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vitamin B12- and folate-independent constitutional megaloblastic anemia - Clinical Profile, Genes & Research | Kisho | Kisho

Rare Disease

vitamin B12- and folate-independent constitutional megaloblastic anemia

MONDO:0020112

Overview

Clinical Presentation

Built from Human Phenotype Ontology (HPO) phenotype annotations and GeneReviews clinical descriptions. Features represent findings documented across known cases — not an exhaustive list of possible symptoms.

No HPO annotations are available for this condition.

GeneReviews

Clinical Guidance

Thiamine-responsive megaloblastic anemia syndrome (TRMA) is characterized by the triad of megaloblastic anemia, progressive sensorineural hearing loss, and diabetes mellitus. To date, more than 183 individuals from more than 138 families have been identified . Table 2. Thiamine-Responsive Megaloblastic Anemia Syndrome: Frequency of Select Features

Diagnosis

Drawn from GeneReviews diagnostic guidelines, newborn screening panel status (RUSP), and ClinGen gene-disease validity classifications. Reflects current clinical evidence and consensus where available.

GeneReviews

Diagnostic Criteria

Suggestive Findings

Thiamine-responsive megaloblastic anemia syndrome (TRMA) should be suspected in individuals with the following triad of clinical features:

Source: GeneReviews — "Thiamine-Responsive Megaloblastic Anemia Syndrome"

Treatment

Compiled from FDA-approved drug records, orphan drug designations, and FDA Adverse Event Reporting System (FAERS) safety data. GeneReviews management guidance is included where available.

No approved treatments are currently available for vitamin B12- and folate-independent constitutional megaloblastic anemia. The disease remains an area of unmet medical need.

GeneReviews

Management Guidelines

Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with thiamine-responsive megaloblastic anemia syndrome (TRMA), the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 4. Recommended Evaluations Following Initial Diagnosis in Individuals with Thiamine-Responsive Megaloblastic Anemia Syndrome

Prognosis

Based on GeneReviews surveillance recommendations, HPO phenotype frequency and severity annotations, and published prevalence estimates from Orphanet and OMIM.

GeneReviews

Surveillance Guidelines

Table 6.

Recommended Surveillance for Individuals with Thiamine-Responsive Megaloblastic Anemia Syndrome

System/Concern | Evaluation | Frequency

Hematologic

| Hematologic tests (CBC, reticulocyte count) | At least annually

Hearing

| Hearing test

Data assembled from 3 of 12 sources · Last updated Sep 20, 2026, 1:42 PM UTC

MONDOHPOClinicalTrials.govFDAPubMedHGNCClinVarClinGenGeneReviewsOrphanetOMIMRUSP

Medical References

External Resources

Orphanet

European rare disease database

Orphanet:98415

GARD

Genetic and Rare Diseases Info Center

GARD:19464

Questions for Your Care Team

→Are there specialists or centers of excellence for this condition in my area?
→Is there a patient registry I should consider joining?

← Back to All Diseases

Feature	% of Personsw/Feature	Comment
Megaloblastic anemia	60%-70%	Anemia is present in 90% of persons.
Progressive sensorineural deafness	90%	—
Non-type I diabetes mellitus	90%	—
Ophthalmologic manifestations	20%-30%	Incl optic atrophy
Cardiovascular abnormalities	20%-30%	—
Neurologic manifestations	20%-40%	—
Thrombocytopenia	10%-30%	Megaloblastic anemia. The earliest findings of significant bone marrow problems have been in the first year of life and the latest in the teenage years.

Differential Diagnosis

Anemia. The combination of megaloblastic red cell changes and ringed sideroblasts in individuals with thiamine-responsive megaloblastic anemia syndrome (TRMA) is unique among anemias influenced by inborn errors of metabolism or nutritional causes. Among acquired anemias, this combination is most suggestive of myelodysplastic syndromes in which megaloblastosis and sideroblasts are often noted. TRMA should not be confused with myelodysplastic disorders of premalignant potential. Progressive sensorineural hearing loss and diabetes mellitus. See . Table 3. Genetic Disorders with Hearing Loss and Diabetes Mellitus in the Differential Diagnosis of Thiamine-Responsive Megaloblastic Anemia Syndrome

Gene / Genetic Mechanism	Disorder	MOI	Overlapping Features	Distinguishing Features / Comment
WFS1	WFS1 Wolfram syndrome spectrum disorder (incl DIDMOAD)	ARAD1	Variable combinations of DM, optic atrophy, deafness	Notably missing megaloblastic anemia thiamine responsiveness
CISD2	Wolfram syndrome type 2 (OMIM 604928)	AR	Variable combinations of DM, optic atrophy, deafness	Notably missing megaloblastic anemia thiamine responsiveness; deafness only at higher frequencies; sometimes presents w/GI ulcers 1,000 genes
Primary mitochondrial disorders	MatARADXL	Combination of DM deafness	Macrocytic anemia, megaloblastic bone marrow, thiamine responsiveness distinguish TRMA from mitochondrial disorders.	—

Source: GeneReviews — "Thiamine-Responsive Megaloblastic Anemia Syndrome"

System/Concern	Evaluation	Comment
Hearing	Audiologic eval	—
Endocrine	Fasting serum glucose concentration, OGTT, urinalysis to diagnose DM	—
Eyes	Ophthalmologic eval	Cardiac
counseling	By genetics professionals1	To inform affected persons families re nature, MOI, implications of TRMA to facilitate medical personal decision making DM = diabetes mellitus; MOI = mode of inheritance; OGTT = oral glucose tolerance test 1.
Treatment of Manifestations in Individuals with Thiamine-Responsive Megaloblastic Anemia Syndrome Manifestation/Concern	Treatment	Considerations/Other Megaloblastic anemia
Sensorineural hearing loss	See Hereditary Hearing Loss and Deafness Overview for treatment strategies for hearing loss. Treatment has incl cochlear implant.2	The efficacy of high-dose thiamine in improving hearing or delaying hearing loss remains unclear. High-dose thiamine supplementation did not prevent hearing loss in some studies.3
Diabetes mellitus	Standard treatment of DM per endocrinologist in addition to thiamine therapy	High-dose thiamine supplementation may delay onset of DM may ameliorate DM in short term perhaps for decades.Insulin requirements are w/thiamine therapy in some persons.1
Thrombocytopenia	Oral thiamine (vitamin B1) lifelong pharmacologic doses (50-100 mg/day)	High-dose thiamine supplementation invariably improves hematologic picture.
Ophthalmologic manifestations	Standard treatment of ophthalmologic manifestations	High-dose thiamine supplementation has not been evaluated as treatment for optic atrophy, cardiovascular abnormalities, or neurologic abnormalities assoc w/TRMA. Cardiovascular manifestations
Recommended Surveillance for Individuals with Thiamine-Responsive Megaloblastic Anemia Syndrome System/Concern	Evaluation	Frequency
Hematologic	Hematologic tests (CBC, reticulocyte count)	At least annually Hearing

Kisho

vitamin B12- and folate-independent constitutional megaloblastic anemia

Overview

Clinical Presentation

Clinical Guidance

Diagnosis

Diagnostic Criteria

Suggestive Findings

Treatment

Management Guidelines

Prognosis

Surveillance Guidelines

Hematologic

Hearing

Medical References

External Resources

Orphanet

GARD

Questions for Your Care Team

Questions for Your Care Team

Differential Diagnosis

Therapies Under Investigation

Clinical Trials

Endocrine

Cardiac

Neurologic

vitamin B12- and folate-independent constitutional megaloblastic anemia

Overview

Clinical Presentation

Clinical Guidance

Diagnosis

Diagnostic Criteria

Suggestive Findings

Treatment

Management Guidelines

Prognosis

Surveillance Guidelines

Hematologic

Hearing

Medical References

External Resources

Orphanet

GARD

Subtypes

Related Diseases

Questions for Your Care Team

Questions for Your Care Team

Differential Diagnosis

Therapies Under Investigation

Clinical Trials

Endocrine

Cardiac

Neurologic