Glutamate formiminotransferase deficiency

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Glutamate formiminotransferase deficiency is a rare inherited disorder that can affect development.

In the past, researchers recognized a mild form and a severe form of glutamate formiminotransferase deficiency. Researchers have since found people who received a diagnosis of glutamate formiminotransferase deficiency as infants who do not appear to have any related health problems. Researchers are actively working to learn more about this condition.

The signs and symptoms associated with glutamate formiminotransferase deficiency have ranged from mild developmental delays with high urine levels of a molecule called formiminoglutamate (FIGLU) to more severe intellectual disabilities and 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).

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Variants (also called mutations) in the FTCD gene cause glutamate formiminotransferase deficiency. The FTCD gene provides instructions for making an enzyme that is involved in the breakdown of histidine, which is a building block (amino acid) of many different proteins. One of the enzyme's jobs is to convert FIGLU to a molecule called 5-formiminotetrahydrofolate.

The FTCD gene variants that cause glutamate formiminotransferase deficiency alter the function of the FTCD enzyme, which disrupts the enzyme’s ability to completely break down histidine. This can cause FIGLU to build up in the body and be released in the urine. It is unclear exactly how these changes are related to the specific health problems seen in some people with glutamate formiminotransferase deficiency.

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

Glutamate formiminotransferase deficiency has an estimated incidence of between 1 in 46,000 people and 1 in 60,000 people, but fewer than 100 people with this condition have been reported in the medical literature. Individuals with the severe form of the disorder have all been of Japanese ancestry.

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.

Abnormal circulating histidine concentration · Very frequent (99-80%)

Any deviation from the normal concentration of histidine in the blood circulation.

Abnormal enzyme/coenzyme activity · Very frequent (99-80%)

Concentration or activity of an enzyme is above or below the limits of normal in the blood circulation.

Abnormality of folate metabolism · Very frequent (99-80%)

Abnormal concentration of acylcarnitine in the urine · Frequent (79-30%)

An abnormal amount of acylcarnitine in the urine.

Increased blood folate concentration · Frequent (79-30%)

The concentration of folic acid in the blood circulation is above the upper limit of normal.

Anemia · Occasional (29-5%)

A reduction in erythrocytes volume or hemoglobin concentration.

Delayed speech and language development · Occasional (29-5%)

A degree of language development that is significantly below the norm for a child of a specified age.

Intellectual disability, severe · Occasional (29-5%)

Severe intellectual disability (ID) is defined as a type of ID characterized by severely sub-average adaptive functioning and intellectual functioning, with an intelligence quotient (IQ) the range of 20-34.

Megaloblastic anemia · Occasional (29-5%)

Anemia characterized by the presence of erythroblasts that are larger than normal (megaloblasts).

Mild global developmental delay · Occasional (29-5%)

A mild delay in the achievement of motor or mental milestones in the domains of development of a child.

Neurodevelopmental delay · Occasional (29-5%)

Neurodevelopmental delay (NDD) refers to delays in the maturation of the brain and central nervous system; infants and young children with NDD may experience delays in the development of one or more skills including gross motor abilities, fine-motor coordination, language abilities and ability to solve increasingly complex problems.

Atrial septal defect · Very rare (<4-1%)

Atrial septal defect (ASD) is a congenital abnormality of the interatrial septum that enables blood flow between the left and right atria via the interatrial septum.

Autism · Very rare (<4-1%)

Autism is a neurodevelopmental disorder characterized by impaired social interaction and communication, and by restricted and repetitive behavior. Autism begins in childhood. It is marked by the presence of markedly abnormal or impaired development in social interaction and communication and a markedly restricted repertoire of activity and interest. Manifestations of the disorder vary greatly depending on the developmental level and chronological age of the individual (DSM-IV).

Which doctor should you see?

The suggested department for discussing Glutamate formiminotransferase deficiency is Metabolic Medicine, with a metabolic specialist / clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with metabolic specialist / clinical geneticist referral.

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.

• Is a biochemical or molecular result needed to clarify the diagnosis?
• Does this condition require an individual plan for illness or reduced food intake?
• Should nutrition advice come from a specialist metabolic dietitian?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Glutamate formiminotransferase deficiency. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

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.