Hereditary folate malabsorption is a disorder that interferes with the body's ability to use certain vitamins from food. During digestion, the body cannot take in (absorb) certain B vitamins called folates. Folates are important for cell growth and function and blood cell formation.

Infants with hereditary folate malabsorption are born with normal amounts of folates in their body because they get these vitamins through the placenta before birth. Affected babies generally begin to show signs and symptoms of the disorder within the first few months of life when they cannot use the folates they get from food.

Infants with hereditary folate malabsorption often experience feeding difficulties, diarrhea, and swelling or irritation on the inside of the mouth (oral mucositis). These babies also do not gain weight and grow at the expected rate (failure to thrive). Affected individuals usually develop a blood disorder called megaloblastic anemia. Megaloblastic anemia occurs when a person has a low number of red blood cells (anemia), and the remaining red blood cells are larger than normal (megaloblastic). People with hereditary folate malabsorption may also have fewer white blood cells (leukopenia), making them more susceptible to infections. In addition, some affected individuals have fewer platelets (thrombocytopenia), which means they can bruise easily.

Without treatment, affected individuals may develop neurological problems such as developmental delays, intellectual disabilities, seizures, and difficulty coordinating movements (ataxia). Abnormal deposits of calcium (calcification) in the brain may also occur.

Pregnant people with hereditary folate malabsorption who are receiving treatment for the vitamin deficiency do not appear to have an increased risk of having children with birth defects caused by folate deficiency, such as spina bifida or anencephaly.

Hereditary folate malabsorption is caused by variants (also called mutations) in the SLC46A1 gene. The SLC46A1 gene provides instructions for making a protein called the proton-coupled folate transporter (PCFT). This protein is found within the membrane of cells, where it helps transport folate into the inside the cell. PCFT is primarily found in cells that line the walls of the small intestine. PCFT transports folate that is absorbed from food into cells of the small intestine so it can be used by the body. PCFT is also found in the brain, where it is involved in the transport of folates between the brain and the surrounding fluid (cerebrospinal fluid).

Variants in the SLC46A1 gene result in a PCFT protein that has little or no activity. In some cases, the altered protein is missing from the cell membranes where it is needed to perform its function. Without functional PCFT, cells in the small intestine cannot absorb folates from food and cells in the brain cannot transport folate to the cerebrospinal fluid. These folate deficiencies result in the digestive issues, neurological problems, and other signs and symptoms of hereditary folate malabsorption.

Normal Function

The SLC46A1 gene provides instructions for making a protein called the proton-coupled folate transporter (PCFT). This protein is found within the membrane of cells, where it helps transport certain B vitamins called folates into the cell. PCFT is primarily found in cells that line the walls of the small intestine. These cells have fingerlike projections called microvilli that absorb nutrients from food as it passes through the intestine. Based on their appearance, groups of these microvilli are known collectively as the brush border. PCFT is involved in transporting folates from food across the brush border membrane so they can be used by the body. PCFT is also found in the brain, where it is involved in the transport of folates between the brain and the surrounding fluid (cerebrospinal fluid).

Health Conditions Related to Genetic Changes

Hereditary folate malabsorption

Variants (also called mutations) in the SLC46A1 gene have been identified in people with hereditary folate malabsorption. This disorder interferes with the body's ability to take in (absorb) folates from food. The SLC46A1 gene variants can change single protein building blocks (amino acids) in the PCFT protein, or they can cause the cell to produce a PCFT protein that is shorter than normal. The altered PCFT protein has little or no activity. In some cases, the altered protein is missing from the cell membranes where it is needed to perform its function. Without functional PCFT, cells in the small intestine cannot absorb folates from food and cells in the brain cannot transport folate to the cerebrospinal fluid. These folate deficiencies result in the digestive issues, neurological problems, and other signs and symptoms of hereditary folate malabsorption.

Other Names for This Gene

• HCP1
• heme carrier protein 1
• PCFT
• proton-coupled folate transporter
• solute carrier family 46 (folate transporter), member 1
• solute carrier family 46, member 1

Genomic Location

Infants with hereditary folate malabsorption experience feeding difficulties, diarrhea, and failure to gain weight and grow at the expected rate (failure to thrive). Affected individuals usually develop a blood disorder called megaloblastic anemia. Megaloblastic anemia occurs when a person has a low number of red blood cells (anemia), and the remaining red blood cells are larger than normal (megaloblastic). The symptoms of this blood disorder may include decreased appetite, lack of energy, headaches, pale skin, and tingling or numbness in the hands and feet. People with hereditary folate malabsorption may also have a deficiency of white blood cells (leukopenia), leading to increased susceptibility to infections. In addition, they may have a reduction in the amount of platelets (thrombocytopenia), which can result in easy bruising and abnormal bleeding.

Some infants with hereditary folate malabsorption exhibit neurological problems such as developmental delay and seizures. Over time, untreated individuals may develop intellectual disability and difficulty coordinating movements (ataxia).

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell must have a variant to cause the disorder. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

The prevalence of hereditary folate malabsorption is unknown. About 60 affected individuals have been reported worldwide. Researchers believe this disorder may not be identified or treated in some infants, particularly in areas where advanced medical care is not available.