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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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Hereditary Folate Malabsorption

Synonym: Congenital Folate Malabsorption

, PhD, , MD, and , MD.

Author Information
, PhD
Department of Molecular Pharmacology
Albert Einstein College of Medicine
Bronx, New York
, MD
Department of Pediatrics
New York Medical College
Valhalla, New York
, MD
Departments of Medicine and Molecular Pharmacology
Albert Einstein College of Medicine
Bronx, New York

Initial Posting: ; Last Update: June 5, 2014.

Summary

Disease characteristics. Hereditary folate malabsorption (HFM) is characterized by folate deficiency with impaired intestinal folate absorption and impaired folate transport into the central nervous system (CNS). Findings include poor feeding and failure to thrive, anemia often accompanied by leukopenia and/or thrombocytopenia, diarrhea and/or oral mucositis, hypoimmunoglobulinemia, and other immunologic dysfunction resulting in infections with unusual organisms. Neurologic manifestations include developmental delays, cognitive and motor impairment, behavioral disorders and, frequently, seizures.

Diagnosis/testing. Diagnosis of HFM is confirmed by impaired absorption of an oral folate load and low cerebrospinal fluid (CSF) folate concentration (even after correction of the serum folate concentration). SLC46A1, encoding the proton-coupled folate transporter (PCFT) protein, a member of the superfamily of solute carriers, is the only gene known to be associated with HFM. Sequence analysis has identified either homozygous or compound heterozygous pathogenic variants in all clinically affected individuals to date.

Management. Treatment of manifestations: Parenteral (intramuscular) or high-dose oral 5-formyltetrahydrofolate (5-formylTHF, folinic acid, Leucovorin®) can obviate the signs and symptoms 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). Folic acid should not be used for the treatment of HFM because it binds very tightly to the folate receptor, therefore potentially blocking transport of physiologic folates across the choroid plexus.

Prevention of primary manifestations: Early treatment readily corrects the systemic folate deficiency and achieves sufficient CSF folate levels to prevent the neurologic consequences of HFM.

Prevention of secondary complications: 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: periodic complete blood counts; measurements of serum and CSF folate concentrations; measurements of serum and CSF homocysteine concentrations; and monitoring of the affected individual’s neurologic status. Serial measurement of immunoglobulins is not necessary once the levels return to the normal range and serum folate and hemoglobin levels remain normal and stable.

Evaluation of relatives at risk: For at-risk sibs, molecular genetic testing when the family-specific pathogenic variant(s) are known; otherwise, assessment of blood 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 folate intake above the maintenance dose prior to attempting to conceive; infants with HFM do not appear to be at an increased risk for malformations typically associated with maternal folate deficiency during pregnancy.

Genetic counseling. HFM is inherited in an autosomal recessive manner. Heterozygotes (carriers) are asymptomatic and do not have clinical signs of folate deficiency. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. If both pathogenic variants have been identified in the family, carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom testing.

Diagnosis

Suggestive Findings

Hereditary folate malabsorption (HFM) is characterized by folate deficiency with impaired intestinal folate absorption and impaired folate transport into the central nervous system (CNS) [Rosenblatt 2001, Geller et al 2002, Zhao et al 2009, Zhao et al 2014].

HFM typically manifests a few months after birth following depletion of folate stores acquired during gestation. Frequently, diagnosis and/or adequate therapy is considerably delayed. HFM should be considered in infants with the following:

  • Anorexia with poor weight gain and failure to thrive
  • Diarrhea and/or oral mucositis
  • Infections with unusual organisms, such as pneumonia caused by Pneumocystis jirovecii, associated with hypoimmunoglobulinemia
  • Neurologic manifestations including developmental delays, cognitive and behavioral disorders, motor impairment, ataxia, and, frequently, seizures
  • Family history consistent with autosomal recessive inheritance; in particular, a history of sibling deaths in early infancy as a result of infection, anemia, and/or a seizure disorder

Preliminary Tests

The following are consistent with, but not diagnostic of, HFM:

  • Anemia, typically with macrocytic red cell indices and macrocytosis and neutrophil hypersegmentation on peripheral smear, associated with low serum folate
    Note: Normocytic anemia can be seen when there is accompanying poor nutrition and/or iron deficiency.
  • Low erythrocyte folate concentration (average: ~70 ng/mL; normal: >200 ng/mL)
  • Leukopenia
  • Thrombocytopenia, typically mild to moderate but sometimes severe

Bone marrow biopsy confirms the diagnosis of megaloblastic anemia and excludes other causes of anemia. The bone marrow can also show dyserythropoesis.

Establishing the Diagnosis

Diagnosis of HFM is confirmed by the following:

  • Impaired absorption of an oral folate load
  • Low cerebrospinal fluid (CSF) folate concentration (even after correction of the serum folate concentration)
    • Baseline CSF folate concentrations in affected individuals range from 0 to 1.5 nM (in unaffected adults, CSF levels are 2-3 times the normal serum folate concentration or ≥10-45 nM). Normal CSF folate levels are higher in infancy and through adolescence (see Treatment of Manifestations).
    • 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, even at its peak, the CSF folate concentration remains below the serum folate concentration in individuals with HFM, a finding consistent with impaired folate transport across the blood:choroid plexus:CSF barrier [Poncz et al 1981, Corbeel et al 1985, Malatack et al 1999].

Molecular Genetic Testing

Gene. SLC46A1, encoding the proton-coupled folate transporter (PCFT) protein, a member of the superfamily of solute carriers, is the only gene in which pathogenic variants are known to cause HFM [Qiu et al 2006, Zhao et al 2007, Zhao et al 2009, Zhao et al 2011, Zhao & Goldman 2013, Visentin et al 2014].

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Hereditary Folate Malabsorption

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by this Method
SLC46A1Sequence analysis 2100% 3

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants.

2. Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3. Represents individuals from 24 families reported to date [Qiu et al 2006, Zhao et al 2007, Lasry et al 2008, Min et al 2008, Borzutzky et al 2009, Atabay et al 2010, Mahadeo et al 2010, Meyer et al 2010, Shin et al 2010, Mahadeo et al 2011, Shin et al 2011, Diop-Bove et al 2013, Wang et al 2014]. Of these, compound heterozygous pathogenic variants were identified in two individuals [Zhao et al 2007, Shin et al 2011]; all the other variants were homozygous.

Testing Strategy

To confirm the diagnosis in a proband. The diagnosis is primarily established by the findings of:

  • Macrocytic anemia with low serum folate concentration
  • Failure to correct the anemia and serum and CSF folate levels with 1.0-5.0 mg/day of oral folate.

Note: Anemia can be normocytic, particularly if there is concurrent iron deficiency.

Sequence analysis of SLC46A1 has confirmed the diagnosis in all individuals tested to date.

Clinical Description

Natural History

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:CSF barrier resulting in central nervous system (CNS) 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 become folate deficient. Low serum and CSF folate concentrations were documented prior to the onset of clinical symptoms in a one-month old whose older sibling was affected. Clinical manifestations of folate deficiency have been reported as early as age two months. The age at which signs of folate deficiency appear in an infant depends at least in part on the folate stores accumulated in utero.

Anemia. Folate deficiency results primarily in megaloblastic anemia but may affect all three hematopoietic lineages resulting in pancytopenia. The anemia may be severe and require transfusion, although with rapid diagnosis and folate repletion, transfusion should not be necessary. The anemia begins to correct within a few days after parenteral administration of folate (see Treatment of Manifestations).

Immunodeficiency. Immunologic deficiency, which may include profound humoral and cellular immodeficiency that mimics severe combined immune deficiency (SCID), may be the initial manifestation of HFM. Infants with HFM and recurrent infections may die in early infancy, prior to diagnosis.

Leukopenia can be a consequence of untreated severe folate deficiency [Urbach et al 1987, Malatack et al 1999, Zhao et al 2007, Borzutzky et al 2009].

Hypoimmunoglobulinemia not associated with lymphopenia can result in infections with Pneumocystis jiroveccii (pneumonia), C. difficile, and cytomegalovirus (CMV) in affected infants and/or their sibs, who may die in early infancy prior to diagnosis [Corbeel et al 1985, Urbach et al 1987, Malatack et al 1999, Geller et al 2002, Sofer et al 2007, Zhao et al 2007, Shin et al 2011]. In one individual, absent antibody responses and lack of mitogen-induced lymphocyte proliferation occurred in conjunction with hypogammaglobulinemia; with adequate treatment, low serum IgA levels persisted while other immunologic parameters normalized [Borzutzky et al 2009]. Neutrophil dysfunction was observed in one individual [Corbeel et al 1985].

Neurologic signs. In some individuals with HFM, neurologic signs are part of the initial manifestations, whereas in most others, they develop later in the disease course. Neurologic features include developmental delays, cognitive and motor impairment, behavioral abnormalities, ataxia and other movement disorders, peripheral neuropathy, and seizures. It is unclear why some individuals do not have neurologic signs, as all affected individuals have very low CSF folate concentrations [Su 1976, Corbeel et al 1985, Urbach et al 1987, Steinschneider et al 1990, Malatack et al 1999, Geller et al 2002, Sofer et al 2007, Zhao et al 2007, Meyer et al 2010, Shin et al 2011].

X-ray, CT, or MRI of the head. Intracranial calcifications have been reported in individuals with HFM [Lanzkowsky et al 1969, Corbeel et al 1985, Jebnoun et al 2001, Wang et al 2014]. Note: Neural calcifications are also a common finding in children treated with methotrexate [McIntosh et al 1977].

Fertility. Although the proton-coupled folate transporter (PCFT) is highly expressed in the placenta [Qiu et al 2006], in at least one case a woman with complete loss of PCFT function who was taking parenteral leucovorin had two normal pregnancies and delivered normal infants [Min et al 2008; Goldman, personal communication to author] (see Pregnancy Management).

Pathophysiology

The proton-coupled folate transporter (PCFT) protein is highly expressed at the apical brush-border membrane of the proximal jejunum and duodenum and is required for intestinal folate absorption. PCFT and folate receptor-α are expressed in the choroid plexus, and both appear to be required for transport of folates into the CSF [Kamen et al 1991, Qiu et al 2006, Wollack et al 2008, Steinfeld et al 2009, Zhao et al 2009, Zhao et al 2011, Visentin et al 2014].

A PCFT-null mouse which recapitulates the hereditary folate malabsorption syndrome was recently generated [Salojin et al 2011]. Affected pups supplemented with folates develop normally and are fertile [personal communication with author]. Similarly, PCFT-null mice deliver normal pups if the mother is folate sufficient [Salojin et al 2011].

Genotype-Phenotype Correlations

Because of the rarity of HFM, genotype-phenotype correlations have not yet been established.

Prevalence

A clinical diagnosis of HFM has been reported in at least one subject in 32 families to date. Of these, the diagnosis was confirmed by genotyping in 24 families. The diagnosis of HFM has been confirmed by genotyping in another five families [unpublished].

The prevalence of this disorder is likely to be much greater than reflected in clinical reports to date because infants with HFM may die undiagnosed in early infancy. This may be particularly relevant in underdeveloped, medically underserved countries in which consanguinity is common.

The carrier frequency for HFM is unknown.

HFM is pan ethnic. However, there is a common pathogenic variant among individuals of Puerto Rican heritage, c.1082-1G>A. To date, eight families in which at least one individual manifests the disorder have been reported in this population; two additional families of Puerto Rican heritage genotyped by the authors have not as yet been reported. Three carriers were detected in a random screen of 1582 newborns in selected provinces in Puerto Rico [Mahadeo et al 2011].

Differential Diagnosis

The differential diagnosis of hereditary folate malabsorption (HFM) includes the following:

  • Vitamin B12 deficiency, as a cause of megaloblastic anemia
  • Methyltetrahydrofolate reductase deficiency (homozygous)
  • Nutritional folate deficiency as a result of inadequate dietary folate
  • Intestinal disease associated with folate malabsorption
  • Erythroleukemia
  • Severe combined immune deficiency disease (SCID) (see X-Linked SCID)
  • Cerebral folate deficiency caused by mutation of folate receptor-α, resulting in impaired transport across the blood:choroid plexus:CSF barrier. However, individuals with cerebral folate deficiency have normal intestinal folate absorption and normal blood folate, and are not anemic. This disorder is characterized by very low CSF folate concentrations and, unlike HFM, neurologic signs typically appear several years after birth [Steinfeld et al 2009, Grapp et al 2012, Toelle et al 2014].
  • Methionine synthase deficiency with megaloblastic anemia and developmental delays
  • Glutamate formiminotransferase deficiency
  • Pharmacologic: the use of phenytoin for the treatment of seizure disorders
  • Tyrosinemia type 1. Children presenting with gastrointestinal bleeding should be evaluated for tyrosinemia type 1.

Of particular interest in the diagnosis of HFM are the potential differences in the pathways to diagnosis, depending on the presenting signs of the disorder. These may delay definitive diagnosis and initiation of treatment. For example:

  • If the child presents with anemia, the initial diagnosis may be a dietary deficiency for which oral folate is administered. It may take several weeks before the absence of a hematologic response is recognized. Alternatively, the oral folate dose may be sufficiently high to partially, or completely, correct the anemia but CSF folate levels remain very low. Similarly, during the initial evaluation, the child may receive intravenous vitamins resulting in transient correction of the anemia but persistence of the CNS folate deficiency.
  • If the child presents with an infection such as Pneumocystis jirovecii pneumonia, and is found to have hypogammaglobulinemia, the accompanying anemia may be considered secondary and the initial impression may be that of a primary immune deficiency disorder; in particular, severe combined immunodeficiency disease.
  • If the child presents with neurologic manifestations such as developmental delays, cognitive or motor impairment, ataxia, and/or seizures in infancy and early childhood, the initial diagnosis may be a primary neurologic disorder with secondary anemia.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in a child diagnosed with hereditary folate malabsorption (HFM), the following evaluations are recommended:

  • Assessment by a pediatric neurologist to determine baseline neurologic status
  • Baseline (and follow-up) formal cognitive testing
    Note: Appropriate monitoring of neurologic/cognitive response to treatment is essential to ensure that the CSF folate levels achieved are adequate.
  • Initial evaluation and follow-up by a metabolic genetic specialist

Treatment of Manifestations

The goal of treatment is to prevent hematologic, immunologic, and neurologic deficits and to optimize the intellectual development of children with this disorder. Complete reversal of the systemic consequences of folate deficiency is easily achieved. While correction of the neurologic consequences is more difficult, favorable neurologic outcomes are possible when adequate treatment is initiated promptly.

“Folates” refers to a family of B vitamin compounds that are interconvertible in a series of intracellular biochemical reactions. Folate can be effective when administered by oral or parenteral routes; however, much higher oral than parenteral doses are required to correct the systemic folate deficiency. The latter route is probably more effective in achieving CSF folate levels appropriate to the age of the affected individual. In either case, achieving CSF folate levels in the normal range for the age of the affected individual is difficult.

Folate Formulations

Based on the current understanding of folate transport and metabolism, the following two reduced folates can be used to treat HFM:

  • 5-formyltetrahydrofolate (5-formylTHF), also known as folinic acid or Leucovorin®, is a racemic stable form of folate. The active isomer is found in low quantities in normal human tissues. Leucovorin is available in oral and parenteral formulations. There is considerable experience in dosing with this folate form (see Folate Dosing).
  • The active isomer of 5-formylTHF, (6S)5-formylTHF also known as Isovorin® or Fusilev®, is available for parenteral administration. Anecdotal observations suggest that the active isomer may be more effective for treatment when there is refractory neurologic disease. The biologic impact of the active isomer is twice that of the racemic mixture when the dose is the same.
  • The physiologic folate predominant in blood, (6S)5-methyltetrahydrofolate or (6S)5-methylTHF, is now available commercially as Metafolin® and Deplin®. Neither drug is available for parenteral administration. Published information on the use of (6S)5-methylTHF for the treatment of HFM is not available, although the dosing should be comparable to that of (6S)5-formylTHF. The commercially available formulation of Metafolin® is too low to make this agent feasible for the treatment of HFM. Deplin® is available as a 15-mg tablet.

Note: Folic acid should not be used for treatment of HFM. Although folic acid is very stable, 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 block folate receptors required for 5-methylTHF transport across the choroid plexus.

Folate Dosing

Because HFM is rare, controlled studies to establish optimal treatment have not been possible. The dose of 5-formylTHF required to overcome the loss of PCFT-mediated intestinal folate absorption appears to vary from individual to individual. The dose required to obviate the neurologic consequences is much higher than that needed to correct the systemic folate deficiency. The dose should be guided by its effect on trough CSF folate concentrations. The end-point is CSF folate concentrations as close as possible to the normal range for the affected individual’s age (see following).

  • The reported oral dose of 5-formylTHF associated with a “good” outcome is approximately 150-200 mg daily [Geller et al 2002]. Much higher doses have been used as well [personal communication with author]. A reasonable starting oral dose of 5-formylTHF in an infant could be 50 mg or 10-15 mg/kg given daily as a single dose.
    Note: Normal CSF folate is approximately 100 nM for infants to age two years, decreasing to approximately 75 nM by age five years and to approximately 65 nM by age 19 years [Verbeek et al 2008].
  • The parenteral dose required to achieve adequate blood folate levels is much lower than the oral dose. With intramuscular injections of approximately 1.0 mg/day of 5-formylTHF, the anemia will fully correct; however, the endpoint for treatment is based on the CSF folate level, which will require higher folate doses.

Prevention of Primary Manifestations

Infants diagnosed by genetic testing before signs and symptoms appear should be treated as soon as the diagnosis is confirmed to prevent the onset of folate deficiency and the metabolic and clinical consequences of the disorder.

Prevention of Secondary Complications

If transfusion is required, care should be taken to administer blood products that are appropriate given the immunologic status of the patient (e.g., washed packed red blood cells for IgA-deficient patients).

Surveillance

The following should be monitored periodically to assess the adequacy of treatment, particularly following initial diagnosis when treatment is being optimized:

  • Complete blood count
  • Serum and CSF folate concentrations. In particular, monitoring the trough CSF folate concentration is critical to assure that the dose of folate is sufficient to achieve CSF folate concentrations as close as possible to what is normal for the affected individual’s age.
  • Neurologic/cognitive status to ensure that CSF folate levels are adequate
  • Serum and CSF homocysteine concentrations. A high homocysteine concentration is the most sensitive indicator of folate deficiency.
  • Serum immunoglobulin concentrations until they are within the normal range and the hemoglobin and serum folate levels are normal and stable

Evaluation of Relatives at Risk

If the family-specific pathogenic variants are known, molecular genetic testing of younger at-risk siblings who have not undergone prenatal testing should be performed immediately after birth. Those with biallelic SLC46A1 pathogenic variants should be treated with folate immediately.

If the family-specific pathogenic variants are not known and genetic testing is not possible, assess blood and CSF folate levels and, if warranted, intestinal absorption of folate in at-risk siblings 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. In one case, known to the author, a women with a homozygous pathogenic variant in SLC46A1 that resulted in a stop codon with no PCFT protein production had two normal pregnancies and delivered two normal infants [Poncz et al 1981, Poncz & Cohen 1996]. The affected woman’s parenteral 5-formyllTHF dose was increased when a pregnancy was planned.

Women with HFM who wish to become pregnant should increase their folate intake above the maintenance dose well in advance of attempting to conceive.

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.

Therapies Under Investigation

Search ClinicalTrials.gov 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

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 obligate heterozygotes (i.e., carriers of one mutant allele).
  • 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

  • Assuming that both parents carry one SLC46A1 pathogenic variant, at conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. To date, no information on the fertility status of women with HFM who have reached reproductive age or on the possible teratogenicity of folate malabsorption/deficiency and/or its treatment has been published. (See Clinical Description, Pathophysiology; Management, Pregnancy Management).

The offspring of an individual with HFM are obligate heterozygotes (carriers) for a pathogenic variant in SLC46A1.

Other family members of a proband. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing of at-risk relatives requires prior identification of the 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, clarification of carrier status, and discussion of the availability of prenatal 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 is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the pathogenic variants have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variants have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Children Living with Inherited Metabolic Diseases (CLIMB)
    Climb Building
    176 Nantwich Road
    Crewe CW2 6BG
    United Kingdom
    Phone: 0800-652-3181 (toll free); 0845-241-2172
    Fax: 0845-241-2174
    Email: info.svcs@climb.org.uk

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Hereditary Folate Malabsorption: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Hereditary Folate Malabsorption (View All in OMIM)

229050FOLATE MALABSORPTION, HEREDITARY
611672SOLUTE CARRIER FAMILY 46 (FOLATE TRANSPORTER), MEMBER 1; SLC46A1

Molecular Genetic Pathogenesis

Hereditary folate malabsorption (HFM) is caused by loss-of-function mutations in SLC46A1 (PCFT).

Gene structure. SLC46A1 (PCFT) transcript is approximately 6.5 kb (NM_080669.5) and has five exons. Two mRNA forms of 2.7 kb and 2.1 kb have been detected [Qiu et al 2006]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. See Table 2. SLC46A1 pathogenic variants reported to date are distributed in exons 1-4. A common site of mutation is in a G-C rich region of the first exon, which encodes the first extracellular loop separating the first and second transmembrane domains. SLC46A1 pathogenic variants encompass insertions, frame shifts, a stop codon, and a splice variant. Point mutations within transmembrane domains, causing amino acid substitutions, result in proteins with markedly different functional properties.

While most identified pathogenic variants have been novel (i.e., seen in only one family), the c.1082-1G>A homozygous pathogenic variant has been reported in eight apparently unrelated families of Puerto Rican ancestry along with an additional two families of Puerto Rican ancestry not as yet published. This pathogenic variant, located in the splice acceptor of intron 2, causes skipping of exon 3. In cell culture studies, the protein produced was not detectable in the cell membrane, consistent with a trafficking defect [Qiu et al 2006].

Table 2. Selected SLC46A1 Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
c.23dup
(18_23 insC)
p.Glu9GlyfsTer156NM_080669​.5
NP_542400​.2
c.194delGp.Gly65AlafsTer25
c.197_198delGCinsAA
(197GC>AA)
p.Cys66Ter
c.194dupGp.Cys66LeufsTer99
c.204_205delCCp.Asp68LysfsTer96
c.337C>Ap.Arg113Ser
c.337C>Tp.Arg113Cys
c.439G>Cp.Gly147Arg
c.466G>Tp.Asp156Tyr
c.954C>Gp.Ser318Arg
c.1004C>Ap.Ala335Asp
c.1012G>Cp.Gly338Arg
c.1082-1G>Ap.Tyr362_Gly389del 2
c.1126C>Tp.Arg376Trp
c.1127G>Ap.Arg376Gln
c.1274C>Gp.Pro425Arg

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. In-frame deletion resulting from skipping of exon 3 was detected in cDNA from transformed lymphocytes of individuals with HFM [Qiu et al 2006]; the resulting transcript variant is BC01069​.1. The same pathogenic variant has now been identified in a total of ten unrelated families of Puerto Rican ancestry [Qiu et al 2006, Borzutzky et al 2009, Mahadeo et al 2011].

Normal gene product. The proton-coupled folate transporter (PCFT) is predicted to have 459 amino acids with a MW of approximately 50 kd. Hydropathy analysis predicted a protein with twelve transmembrane domains [Qiu et al 2006, Nakai et al 2007, Qiu et al 2007]. This secondary structure has now been confirmed by the substituted cysteine accessibility method [Zhao et al 2010]. PCFT has high affinity for folic acid, reduced folates, and anti-folates and has a low pH optimum [Zhao et al 2009, Zhao et al 2011].

Abnormal gene product. Some of the mutated proteins trafficked to the cell membrane and some did not. In three cases (p.Gly147Arg, p.Pro425Arg, p.Arg376Gln) [Zhao et al 2007, Mahadeo et al 2010], mutant isoforms had residual transport activity upon transfection into HeLa cells null for constitutive folate-specific transporters.

References

Literature Cited

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  2. Borzutzky A, Crompton B, Bergmann AK, Giliani S, Baxi S, Martin M, Neufeld EJ, Notarangelo LD. Reversible severe combined immunodeficiency phenotype secondary to a mutation of the proton-coupled folate transporter. Clin Immunol. 2009;133:287–94. [PMC free article: PMC2783538] [PubMed: 19740703]
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Chapter Notes

Author History

Ndeye Diop-Bove, PhD (2010-present)
I David Goldman, MD (2008-present)
David Kronn, MD (2008-present)
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

  • 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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