Hereditary Folate Malabsorption

We’ve all heard of folate and we know that it’s important especially during pregnancy but did you know that Folate Malabsorption can also be hereditary?

Hereditary Folate Malabsorption (HFM) is a genetic disorder relating to a persons impaired ability to absorb ingested folate within the intestine, along with the inability of transporting serum folates across the blood-brain barrier into the central nervous system, specifically the cerebrospinal fluid. HFM is inherited in an autosomal recessive pattern because of a homozygous or compound heterozygous mutation. This means that mutations exist in both copies of the gene, however the parents of an individual with HFM may not show any signs/symptoms of the condition themselves.

The mutation results in skipping exon 3 during mRNA splicing thus creating a loss of function in the human SLC46A1 gene which encodes the Proton-Coupled Folate Transporter (PCFT) on chromosome 17q11.2. The mutation substitutes one amino acid for another or effectively reduces the PCFT protein so that it is shorter than normal. Either way the PCFT protein has little or no activity.

PCFT, a facilitative carrier and mediator, is a vital component in the normal functioning of the intestinal epithelial cells. The microvilli, which are the fingerlike projections from the cell absorb the nutrients from food as it passes through the intestine. Collective groups of microvilli are known as the brush border and it is here that PCFT takes part in active transport, using energy to move specific B vitamins called folates across the brush border membrane for absorption. Furthermore, PCFT also takes part in the transportation of folates between the brain and the fluid that surrounds it (cerebrospinal fluid)

Humans are unable to synthesize folate and are thus required to obtain folate from dietary sources in order to meet their metabolic requirement. Folates are essential for numerous cell functions, including the production of DNA and RNA synthesis. Without it living cells are unable to divide. Folate functions as a coenzyme in single-carbon transfers in the metabolism of nucleotides and amino acids. Women require higher volumes of folate during pregnancy due to the increase in cell turnover (foetal development).

The diagnosis of HFM is usually identified within the first year of life when infants fail to thrive. There are numerous symptoms presented as a result of HFM, including anemia, low serum and cerebrospinal fluid folate levels, recurrent infections, leukopenia and thrombocytopenia, diarrhea and/or oral mucositis and hypoimmunoglobulinemia. A bone marrow biopsy can be conducted to confirm the presence of megaloblastic anemia. Additionally, severe cases where HFM treatment is delayed may result in developmental delays, behavioural disorders, seizures and cognitive impairment.

Folate deficiency is a key indicator of HFM.  The initial test for folate deficiency is assay of serum folate (reference range 7-40 nmol/L*). Furthermore, in order to correctly identify HFM a complete blood count along with the above-mentioned bone marrow analysis is needed. Additional tests to measure serum levels, red blood cells and CSF folate levels can also identify HFM along with molecular genetic testing to detect biallelic pathogenic variants in the SLC46A1 gene.

Signs and symptoms of HFM can be alleviated upon early diagnosis with high oral doses of folate. The oral folates may be in the form of “5-formyltetrahydrofolate (5-formylTHF, folinic acid, Leucovorin®) or the active isomer of 5-formylTHF (Isovorin® or Fusilev®)1”. When folate doses are administered, the treatment must be aimed at achieving folate levels as equivalent to the normal range of the affected individual.

Although the early treatment doses will prevent any neurological, heamatological and gastrointestinal outcomes that occur as a result of HFM, they cannot reverse them. More severe cases may require a blood transfusion and in the instance that HFM is untreated, it can be fatal. Overall, with proper treatment of HFM the prognosis is good and many of the issues present due to the disease are reversed. It is only when HFM is untreated that the prognosis poor.

It is important to note that folic acid should not be used to treat HFM. Folic acid binds firmly to the folate receptor thus impairing the transport of physiological folates across the choroid plexus. Furthermore, pregnant women with HFM should commence increasing their folate intake prior to conception and should increase to levels above the recommended maintenance amounts for optimal results.

To measure the effectiveness of the treatment, regular monitoring is required. Monitoring includes blood counts, measurements of CSF folate concentrations and serum and an assessment of the affected individuals neurological and cognitive functions.

Amanda de Souza
Amanda de Souza

My health and fitness journey began in 2012 and although I am still a work in progress I am learning more every day and want to educate others as much as I can. Follow more great advice from Amanda on Instagram.