needed; anti-seizure medication (avoid phenytoin and valproic acid) per neurologist for those with seizures.

Surveillance: To assess adequacy of treatment, surveillance should include measurement of serum and CSF folate and homocysteine concentrations and complete blood counts. Serum immunoglobulins are monitored until they return to normal range and serum folate concentration and hemogram remain normal and stable. Assessment of neurologic and developmental milestones frequently during childhood; assessment of cognitive function to optimize folate dosing.

Agents/circumstances to avoid: If possible, folic acid should not be used for the treatment of HFM because it binds very tightly to the folate receptor. This may impair transport of physiologic folates across the choroid plexus. Phenytoin and valproic acid should be avoided due to their effects on folate intestinal absorption and metabolism, respectively.

Evaluation of relatives at risk: For at-risk sibs, molecular genetic testing if the family-specific pathogenic variants are known; otherwise, measurement of serum and CSF folate concentrations and intestinal absorption of folate, immediately after birth or as soon as the diagnosis is confirmed in the proband.

Pregnancy management: Affected women should be certain to adhere to their required 5-formylTHF regimen well in advance of attempting to conceive; infants of mothers with HFM do not appear to be at increased risk for neural tube defects typically associated with maternal folate deficiency during pregnancy, but care must be taken to assure that maternal folate intake is sufficient.

Genetic counseling.

HFM is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an SLC46A1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial SLC46A1 pathogenic variants. Once the SLC46A1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing for HFM are possible.

Suggestive Findings

HFM should be suspected in infants with the following clinical findings, family history, and supportive laboratory, bone marrow examination, and imaging findings.

Clinical findings

• Anorexia with poor weight gain and growth deficiency
• Diarrhea and/or oral mucositis
• Infections with unusual organisms (typically pneumonia caused by Pneumocystis jirovecii) associated with hypoimmunoglobulinemia
• Neurologic manifestations including developmental delays, cognitive and behavioral disorders, motor disorders, and, frequently, seizures

Family history is consistent with autosomal recessive inheritance: affected sibs, sib deaths in early infancy as a result of infection, anemia, seizure disorders, parental consanguinity, and/or Puerto Rican ancestry. Absence of a known family history does not preclude the diagnosis.

Supportive laboratory findings

• Complete blood count
  • Anemia, typically with macrocytic red cell indices and neutrophil hypersegmentation on peripheral smear, associated with low serum folate. Note: Normocytic anemia is possible when there is accompanying poor nutrition and/or iron deficiency.
  • In at least 30% of individuals there is leukopenia, thrombocytopenia, or pancytopenia.
• Low quantitative serum immunoglobulin (Ig) concentrations. In ~25% of individuals, there are low concentrations of serum IgG, IgM, and IgA [Kishimoto et al 2014, Erlacher et al 2015, Zhao et al 2017, Tozawa et al 2019, Miyashita et al 2020, Sarhan et al 2022].
• Erythrocyte and serum folate concentrations
  • Low erythrocyte folate concentration
  • Very low baseline serum folate concentrations in untreated individuals (typically <1.5 nmol/L). In countries in which grains are folate supplemented, normal folate concentration is 10-45 nmol/L or as specified by the laboratory.
  • After an oral load of 5 mg of folic acid, measurement of serum folate concentration over a minimum of four hours demonstrates little or no increase in affected individuals; in unaffected individuals the serum folate concentration increases to at least 200 nmol/L [Malatack et al 1999, Geller et al 2002].
• Cerebrospinal fluid (CSF) folate concentration
  • Low CSF folate concentration even after correction of the serum folate concentration
    • Baseline CSF folate concentration in untreated affected individuals is typically <5 nmol/L.
    • Normal CSF folate concentrations are higher in infancy and through adolescence (normal CSF folate is ~100 nmol/L for infants to age two years, decreasing to ~75 nmol/L by age five years and to ~65 nmol/L by age 19 years [Verbeek et al 2008]).
    • Note: In unaffected adults, normal CSF folate concentrations are two to three times the normal serum folate concentration.
  • Following intramuscular administration of 5 mg of 5-formyl-tetrahydrofolate (5-formylTHF or leucovorin) to normal individuals, the CSF folate concentration peaks transiently at one to two hours and returns to the baseline value within approximately 24 hours. However, in individuals with HFM, the CSF folate concentration remains far below the serum folate concentration, a finding consistent with impaired folate transport across the blood-choroid plexus-CSF barrier [Torres et al 2015, Aluri et al 2018, Manea et al 2018].

Supportive bone marrow biopsy findings. Megaloblastic erythropoiesis with exclusion of other causes of anemia

Imaging findings

• Frequent intracranial calcifications, particularly involving the basal ganglia
• Diffuse hypomyelination along with cerebral and cerebellar atrophy on MRI

Establishing the Diagnosis

The diagnosis of HFM is established in a proband:

• With anemia and low serum and CSF folate concentrations (the latter even after correction of the serum folate concentration). When genetic testing is not available, absorption of an oral folate load should be assessed; impaired absorption is consistent with a diagnosis of HFM (see Suggestive Findings, Supportive laboratory findings).
  OR
• By the identification of biallelic pathogenic (or likely pathogenic) variants in SLC46A1 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 SLC46A1 variants of uncertain significance (or of one known SLC46A1 pathogenic variant and one SLC46A1 variant of uncertain significance) does not establish or rule out the diagnosis.

The recommended approach to molecular genetic testing is single-gene testing.

Single-gene testing. Sequence analysis of SLC46A1 is performed to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. However, to date, large deletions or duplications have not been reported in individuals with HFM.

Note: Targeted analysis for founder variants can be performed first in individuals of Puerto Rican or Japanese ancestry (see Table 6).

Clinical Description

Hereditary folate malabsorption (HFM) is characterized by (1) impaired intestinal absorption of folates causing systemic folate deficiency and (2) impaired transport of folates across the blood-choroid plexus-cerebrospinal fluid (CSF) barrier, resulting in central nervous system folate deficiency. Infants with HFM may be born with adequate stores of folate but subsequently are unable to absorb folate from breast milk or formula and thus rapidly become folate deficient. Low serum and CSF folate concentrations are documented prior to the onset of clinical signs within one month after birth. One infant presented with pancytopenia (macrocytic) and pneumonia at age one month [Tan et al 2017].

Anemia. Folate deficiency results primarily in megaloblastic anemia but often affects all three hematopoietic lineages. The anemia may be severe, but with rapid diagnosis and folate repletion, transfusion is rarely necessary. Hematopoiesis is initiated within a few days after intramuscular administration of folate.

Thrombocytopenia. At least 30% of affected individuals present with thrombocytopenia usually within the context of pancytopenia, but bleeding complications have not been reported.

Immunodeficiency. Hypoimmunoglobulinemia results in pulmonary infections with Pneumocystis jirovecii (pneumonia), cytomegalovirus, and other pathogens. Overall, ~25% of reported individuals have documented hypogammaglobulinemia. The incidence is likely to be much higher since many reports of individuals with pneumonia and other infections did not include information on immunoglobulin concentrations. The immune deficiency may be associated with T and B cell abnormalities. Infants with HFM may die of infections in early infancy prior to diagnosis. The immunologic defects are reversed rapidly when systemic folate sufficiency is restored [Kishimoto et al 2014, Erlacher et al 2015, Zhao et al 2017, Miyashita et al 2020, Sarhan et al 2022].

Neurologic manifestations. Subtle developmental delays are often present when the disorder is diagnosed early in infancy (within a few months). As the disease progresses without treatment or with inadequate treatment, neurocognitive complications develop in the majority of individuals. These can include progressive developmental delays, movement disorders, peripheral neuropathy, and behavioral and cognitive impairments. In approximately 40% of individuals, seizures typically begin at age six to 12 months, although they can occur earlier, and can become intractable when treatment is delayed. Rapid diagnosis and treatment can prevent or mitigate the seizures and improve the neurologic and developmental status. It is unclear why some individuals do not have neurologic manifestations, as all affected individuals have very low CSF folate concentrations [Geller et al 2002, Zhao et al 2017, Lubout et al 2020]. Phenytoin and valproic acid should be avoided for seizure control due to their effects on folate intestinal absorption and metabolism, respectively.

Radiograph, CT, or MRI of the head. Intracranial calcifications, particularly involving the basal ganglia, are common [Ahmad et al 2015, Wang et al 2015, Aluri et al 2018, Gowda et al 2021]. On MRI there is hypomyelination along with cerebral and cerebellar atrophy [Erlacher et al 2015, Gowda et al 2021, Huddar et al 2021, Kumar et al 2022].

Genotype-Phenotype Correlations

Because of the rarity of HFM, genotype-phenotype correlations have not yet been established. Anecdotally, a completely benign clinical phenotype was seen in an individual (now age 45 years) with homozygous SLC46A1 variants resulting in a stop codon and the complete absence of the proton-coupled folate transporter (PCFT) protein who was treated from early in infancy with low-dose intramuscular 5-formyl-tetrahydrofolate (5-formylTHF) (see Pregnancy Management).

Prevalence

Fifty families with one or more individuals with HFM have been reported, all but five with molecular confirmation. Another six affected individuals are known to the author [Zhao et al 2017, Aluri et al 2018]. Prevalence is likely to be much greater than reflected in clinical reports to date, as infants with HFM may die undiagnosed, particularly in populations with a high rate of consanguinity and limited access to health care.

Three carriers of the common Puerto Rican c.1082-1G>A pathogenic variant were detected in a random screen of 1,582 newborns in selected provinces in Puerto Rico [Mahadeo et al 2011].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in a child diagnosed with HFM, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

Agents/Circumstances to Avoid

If possible, folic acid should be avoided as a treatment for HFM. Although folic acid is very stable and inexpensive, and is the most common pharmacologic source of folate, it is not a physiologic folate. Folic acid binds very tightly to folate receptors, which transport the physiologic folate, 5-methylTHF, into cells by an endocytic mechanism [Kamen & Smith 2004]. Thus, folic acid may interfere with the interaction between 5-methylTHF and folate receptors required for 5-methylTHF transport across the choroid plexus into the CSF [Grapp et al 2013, Zhao et al 2017].

Phenytoin and valproic acid should be avoided due to their effects on folate intestinal absorption and metabolism, respectively.

Evaluation of Relatives at Risk

It is appropriate to evaluate newborn sibs and apparently asymptomatic younger sibs of a proband to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Early treatment will prevent or fully reverse the hematologic, immunologic, and gastrointestinal complications of HFM. Achievement of adequate CSF folate concentration can prevent or mitigate the neurologic consequences of HFM and optimize the cognitive development of children with this disorder.

Prenatal testing of a fetus at risk. When the SLC46A1 pathogenic variants in the family are known, prenatal testing of fetuses at risk may be performed via amniocentesis or chorionic villus sampling to allow for institution of 5-formylTHF treatment at birth.

Newborn sibs and apparently asymptomatic younger sibs

• If the pathogenic variants in the family are known, molecular genetic testing of younger at-risk sibs who have not undergone prenatal testing should be performed immediately after birth. Those with biallelic SLC46A1 pathogenic variants should be treated with 5-formylTHF immediately.
• If the pathogenic variants in the family are not known and genetic testing is not possible, measurement of serum and CSF folate concentrations and intestinal absorption of folate 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

There is no systematic information on the outcome of pregnancy in women with HFM.

Although PCFT is highly expressed in the placenta [Qiu et al 2006], a woman with SLC46A1 homozygous nonsense variants that resulted in the complete absence of the PCFT protein had two normal pregnancies and delivered two healthy infants. The affected woman's intramuscular 5-formylTHF dose was increased when pregnancy was planned [Poncz et al 1981; Poncz & Cohen 1996; Min et al 2008; M Poncz, personal communication].

Women with HFM who wish to become pregnant should be certain to be on their maintenance 5-formylTHF dose well in advance of attempting to conceive. Prenatal vitamins are available containing 5-methylTHF rather than folic acid.

Note: Infants of mothers with HFM do not appear to be at an increased risk for malformations (e.g., neural tube defects) typically associated with maternal folate deficiency during pregnancy, assuming that maternal folate intake is adequate well before attempting conception.

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

Hereditary folate malabsorption (HFM) 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 SLC46A1 pathogenic variant.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an SLC46A1 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, the following possibilities should be considered:
  • 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].
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and do not have clinically apparent evidence of folate deficiency. It is unclear at this time whether heterozygotes may have a mild decrease in serum folate and hemoglobin or whether manifestations might arise if there is concurrent mild dietary folate deficiency or intestinal malabsorption.

Sibs of a proband

• If both parents are known to be heterozygous for an SLC46A1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial SLC46A1 pathogenic variants.
• Heterozygotes (carriers) are asymptomatic and do not have clinically apparent evidence of folate deficiency. It is unclear at this time whether heterozygotes may have a mild decrease in serum folate and hemoglobin or whether manifestations might arise if there is concurrent mild dietary folate deficiency or intestinal malabsorption.

Offspring of a proband. Unless an affected individual's reproductive partner also has HFM or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in SLC46A1.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an SLC46A1 pathogenic variant.

Carrier Detection

Carrier testing of at-risk relatives requires prior identification of the SLC46A1 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

• Females with HFM who wish to become pregnant should be certain to continue their maintenance 5-formyltetrahydrofolate (5-formylTHF) intake well in advance of attempting to conceive. A woman with biallelic SLC46A1 pathogenic variants who was treated with intramuscular folate soon after birth had no discernable clinical phenotype, had two normal pregnancies, and delivered two healthy infants (see Pregnancy Management).
• 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.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the SLC46A1 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing for HFM 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 providers would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

SLC46A1 encodes the proton-coupled folate transporter (PCFT) protein, a member of the superfamily of solute carriers. PCFT is highly expressed at the apical membrane of the proximal jejunum and duodenum and is required for intestinal folate absorption. PCFT and folate receptor alpha are expressed in the choroid plexus, and both are required for transport of folates into the cerebrospinal fluid (CSF) [Qiu et al 2006, Zhao et al 2011, Grapp et al 2012, Grapp et al 2013, Visentin et al 2014, Zhao et al 2017].

Hydropathy analysis by the substituted cysteine accessibility model predicted a protein with twelve transmembrane domains [Qiu et al 2006, Qiu et al 2007, Zhao et al 2010, Duddempudi et al 2013, Date et al 2016], now confirmed by a cryo-electron microscopy structure of mammalian PCFT [Parker et al 2021]. PCFT has high affinity for folic acid, reduced folates, and anti-folates and has a low pH optimum [Qiu et al 2006, Zhao et al 2017].

Single-nucleotide variants within transmembrane domains, causing amino acid substitutions, result in unstable proteins, proteins with markedly impaired function, or complete loss of protein. Some of the mutated proteins traffic to the cell membrane and some do not. Three mutated isoforms had residual transport activity upon transfection into HeLa cells null for constitutive folate-specific transporters [Mahadeo et al 2010, Zhao et al 2017, Aluri et al 2018]. Pathogenic variants identified in individuals with hereditary folate malabsorption (HFM) have informed understanding of the relationship between the structure and function of PCFT. For instance, variant c.1233C>G (p.Asn411Lys) is located in the external gate that controls entry of folates into the transport channel [Aluri et al 2018]. The c.1174T>G (p.Phe392Val) variant affects a residue required for the flow of folates into and through the transport channel [Zhan et al 2020, Nandigrami et al 2025].

Mechanism of disease causation. Loss of transport function

SLC46A1-specific laboratory technical considerations. One reported variant was a deep intron 3 single-nucleotide variant (c.1166-284T>G) that generated a cryptic splice donor site resulting in a 168-bp insertion [Kishimoto et al 2014, Tozawa et al 2019, Sakurai et al 2022]. A variant found in individuals with HFM of Puerto Rican ancestry occurs at the splice acceptor site of intron 2, resulting in the deletion of exon 3 (c.1082-1G>A) [Mahadeo et al 2011, Zhao et al 2017]. Sequencing methodologies that can detect such variants should be considered.

Author History

Ndeye Diop-Bove, PhD; Albert Einstein College of Medicine (2010-2017)
I David Goldman, MD (2008-present)
David Kronn, MD; New York Medical College (2008-2022)
Kris M Mahadeo, MD, MPH; Albert Einstein College of Medicine (2010-2011)
Sang Hee Min, MD; Albert Einstein College of Medicine (2008-2011)
Claudio Sandoval, MD; New York Medical College (2008-2010)

Revision History

• 25 March 2026 (sw) Comprehensive update posted live
• 5 May 2022 (sw) Comprehensive update posted live
• 27 April 2017 (ma) Comprehensive update posted live
• 5 June 2014 (me) Comprehensive update posted live
• 8 December 2011 (me) Comprehensive update posted live
• 6 May 2010 (me) Comprehensive update posted live
• 17 June 2008 (me) Review posted live
• 4 March 2008 (idg) Initial submission

Literature Cited

• Ahmad I, Mukhtar G, Iqbal J, Ali S W. Hereditary folate malabsorption with extensive intracranial calcification. Indian Pediatr. 2015;52:67-8. [PubMed: 25638192]
• Aluri S, Zhao R, Lubout C, Goorden, SMI, Fiser A, Goldman ID. Hereditary folate malabsorption due to a mutation in the external gate of the proton-coupled folate transporter-SLC46A1. Blood Adv. 2018;2:61-8. [PMC free article: PMC5761628] [PubMed: 29344585]
• Date SS, Chen CS, Chen Y, Jansen M. Experimentally optimized threading structure of the proton-coupled folate transporter. FEBS Open Bio. 2016;6:216-30. [PMC free article: PMC4794783] [PubMed: 27047750]
• Duddempudi PK, Goyal R, Date SS, Jansen M. Delineating the extracellular water-accessible surface of the proton-coupled folate transporter. PLoS One. 2013;8:e78301. [PMC free article: PMC3799626] [PubMed: 24205192]
• Erlacher M, Grunert SC, Cseh A, Steinfeld R, Salzer U, Lausch E, Nosswitz U, Duckers G, Niehues T, Ehl S, Niemeyer CM, Speckmann C. Reversible pancytopenia and immunodeficiency in a patient with hereditary folate malabsorption. Pediatr Blood Cancer. 2015;62:1091-4. [PubMed: 25504888]
• Froese DS, Gravel RA. Genetic disorders of vitamin B12 metabolism: eight complementation groups--eight genes. Expert Rev Mol Med.2010;12:e37. [PMC free article: PMC2995210] [PubMed: 21114891]
• Geller J, Kronn D, Jayabose S, Sandoval C. Hereditary folate malabsorption: family report and review of the literature. Medicine (Baltimore). 2002;81:51-68. [PubMed: 11807405]
• Gök V, Erdem Ş, Haliloğlu Y, Bişgin A, Belkaya S, Başaran KE, Canatan MF, Özcan A, Yılmaz E, Acıpayam C, Karakükcü M, Canatan H, Per H, Patıroğlu T, Eken A, Ünal E. Immunodeficiency associated with a novel functionally defective variant of SLC19A1 benefits from folinic acid treatment. Genes Immun. 2023;24:12-20. [PubMed: 36517554]
• Gowda VK, Battina M, Shivappa SK, Benakappa N. Treatable cause of pancytopenia, recurrent infections and refractory epilepsy: secondary to hereditary folate malabsorption (HFM) due to novel pathogenic variant. Indian J Pediatr. 2021;88:586-8. [PubMed: 33146883]
• Grapp M, Just IA, Linnankivi T, Wolf P, Lucke T, Hausler M, Gartner J, Steinfeld R. Molecular characterization of folate receptor 1 mutations delineates cerebral folate transport deficiency. Brain. 2012;135:2022-31. [PubMed: 22586289]
• Grapp M, Wrede A, Schweizer M, Huwel S, Galla HJ, Snaidero N, Simons M, Buckers J, Low PS, Urlaub H, Gartner J, Steinfeld R. Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma. Nat Commun. 2013;4:2123. [PubMed: 23828504]
• Hilton JF, Christensen KE, Watkins D, Raby BA, Yannick R, de la Luna S, Estivill X, MacKenzie RE, Hudson TJ, Rosenblatt DS. The molecular basis of glutamate formiminotransferase deficiency. Hum Mutat. 2003;22:67-73. [PubMed: 12815595]
• Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389-97. [PMC free article: PMC9314484] [PubMed: 35834113]
• Huddar A, Chiplunkar S, Nagappa M, Govindaraj P, Sinha S, Taly AB, Sankaran BP. Child neurology: hereditary folate malabsorption. Neurology. 2021;97:40-3. [PubMed: 33893200]
• Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519-22. [PubMed: 28959963]
• Kamen BA, Smith AK. A review of folate receptor alpha cycling and 5-methyltetrahydrofolate accumulation with an emphasis on cell models in vitro. Adv Drug Deliv Rev. 2004;56:1085-97. [PubMed: 15094208]
• Kishimoto K, Kobayashi R, Sano H, Suzuki D, Maruoka H, Yasuda K, Chida N, Yamada M, Kobayashi K. Impact of folate therapy on combined immunodeficiency secondary to hereditary folate malabsorption. Clin Immunol. 2014;153:17-22. [PubMed: 24691418]
• Kobayashi R, Kishimoto K, Sano H, Hori D, Kobayashi K. Long follow-up of hereditary folate malabsorption using intravenous folinate. Pediatr Int. 2022;64:e14667. [PubMed: 34529878]
• Kumar M, Yoganathan S, Todari S, Suresh P, Chandran M, Danda S, Mathew LG, Koshy B, Thomas M. Hereditary folate malabsorption: a rare treatable disorder with hematological and neurological manifestations. Ann Indian Acad Neurol. 2022;25:1238-41. [PMC free article: PMC9996535] [PubMed: 36911455]
• Lubout CMA, Goorden SMI, van den Hurk K, Jaeger B, Jager NGL, van Koningsbruggen S, Chegary M, van Karnebeek CDM. Successful treatment of hereditary folate malabsorption with intramuscular folinic acid. Pediatr Neurol. 2020;102:62-6. [PubMed: 31371121]
• Mahadeo K, Diop-Bove N, Shin D, Unal E, Teo J, Zhao R, Chang MH, Fulterer A, Romero MF, Goldman ID. Properties of the Arg376 residue of the proton-coupled folate transporter (PCFT-SLC46A1) and a glutamine mutant causing hereditary folate malabsorption. Am J Physiol Cell Physiol. 2010;299:C1153-61. [PMC free article: PMC2980313] [PubMed: 20686069]
• Mahadeo KM, Diop-Bove N, Ramirez SI, Cadilla CL, Rivera E, Martin M, Lerner NB, DiAntonio L, Duva S, Santiago-Borrero PJ, Goldman I D. Prevalence of a loss-of-function mutation in the proton-coupled folate transporter gene (PCFT-SLC46A1) causing hereditary folate malabsorption in Puerto Rico. J Pediatr. 2011;159:623-7.e1. [PMC free article: PMC3935241] [PubMed: 21489556]
• Malatack JJ, Moran MM, Moughan B. Isolated congenital malabsorption of folic acid in a male infant: insights into treatment and mechanism of defect. Pediatrics. 1999;104:1133-7. [PubMed: 10545560]
• Manea E, Gissen P, Pope S, Heales SJ, Batzios S. Role of intramuscular levofolinate administration in the treatment of hereditary folate malabsorption: report of three cases. JIMD Rep. 2018;39:7-12. [PMC free article: PMC5953899] [PubMed: 28685492]
• Min SH, Oh SY, Karp GI, Poncz M, Zhao R, Goldman ID. The clinical course and genetic defect in the PCFT in a 27-year-old woman with hereditary folate malabsorption. J Pediatr. 2008;153:435-7. [PMC free article: PMC3835188] [PubMed: 18718264]
• Miyashita N, Kurosawa H, Yamashita Y, Miki Y, Ishida T Pulmonary hypertension related to hereditary folate malabsorption in an infant. Pediatr Int. 2020;62:1119-1120. [PubMed: 32893915]
• Nandigrami P, Goldman ID, Fiser A. Mechanistic insights into mutation in the proton-coupled folate transporter (SLC46A1) causing hereditary folate malabsorption. J Biol Chem. 2025;301:108280. [PMC free article: PMC11929075] [PubMed: 39924111]
• Parker JL, Deme JC, Kuteyi G, Wu Z, Huo J, Goldman ID, Owens RJ, Biggin PC, Lea SM, Newstead S. Structural basis of antifolate recognition and transport by PCFT. Nature. 2021;595:130-4. [PMC free article: PMC9990147] [PubMed: 34040256]
• Pérez-Dueñas B, Ormazabal A, Toma C, Torrico B, Cormand B, Serrano M, Sierra C, De GE, Marfa MP, Garcia-Cazorla A, Campistol J, Pascual JM, Artuch R. Cerebral folate deficiency syndromes in childhood: clinical, analytical, and etiologic aspects. Arch Neurol. 2011;68:615-21. [PubMed: 21555636]
• Poncz M, Cohen A. Long-term treatment of congenital folate malabsorption. J Pediatr. 1996;129:948. [PubMed: 8969750]
• Poncz M, Colman N, Herbert V, Schwartz E, Cohen AR. Therapy of congenital folate malabsorption. J Pediatr. 1981;98:76-9. [PubMed: 6969796]
• Pope S, Artuch R, Heales S, Rahman S. Cerebral folate deficiency: analytical tests and differential diagnosis. J Inherit Metab Dis. 2019;42:655-72. [PubMed: 30916789]
• Qiu A, Jansen M, Sakaris A, Min SH, Chattopadhyay S, Tsai E, Sandoval C, Zhao R, Akabas MH, Goldman ID. Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell. 2006;127:917-28. [PubMed: 17129779]
• Qiu A, Min SH, Jansen M, Malhotra U, Tsai E, Cabelof DC, Matherly LH, Zhao R, Akabas MH, Goldman ID. Rodent intestinal folate transporters (SLC46A1): secondary structure, functional properties, and response to dietary folate restriction. Am J Physiol Cell Physiol. 2007;293:C1669-C1678. [PubMed: 17898134]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Sakurai Y, Toriumi N, Sarashina T, Ishioka T, Nagata M, Kobayashi H, Azuma H. An infantile case of hereditary folate malabsorption with sudden development of pulmonary hemorrhage: a case report. J Med Case Rep. 2022;16:268. [PMC free article: PMC9245286] [PubMed: 35773682]
• Sarhan FMA, Jobran AWM, Mansour IIA, Dukmak ON, Rashed MAM, Hamdan DMA, Abdalhadi IAA. Hereditary Folate Malabsorption presenting as neutropenic fever in a newborn from the first Palestinian family with the novel SLC46A1-mutation, a case report. Ann Med Surg (Lond). 2022;80:104253. [PMC free article: PMC9422282] [PubMed: 36045837]
• Shiraishi A, Uygun V, Sharfe N, Beldar S, Sun MGF, Dadi H, Vong L, Maxson M, Karaca NE, Mevlitoğlu S, Grinstein S, Artan R, Merico D, Roifman CM. Novel immunodeficiency caused by homozygous mutation in solute carrier family 19 member 1, which encodes the reduced folate carrier. Blood. 2023;141:3226-30. [PubMed: 36745868]
• Steinfeld R, Grapp M, Kraetzner R, Dreha-Kulaczewski S, Helms G, Dechent P, Wevers R, Grosso S, Gartner J. Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism. Am J Hum Genet. 2009;85:354-63. [PMC free article: PMC2771535] [PubMed: 19732866]
• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197-207. [PMC free article: PMC7497289] [PubMed: 32596782]
• Svaton M, Skvarova Kramarzova K, Kanderova V, Mancikova A, Smisek P, Jesina P, Krijt J, Stiburkova B, Dobrovolny R, Sokolova J, Bakardjieva-Mihaylova V, Vodickova E, Rackova M, Stuchly J, Kalina T, Stary J, Trka J, Fronkova E, Kozich V. A homozygous deletion in the SLC19A1 gene as a cause of folate-dependent recurrent megaloblastic anemia. Blood. 2020;135:2427-31. [PMC free article: PMC7330012] [PubMed: 32276275]
• Tan J, Li X, Guo Y, Xie L, Wang J, Ma J, Jiang L. Hereditary folate malabsorption with a novel mutation on SLC46A1: a case report. Medicine (Baltimore). 2017;96:e8712. [PMC free article: PMC5815676] [PubMed: 29390264]
• Torres A, Newton SA, Crompton B, Borzutzky A, Neufeld EJ, Notarangelo L, Berry GT. CSF 5-methyltetrahydrofolate serial monitoring to guide treatment of congenital folate malabsorption due to proton-coupled folate transporter (PCFT) deficiency. JIMD Rep. 2015;24:91-6. [PMC free article: PMC4582027] [PubMed: 26006721]
• Tozawa Y, Abdrabou SSMA, Nogawa-Chida N, Nishiuchi R, Ishida T, Suzuki Y, Sano H, Kobayashi R, Kishimoto K, Ohara O, Imai K, Naruto T, Kobayashi K, Ariga T, Yamada M. A deep intronic mutation of c.1166-285 T > G in SLC46A1 is shared by four unrelated Japanese patients with hereditary folate malabsorption (HFM). Clin Immunol. 2019;208:108256. [PubMed: 31494288]
• Verbeek MM, Blom AM, Wevers RA, Lagerwerf AJ, van de Geer J, Willemsen MA. Technical and biochemical factors affecting cerebrospinal fluid 5-MTHF, biopterin and neopterin concentrations. Mol Genet Metab. 2008;95:127-32. [PubMed: 18722797]
• Visentin M, Diop-Bove N, Zhao R, Goldman ID. The intestinal absorption of folates. Annu Rev Physiol. 2014;76:251-74. [PMC free article: PMC3982215] [PubMed: 24512081]
• Wang Q, Li X, Ding Y, Liu Y, Qin Y, Yang Y. The first chinese case report of hereditary folate malabsorption with a novel mutation on SLC46A1. Brain Dev. 2015;37:163-7. [PubMed: 24534056]
• Zhan HQ, Najmi M, Lin K, Aluri S, Fiser A, Goldman ID, Zhao R. A proton-coupled folate transporter mutation causing hereditary folate malabsorption locks the protein in an inward-open conformation. J Biol Chem. 2020;295:15650-15661. [PMC free article: PMC7667981] [PubMed: 32893190]
• Zhao R, Aluri S, Goldman ID. The proton-coupled folate transporter (PCFT-SLC46A1) and the syndrome of systemic and cerebral folate deficiency of infancy: hereditary folate malabsorption. Mol Aspects Med. 2017;53:57-72. [PMC free article: PMC5253092] [PubMed: 27664775]
• Zhao R, Diop-Bove N, Visentin M, Goldman ID. Mechanisms of membrane transport of folates into cells and across epithelia. Annu Rev Nutr. 2011;31:177-201. [PMC free article: PMC3885234] [PubMed: 21568705]
• Zhao R, Unal ES, Shin DS, Goldman ID. Membrane topological analysis of the proton-coupled folate transporter (PCFT-SLC46A1) by the substituted cysteine accessibility method. Biochemistry. 2010;49:2925-31. [PMC free article: PMC2866095] [PubMed: 20225891]