Hereditary Folate Malabsorption: A Genetic Disorder

January 10, 2026 •

3 min read

Hereditary Folate Malabsorption (HFM) is a rare genetic disorder, with only about 60 cases reported worldwide, that prevents the body from properly absorbing and transporting folate. This inherited condition manifests early in life and is distinctly different from folate deficiency caused by a poor diet.

Quick Summary

This article explains Hereditary Folate Malabsorption (HFM), the rare genetic disorder caused by a mutation in the SLC46A1 gene, detailing its symptoms, diagnostic methods, and parenteral treatments to manage the resulting systemic and central nervous system folate deficiency.

Key Points

Genetic Disorder: Hereditary Folate Malabsorption (HFM) is an autosomal recessive condition caused by mutations in the SLC46A1 gene.
Impaired Absorption and Transport: The condition impairs both intestinal absorption of folate and its transport into the central nervous system (CSF).
Characteristic Symptoms: Initial signs in infants often include poor feeding, diarrhea, and megaloblastic anemia, along with potential neurological and developmental delays.
Treatment Approach: Treatment involves high-dose, parenteral (intramuscular) or oral administration of folinic acid to bypass the malabsorption defect.
Avoid Folic Acid: Conventional folic acid should be avoided as a treatment for HFM, as it can worsen neurological outcomes by competing with physiologic folates.
Criticality of Early Intervention: Early diagnosis and management are vital to prevent irreversible neurological damage and optimize developmental outcomes.

Understanding Hereditary Folate Malabsorption (HFM)

Hereditary Folate Malabsorption (HFM) is an autosomal recessive disorder caused by mutations in the SLC46A1 gene. This gene provides the blueprint for creating the proton-coupled folate transporter (PCFT), a protein crucial for transporting folate into cells. PCFT is primarily active in the small intestine, where it helps absorb dietary folate, and in the brain, facilitating folate transport across the blood-cerebrospinal fluid (CSF) barrier. When a mutation occurs, the PCFT protein may have reduced or no function, leading to impaired folate uptake and a subsequent deficiency that affects multiple bodily systems.

The Role of Folate in the Body

Folate, or vitamin B9, is a water-soluble vitamin essential for many fundamental biological processes. It is a critical component for the synthesis of DNA and RNA, which are necessary for cell growth, division, and repair. Folate also plays a vital role in red blood cell formation and works alongside vitamin B12 in various metabolic pathways. A deficiency disrupts these processes, with the most common and visible effect being megaloblastic anemia, where red blood cells are abnormally large and fewer in number.

Genetic Basis of HFM

HFM is inherited in an autosomal recessive pattern. This means an infant must inherit a copy of the mutated SLC46A1 gene from each parent to develop the disorder. Parents who carry one copy of the mutated gene are typically asymptomatic, but each of their children has a 25% chance of inheriting the disorder and a 50% chance of being a carrier. The rarity of this condition means that many cases go undiagnosed, especially in regions with limited access to advanced medical care.

Symptoms and Clinical Manifestations

Symptoms of HFM typically begin within the first few months of life, as the infant's folate stores from their mother deplete. The presentation can vary but often includes:

Gastrointestinal Issues: Poor feeding, diarrhea, and irritation or swelling of the mouth (oral mucositis).
Hematological Problems: Megaloblastic anemia, leukopenia (low white blood cells, increasing risk of infection), and thrombocytopenia (low platelets, causing easy bruising).
Neurological Complications: Developmental delays, cognitive impairments, seizures, motor disorders, and intellectual disabilities.
Growth Issues: Failure to thrive, where an infant does not gain weight and grow at the expected rate.

In severe cases, infants may die from infections, such as Pneumocystis jirovecii pneumonia, before a diagnosis is made. Intracranial calcifications, particularly in the basal ganglia, can also occur. Early diagnosis and treatment are crucial to preventing or mitigating these serious neurological consequences.

Differential Diagnosis and Treatment

Correctly diagnosing HFM requires distinguishing it from other conditions that can cause similar symptoms.


Feature	Hereditary Folate Malabsorption (HFM)	Cerebral Folate Deficiency (CFD)	Folate Deficiency Anemia (Dietary)
Cause	Genetic mutation in SLC46A1 gene affecting folate absorption and transport	Gene mutation (FOLR1) affecting folate transport into the CSF; systemic levels are normal	Insufficient dietary intake of folate
Presentation	Symptoms typically begin a few months after birth	Neurological symptoms usually appear around age 2-3	Any age, depending on dietary habits and other risk factors
Key Lab Finding	Very low serum and CSF folate levels	Normal serum folate levels, very low CSF folate levels	Low serum folate levels; normal CSF folate
Treatment	Parenteral or high-dose oral 5-formyltetrahydrofolate (folinic acid)	Targeted folate transport therapy, often involving folinic acid	Oral folic acid supplements and dietary changes
Distinguishing Factor	Both absorption and transport impaired	Only CSF transport impaired, not systemic absorption	Lack of intake, not inability to absorb

Treatment for HFM involves bypassing the absorption defect by administering high doses of a reduced, more active form of folate, such as 5-formyltetrahydrofolate (folinic acid), either intramuscularly or orally. Folic acid should be avoided, as it may interfere with folate transport. Regular monitoring of serum and CSF folate levels, complete blood counts, and neurological function is necessary to assess the effectiveness of the treatment. Early and consistent management can reverse the hematological and gastrointestinal symptoms and significantly mitigate the neurological damage.

Conclusion

The inability to absorb folic acid, especially from infancy, is most accurately described as Hereditary Folate Malabsorption (HFM). This rare genetic disorder, caused by mutations in the SLC46A1 gene, severely impairs the body's ability to transport folate into its cells, particularly affecting the blood and brain. While it presents with serious symptoms like megaloblastic anemia and severe neurological issues, prompt diagnosis and treatment with high-dose folinic acid can dramatically improve a patient's prognosis. This disorder highlights the critical importance of proper folate metabolism, distinct from dietary deficiency, and the need for specialized medical care in such cases.

Frequently Asked Questions

The primary cause of hereditary folate malabsorption is a mutation in the SLC46A1 gene, which is responsible for creating a protein called the proton-coupled folate transporter (PCFT) needed to absorb and transport folate.

The disorder is inherited in an autosomal recessive pattern, meaning a child must receive one mutated copy of the SLC46A1 gene from each parent to be affected.

Megaloblastic anemia is a blood disorder that often results from folate malabsorption, where the body produces fewer, but abnormally large, red blood cells.

No, dietary changes alone are insufficient to treat HFM because the body cannot effectively absorb folate through the digestive system. Instead, high-dose injections or specialized oral supplements are required.

Regular folic acid is not used because it can interfere with the transport of more active, physiological folates across the blood-brain barrier, potentially worsening neurological symptoms.

Common neurological symptoms include developmental delays, cognitive impairment, seizures, poor motor coordination, and in some cases, intellectual disability.

Diagnosis is made based on clinical signs, blood tests showing megaloblastic anemia and low serum folate, and a crucial lumbar puncture to confirm low cerebrospinal fluid (CSF) folate levels. Genetic testing can confirm the SLC46A1 mutation.