Clinical Diagnosis

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

HFM typically becomes evident within one or more months after birth following depletion of folate stores acquired during gestation. In some cases, diagnosis and/or adequate therapy has been delayed beyond age one year. HFM should be considered in infants with the following:

• Anorexia with poor weight gain and failure to thrive

• Megaloblastic anemia, often accompanied by leukopenia and/or thrombocytopenia Note: Anemia can be normocytic, particularly if there is concurrent iron deficiency.

• 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 that occur starting in infancy and early childhood

• 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

Testing

Diagnosis of HFM is confirmed by the following:

• Impaired absorption of an oral folate load

  • Baseline serum folate concentrations are very low (often <1.0 ng/mL; normal: 5-15 ng/mL, or as specified by the laboratory).

  • After an oral folate load of 5-formyltetrahydrofolate (5-formylTHF or Leucovorin^®), 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 100 ng/mL [Lanzkowsky et al 1969, Santiago-Borrero et al 1973, Poncz et al 1981, Corbeel et al 1985, Urbach et al 1987, Malatack et al 1999, Geller et al 2002].

• 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: ~100 nM in infants to age 2 years, decreasing to 75 nM by age 5 years and to ~65 nM by age 19 years [Verbeek et al 2008].

  • 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].

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

• Anemia, typically with macrocytic red cell indices and macrocytosis and neutrophil hypersegmentation on peripheral smear
  
  Note: The finding of normocytic anemia, which can be seen when there is poor nutrition and/or iron deficiency, can lead to a delay in establishing the correct diagnosis.

• Leukopenia

• Thrombocytopenia, typically mild to moderate but sometimes severe

• Low serum concentrations of IgG, IgM, and IgA [Corbeel et al 1985, Urbach et al 1987, Malatack et al 1999, Geller et al 2002, Zhao et al 2007, Borzutzky et al 2009]

• Low erythrocyte folate concentration (average: ~70 ng/mL; normal: >200 ng/mL)

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

Molecular Genetic Testing

Gene. SLC46A1, encoding the proton-coupled folate transporter (PCFT) protein, a member of the superfamily of facilitative carriers, is the only gene in which mutation is known to cause HFM [Qiu et al 2006, Zhao et al 2007, Zhao et al 2009, Zhao et al 2011].

Clinical testing

• Sequence analysis. Sequencing of the entire SLC46A1 coding region and exon-intron junctions detected loss-of-function mutations in 22 individuals with a clinical diagnosis of HFM [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]. Of these, compound heterozygous mutations were identified in two individuals [Zhao et al 2007, Shin et al 2011]; the rest were homozygous, although most parents of affected children deny consanguinity. While most identified mutations have been novel (i.e., seen in one family only), the c.1082-1G>A homozygous mutation has been observed in eight apparently unrelated families of Puerto Rican ancestry. Screening of randomly selected newborn blood spots from Villalba, Puerto Rico, identified several carriers of HFM [Mahadeo et al 2011].

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

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
SLC46A1	Sequence analysis	Sequence variants 2	100% 3	Clinical

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. Represents 22 individuals 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]

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

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 and failure to correct the anemia with 1.0-5.0 mg/day of oral 5-formylTHF. Note: Anemia can be normocytic, particularly if there is concurrent iron deficiency.

• Molecular testing (sequence analysis) of SLC46A1 has confirmed the diagnosis in all individuals tested to date.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in SLC46A1.

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 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 manifestation, whereas in 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. In early reports, three individuals with HFM had calcifications in the cortex or basal ganglia [Lanzkowsky et al 1969, Corbeel et al 1985, Jebnoun et al 2001]. 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 delivered a normal infant [Min et al 2008; Goldman, personal communication to author].

Of note, infants with HFM do not have an increased risk of malformations (e.g., neural tube defects) typically associated with maternal folate deficiency during pregnancy.

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].

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].

Genotype-Phenotype Correlations

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

Prevalence

Thirty individuals with a clinical diagnosis of HFM have been reported to date; the prevalence is unknown.

To date, SLC46A1 mutations have been reported in twenty-two individuals with a clinical diagnosis of HFM. The frequency of this disorder is likely to be much greater than reflected in clinical reports because infants with HFM may die undiagnosed in early infancy. This may be particularly important in underdeveloped, medically underserved countries in which consanguinity is common.

The carrier frequency for HFM is unknown.

HFM is pan ethnic.

Evaluations Following Initial Diagnosis

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

• Assessment by a pediatric neurologist to determine baseline neurologic findings and appropriate monitoring of neurologic response to treatment

• Consideration of baseline and follow-up formal cognitive testing

• Initial evaluation and follow-up by a metabolic genetic specialist

Treatment of Manifestations

The goal of treatment is to prevent hematologic, immunologic, and neurologic defects 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 utilized effectively when administered by oral or parenteral routes; however, much higher oral doses than parenteral doses are required to achieve normal CSF folate concentrations in individuals with HFM.

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 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 that are normal for age.

• 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 concentration is stable

Evaluation of Relatives at Risk

If the family-specific disease-causing mutations are known, molecular genetic testing of younger at-risk siblings who have not undergone prenatal testing should be performed immediately after birth. Those with disease-causing mutations affecting both SLC46A1 alleles should be treated with folate.

If the family-specific disease-causing mutations are not known, assess intestinal absorption of folate and CSF folate concentration 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.

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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

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.

Sibs of a proband

• Assuming that each parent carrier has one mutated SLC46A1 (PCFT) allele, 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 Pathophysiology).

The offspring of an individual with HFM are obligate heterozygotes (carriers) for a disease-causing mutation 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 is possible if the disease-causing mutations in the family have been identified.

Heterozygotes do not have hematologic abnormalities or low blood folate concentrations.

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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

No laboratories listed in the GeneTests Laboratory Directory offer molecular genetic testing for prenatal diagnosis of HFM. However, prenatal testing may be available for families in which the disease-causing mutation has been identified. For laboratories offering custom prenatal testing, see .

Prenatal diagnosis of a treatable condition may be controversial if such testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider this to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

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

Normal allelic variants. SLC46A1 (PCFT) transcript is approximately 6.5 kb (NM_080669.3) and has five exons. Two mRNA forms of 2.7 kb and 2.1 kb have been detected [Qiu et al 2006].

Pathologic allelic variants. See Table 2. SLC46A1 mutations 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 mutations encompass insertions, frame shifts, and a stop codon. Point mutations within transmembrane domains result in substitution of amino acids with markedly different properties.

The mutation c.1082-1G>A, 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].

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 antifolates and has a low pH optimum [Zhao et al 2009, Zhao et al 2011].

Abnormal gene product. See Pathologic allelic variants. 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 forms had residual transport activity on transfection into HeLa cells.

Literature Cited

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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

• 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