Hereditary folate malabsorption

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

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 (faltering weight). 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 women 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.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

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.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

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.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

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.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Abnormality of movement · Very frequent (99-80%)

An abnormality of movement with a neurological basis characterized by changes in coordination and speed of voluntary movements.

Abnormality of the immune system · Very frequent (99-80%)

An abnormality of the immune system.

Anorexia · Very frequent (99-80%)

Lack of desire to eat (loss of appetite).

Cheilitis · Very frequent (99-80%)

Inflammation of the lip.

Decreased circulating antibody level · Very frequent (99-80%)

An abnormally decreased level of immunoglobulin in blood.

Diarrhea · Very frequent (99-80%)

Abnormally increased frequency (usually defined as three or more) loose or watery bowel movements a day.

Failure to thrive · Very frequent (99-80%)

Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.

Global developmental delay · Very frequent (99-80%)

A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.

Other findings in the same source

From: Orphanet

Additional reported features include Glossitis (Very frequent (99-80%)); Megaloblastic anemia (Very frequent (99-80%)); Nausea and vomiting (Very frequent (99-80%)); Pallor (Very frequent (99-80%)); Atypical behavior (Frequent (79-30%)); Gastroesophageal reflux (Frequent (79-30%)); Peripheral neuropathy (Frequent (79-30%)); Seizure (Frequent (79-30%)); Cerebral calcification (Occasional (29-5%)); Hyperreflexia (Occasional (29-5%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Hereditary folate malabsorption is Haematology, with a haematologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Which blood-cell, marrow, bleeding or clotting finding matters most?
• Does the diagnosis need confirmation or a more precise subtype?
• Which symptoms or laboratory changes should trigger earlier review?

Treatment discussions and follow-up

Where the source describes treatments, these are an overview of possible care, not a prescription for an individual. Ask which option applies to the confirmed diagnosis, what benefit is expected, what adverse effects to watch for and how progress will be assessed. Availability, approvals and local practice can differ from the country described in the source.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.