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, failure to thrive, and anemia. There can be leukopenia and thrombocytopenia, diarrhea and/or oral mucositis, hypoimmunoglobulinemia, and other immunologic dysfunction resulting in infections, most 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 identified on molecular genetic testing.

Management.

Targeted therapy: Early treatment with intramuscular or high-dose oral 5-formyltetrahydrofolate (5-formylTHF; also known as folinic acid or leucovorin) or, preferably, the active isomer of 5-formylTHF (Isovorin^® or Fusilev^®) readily corrects the systemic folate deficiency and, if the dose is sufficient, can achieve CSF folate levels 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 levels than adults).

Supportive care: Blood transfusion is rarely needed for severe anemia; in affected individuals with selective IgA deficiency, appropriate precautions for blood product transfusion should be taken.

Surveillance: To assess adequacy of treatment, surveillance should include: complete blood counts; measurement of serum and CSF folate concentrations; measurement of CSF homocysteine concentrations; and monitoring of neurologic and cognitive function. Serum immunoglobulins are monitored until they return to the normal range and serum folate level and hemogram remain normal and stable.

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.

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

Pregnancy management: Affected women should increase their 5-formylTHF intake above the maintenance dose well in advance of attempting to conceive; infants with HFM do not appear to be at increased risk for neural malformations typically associated with maternal folate deficiency during pregnancy, but care must be taken to assure that maternal folate intake is increased and 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 being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial SLC46A1 pathogenic variants. If both pathogenic variants have been identified in the family, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing for HFM are possible.

Suggestive Findings

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

Clinical features

• Anorexia with poor weight gain and failure to thrive
• 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, macrocytosis, 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 ~30% of individuals, thrombocytopenia and/or pancytopenia
• Quantitative serum immune globulin levels. In ~25% of individuals, low concentrations of serum IgG, IgM, and IgA [Kishimoto et al 2014, Erlacher et al 2015, Zhao et al 2017, Tozawa et al 2019]
• Erythrocyte and serum folate concentrations
  • Low erythrocyte folate concentration (normal: >200 ng/mL)
  • Very low baseline serum folate concentrations in untreated individuals (typically <1.5 nmol/L). In countries in which grains are folate supplemented, the normal level is 10-45 nmol/L to age 12 years 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 200-3,000 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 level:
    • Baseline CSF folate concentration in untreated affected individuals is typically <1.5 nmol/L.
    • Normal CSF folate levels are higher in infancy and through adolescence (see Treatment of Manifestations).
    • Note: In unaffected adults, normal CSF folate levels are 2-3 times the normal serum folate concentration.
  • Following intramuscular administration of 5 mg of 5-formyltetrahydrofolate (5-formylTHF or leucovorin), the CSF folate concentration peaks transiently at one to two hours and returns to the baseline value within approximately 24 hours. However, the CSF folate concentration remains far below the serum folate concentration in individuals with HFM, 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

Radiographic findings. Frequent intracranial calcifications, particularly involving the basal ganglia, when treatment is delayed or the dose of 5-formylTHF is insufficient to restore adequate CSF folate levels

Establishing the Diagnosis

The diagnosis of HFM is established in a proband:

• With anemia, impaired absorption of an oral folate load, and low serum and CSF folate concentrations (the latter even after correction of the serum folate level);
• By the identification of biallelic pathogenic (or likely pathogenic) variants in SLC46A1 on molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP 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. The anemia begins to correct within a few days after intramuscular administration of folate (see Treatment of Manifestations).

Thrombocytopenia. At least 30% of affected individuals present with thrombocytopenia alone or within the context of pancytopenia, but bleeding complications have not been reported. Leukopenia with anemia in the absence of thrombocytopenia is unusual.

Immunodeficiency. Hypoimmunoglobulinemia results in pulmonary infections with Pneumocystis jirovecii (pneumonia), cytomegalovirus, and other pathogens. Overall, approximately 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 immunoglobulin levels. 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].

Neurologic signs. 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, neurologic complications develop in the majority of individuals. These can include marked 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 neurologic and developmental status. It is unclear why some individuals do not have neurologic signs, as all affected individuals have very low CSF folate concentrations [Geller et al 2002, Zhao et al 2017, Lubout et al 2020].

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].

Genotype-Phenotype Correlations

Because of the rarity of HFM, genotype-phenotype correlations have not as yet been established. Anecdotally, a benign clinical phenotype was seen in an individual (now age 41 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-formylTHF (see Pregnancy Management).

Prevalence

Fifty-three individuals with HFM (44 with genotypic confirmation) have been reported from 45 families. Another six affected individuals are known to the author [Zhao et al 2017, Aluri et al 2018, Tozawa et al 2019, Gowda et al 2021, Huddar et al 2021]. 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 higher 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

The following should be monitored periodically to assess the adequacy of treatment, and more frequently following initial diagnosis when treatment is being optimized.

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]. As indicated above, when the administration of the active (6S) isomer of 5-formylTHF is feasible, it is the preferred form of folate, because unlike the racemic form the entire, versus half, of the dose is effective. Also, the inactive isomer may interfere/compete with transport of the active isomer into cells and its subsequent polyglutamation.

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 levels 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, assessment of serum and CSF folate levels and, if warranted, intestinal absorption of folate in at-risk sibs should commence 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 no PCFT 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 increase their dose of 5-formylTHF intake above the maintenance dose well in advance of attempting to conceive. Prenatal vitamins are available containing 5-methylTHF rather than folic acid.

Of note, infants 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 has been increased 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. Note: At least one fertile woman with biallelic pathogenic variants in SLC46A1 treated with an intramuscular drug soon after birth had no discernable phenotype (see Pregnancy Management).
• 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.

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 being affected, a 50% chance of 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.

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

• Women with HFM who wish to become pregnant should increase their dose of 5-formylTHF intake above the maintenance dose well in advance of attempting to conceive (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 testing. While most centers would consider use of prenatal 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 appear to be required for transport of folates into the 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 trafficked to the cell membrane and some did 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 HFM have informed understanding of the relationship between the structure and function of PCFT. For instance, variant p.Asn411Lys is located in the external gate that controls entry of folates into the transport channel [Aluri et al 2018]. Variant p.Phe392Val affects a residue of the transport protein required for the opening of the external gate to allow folates into the transport channel [Zhan et al 2020].

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]. 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 [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

• 15 February 2024 (cm) Revision: Treatment of Manifestations section revised to include Targeted Therapy Key Section
• 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

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