Thiamine-responsive megaloblastic anemia syndrome

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Thiamine-responsive megaloblastic anemia syndrome (TRMA) is a rare condition that is characterized by hearing loss, diabetes, and a blood disorder called megaloblastic anemia. Megaloblastic anemia occurs when a person has a low number of red blood cells (anemia), and the red blood cells that are present are larger than normal (megaloblastic). The symptoms of this blood disorder may include decreased appetite, lack of energy, headaches, pale skin, diarrhea, and tingling or numbness in the hands and feet. Individuals with TRMA typically develop megaloblastic anemia between infancy and adolescence. TRMA is called "thiamine-responsive" because the anemia can be treated with daily doses of vitamin B1 (thiamine).

In people with TRMA, hearing loss typically develops during early childhood and is caused by abnormalities of the inner ear (sensorineural hearing loss). The hearing loss usually worsens over time. It remains unclear whether treatment with thiamine can improve hearing or delay hearing loss in people with TRMA.

People with TRMA often develop diabetes mellitus, a condition in which glucose levels can become dangerously high, at an early age. Although some individuals with TRMA develop diabetes during childhood, they do not have the autoimmune form of diabetes that typically develops in children, called type 1 diabetes. People with TRMA usually require insulin to treat their diabetes. In some cases, treatment with thiamine may delay the onset of diabetes or reduce the amount of insulin a person needs.

Some individuals with TRMA have abnormalities of the eye, including optic atrophy, which is the degeneration (atrophy) of the nerves that carry information from the eyes to the brain. Additional features of this condition may include heart and blood vessel (cardiovascular) problems, intellectual disabilities, behavioral changes, and seizures.

ORPHANET DEFINITION Thiamine-responsive megaloblastic anemia (TRMA) is characterized by a triad of megaloblastic anemia, non-type I diabetes mellitus, and sensorineural deafness.

Inheritance

From: MedlinePlus Genetics, National Library of Medicine

Autosomal recessive

Frequency in the source

From: MedlinePlus Genetics, National Library of Medicine

Reported case(s): 80.0; Worldwide. This is a published case count, not prevalence. Point prevalence: <1 / 1 000 000; Worldwide; Class only.

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.

Anorexia · Very frequent (99-80%)

Lack of desire to eat (loss of appetite).

Diabetes mellitus · Very frequent (99-80%)

A group of abnormalities characterized by hyperglycemia and glucose intolerance.

Diarrhea · Very frequent (99-80%)

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

Headache · Very frequent (99-80%)

Cephalgia, or pain sensed in various parts of the head, not confined to the area of distribution of any nerve.

Lethargy · Very frequent (99-80%)

A state of fatigue, either physical or mental slowness and sluggishness, with difficulties in initiating or performing simple tasks. Distinguished from apathy which implies indifference and a lack of desire or interest in the task. A person with lethargy may have the desire, but not the energy to engage in personal or socially relevant tasks.

Megaloblastic anemia · Very frequent (99-80%)

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

Pallor · Very frequent (99-80%)

Abnormally pale skin.

Paresthesia · Very frequent (99-80%)

Abnormal sensations such as tingling, pricking, or numbness of the skin with no apparent physical cause.

Sensorineural hearing impairment · Very frequent (99-80%)

A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.

Optic atrophy · Frequent (79-30%)

Atrophy of the optic nerve. Optic atrophy results from the death of the retinal ganglion cell axons that comprise the optic nerve and manifesting as a pale optic nerve on fundoscopy.

Thrombocytopenia · Frequent (79-30%)

A reduction in the number of circulating thrombocytes.

Atrial septal defect · Occasional (29-5%)

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.

Cardiac arrest · Occasional (29-5%)

An abrupt loss of heart function.

Congestive heart failure · Occasional (29-5%)

The presence of an abnormality of cardiac function that is responsible for the failure of the heart to pump blood at a rate that is commensurate with the needs of the tissues or a state in which abnormally elevated filling pressures are required for the heart to do so. Heart failure is frequently related to a defect in myocardial contraction.

Other findings in the same source

From: Orphanet

Additional reported features include Retinal dystrophy (Occasional (29-5%)); Short stature (Occasional (29-5%)); Stroke (Occasional (29-5%)); Ventricular septal defect (Occasional (29-5%)); Visual loss (Occasional (29-5%)); Paroxysmal atrial tachycardia (Occasional (29-5%)). This is a selected summary, not a complete description of the condition.

When it may begin

From: MedlinePlus Genetics, National Library of Medicine

Childhood

Inheritance in the source

From: MedlinePlus Genetics, National Library of Medicine

Autosomal recessive

Frequency and the population described

From: MedlinePlus Genetics, National Library of Medicine

Reported case(s): 80.0; Worldwide. This is a published case count, not prevalence. Point prevalence: <1 / 1 000 000; Worldwide; Class only.

Understanding the inheritance label

From: MedlinePlus Genetics

An autosomal recessive pattern usually involves disease-causing changes in both copies of a gene. Parents may each carry one altered copy without having the condition themselves. A genetic counsellor can explain carrier testing and reproductive implications using the actual laboratory findings, rather than the condition name alone.

Which doctor should you see?

The suggested department for discussing Thiamine-responsive megaloblastic anemia syndrome 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.