Hereditary Folate Malabsorption

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2021-01-18
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Summary

Clinical characteristics.

Hereditary folate malabsorption (HFM) is characterized by folate deficiency with 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 jerovicii pneumonia. Neurologic manifestations include developmental delays, cognitive and motor impairment, behavioral disorders and, frequently, seizures.

Diagnosis/testing.

The diagnosis of HFM is established in a proband: with anemia, impaired absorption of an oral folate load, and low cerebrospinal fluid (CSF) folate concentration (even after correction of the serum folate concentration); and/or by the identification of biallelic pathogenic variants in SLC46A1 on molecular genetic testing.

Management.

Treatment of manifestations: Parenteral (intramuscular) or high-dose oral 5-formyltetrahydrofolate (5-formylTHF, folinic acid, Leucovorin®) or the active isomer of 5-formylTHF (Isovorin® or Fusilev®) 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).

Prevention of primary manifestations: Early treatment readily corrects the systemic folate deficiency and can achieve 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.

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 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 neural 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, prenatal diagnosis for a pregnancy at increased risk, and preimplantation genetic testing for HFM are possible.

Diagnosis

Hereditary folate malabsorption (HFM) is characterized by folate deficiency with impaired intestinal folate absorption and impaired folate transport into the central nervous system [Geller et al 2002, Zhao et al 2009, Zhao et al 2014, Zhao et al 2017].

Suggestive Findings

Hereditary folate malabsorption (HFM) should be suspected in infants with the following clinical, family history, supportive laboratory, and bone marrow biopsy 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 impairment, ataxia, and, frequently, seizures

Family history

  • History of sib deaths in early infancy as a result of infection, anemia, and/or a seizure disorder
  • Pedigree analysis consistent with autosomal recessive inheritance

Note: Lack of a family history of other individuals with clinical features of HFM does not preclude the diagnosis.

Supportive laboratory findings

  • Complete blood count
    • 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.
    • In some cases, leukopenia and/or thrombocytopenia – the latter typically mild to moderate but sometimes severe
  • Quantitative serum immunoglobulin levels. Low concentrations of IgG, IgM, and IgA [Zhao et al 2007, Borzutzky et al 2009, Kishimoto et al 2014, Erlacher et al 2015, Zhao et al 2017]
  • Erythrocyte and serum folate concentrations
    • Low erythrocyte folate concentration (average: ~70 ng/mL; normal: >200 ng/mL)
    • Very low baseline serum folate concentrations in untreated individuals (typically <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].
  • Cerebrospinal fluid (CSF) folate concentration
    • Low CSF folate concentration even after correction of the serum folate concentration:
      • Baseline CSF folate concentrations in untreated affected individuals range from 0 to 1.5 nmol/L.
      • Normal CSF folate levels are higher in infancy and through adolescence (see Treatment of Manifestations).
      • In unaffected adults, CSF levels are 2-3 times the normal serum folate concentration or ≥10-45 nmol/L). The levels are much higher in infants and young children.
    • 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 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, Zhao et al 2017].

Bone marrow biopsy

  • Evidence of megaloblastic anemia with exclusion of other causes of anemia
  • Dyserythropoesis variably found

Establishing the Diagnosis

The diagnosis of HFM is established in a proband:

  • With anemia, impaired absorption of an oral folate load, and low cerebrospinal fluid (CSF) folate concentration (even after correction of the serum folate concentration); AND/OR
  • By the identification of biallelic pathogenic variants in SLC46A1 on molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

  • Single-gene testing. Sequence analysis of SLC46A1 is performed first and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
  • A multigene panel that includes SLC46A1 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Molecular Genetic Testing Used in Hereditary Folate Malabsorption

Gene 1MethodProportion of Probands with Pathogenic Variants 2 Detectable by Method
SLC46A1Sequence analysis 3100% 4, 5, 6
1.

See Table A. Genes and Databases for chromosome locus and protein.

2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

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

4.

Represents individuals from 31 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, Kishimoto et al 2014, Erlacher et al 2015, Wang et al 2015, Zhao et al 2017]. Of these, compound heterozygous pathogenic variants were identified in four individuals [Zhao et al 2007, Shin et al 2011, Kishimoto et al 2014, Wang et al 2015] ; all the other variants were homozygous.

5.

There is a common pathogenic variant among individuals of Puerto Rican heritage: c.1082-1G>A.

6.

One variant was a deep intron 3 single-nucleotide variant that generated a cryptic splice donor site resulting in a 168-bp insertion [Kishimoto et al 2014]. Sequencing methodologies that can detect such variants should be considered.

Clinical Characteristics

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: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 become folate deficient. Low serum and CSF folate concentrations were documented prior to the onset of clinical signs in a one-month old whose older sib 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 level of folate stores accumulated in utero.

Anemia. Folate deficiency results primarily in megaloblastic anemia but may affect all three hematopoietic lineages. 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, may accompany the initial manifestations 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 [Malatack et al 1999, Takeda et al 2002, 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 in affected infants and/or their sibs, who may die in early infancy prior to diagnosis [Malatack et al 1999, Geller et al 2002, Sofer et al 2007, Zhao et al 2007, Shin et al 2011, Kishimoto et al 2014, Erlacher et al 2015]. 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].

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, Zhao et al 2017].

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, Ahmad et al 2015, Wang et al 2015]. Note: Neural calcifications are also a common finding in children treated with methotrexate [McIntosh et al 1977].

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 36) with homozygous pathogenic SLC46A1 variants resulting in the complete absence of the PCFT protein, who was treated early in infancy with parenteral 5-formylTHF (see Pregnancy Management).

Prevalence

A clinical diagnosis of HFM has been reported in at least one person in 38 families to date. Of these, the diagnosis was confirmed by molecular genetic testing in 31 families [Zhao et al 2017].

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

HFM is pan ethnic. The carrier frequency for HFM is unknown. Three carriers of the common Puerto Rican c.1082-1G>A pathogenic variant 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.

Nutritional and pharmacologic

  • Vitamin B12 deficiency as a cause of megaloblastic anemia
  • Nutritional folate deficiency as a result of inadequate dietary folate
  • Intestinal disease associated with folate malabsorption
  • The use of phenytoin for the treatment of seizure disorders

Immunologic. X-linked severe combined immunodeficiency, a disorder resulting from hemizygous pathogenic variants in IL2RG

Inborn errors of metabolism

  • Glutamate formiminotransferase deficiency (OMIM 229100), an autosomal recessive disorder resulting from biallelic pathogenic variants in FTCD
  • Methionine synthase deficiency with megaloblastic anemia and developmental delays (see Disorders of Intracellular Cobalamin Metabolism)
  • Mitochondrial disorders. A variety of mitochondrial disorders, such as Kearns-Sayre syndrome, result in low CSF folate [Pérez-Dueñas et al 2011]. However, Kearns-Sayre syndrome has defining signs that distinguish it from HFM and the blood folate level in this and other mitochondrial disorders is normal. There is no evidence that these disorders are caused by a specific defect in a folate transporter. Impaired transport into the CSF may be due to the mitochondrial metabolic defects that impair energy metabolism and, secondarily, choroid plexus transport function

Folate transporter deficiency. Cerebral folate deficiency (OMIM 613068), an autosomal recessive disorder caused by biallelic pathogenic variants in FOLR1, which encodes the folate receptor-α. This condition results from impaired folate 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].

Malignancy. Erythroleukemia

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 recommended to ensure that the CSF folate levels achieved with treatment 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 cognitive 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 B9 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 parenteral 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 challenging [Torres et al 2015].

Folate Formulations

Based on the current understanding of folate transport and metabolism, the following 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 and tissues, (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 formulation of Metafolin® is too low (800 µg) to make this agent feasible for the treatment of HFM. Deplin® is available as a 15-mg tablet.

Note: If possible, folic acid should be avoided as a treatment of HFM (see Agents/Circumstances to Avoid).

Folate Dosing

Because HFM is rare, controlled studies to establish optimal treatment have not been possible. The oral 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:

  • 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 to 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 nmol/L for infants to age two years, decreasing to approximately 75 nmol/L by age five years and to approximately 65 nmol/L 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 much higher folate doses [Torres et al 2015].

Prevention of Primary Manifestations

Infants diagnosed by genetic testing before signs and symptoms appear should be treated immediately 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 affected individual (e.g., washed packed red blood cells for those who have IgA-deficienciency).

Surveillance

The following should be monitored periodically to assess the adequacy of treatment, and more frequently 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

Agents/Circumstances to Avoid

If possible, folic acid should be avoided as a treatment of 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 cerebrospinal fluid [Grapp et al 2013, Zhao et al 2017].

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic younger sibs of a proband in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.

Evaluations can include the following:

  • Molecular genetic testing 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-formyltetrahydrofolate immediately.
  • If the pathogenic variants in the family are not known and genetic testing is not possible, assessment of blood and CSF folate levels and, if warranted, intestinal absorption of folate 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 the proton-coupled folate transporter (PCFT) is highly expressed in the placenta [Qiu et al 2006], a woman with homozygous pathogenic variants in SLC46A1 that resulted in no PCFT protein production had two normal pregnancies and delivered two healthy infants. The affected woman's parenteral 5-formylTHF dose was increased when pregnancy was planned [Poncz et al 1981; Poncz & Cohen 1996; Min et al 2008; Goldman, personal communication to Author].

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.

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.