Thiamine-Responsive Megaloblastic Anemia Syndrome

Clinical characteristics.

Thiamine-responsive megaloblastic anemia syndrome (TRMA) is characterized by megaloblastic anemia, progressive sensorineural hearing loss, and diabetes mellitus. Onset of megaloblastic anemia occurs between infancy and adolescence. The anemia is corrected with thiamine treatment, but the red cells remain macrocytic and anemia can recur if treatment is withdrawn. Progressive sensorineural hearing loss often occurs early and can be detected in toddlers; hearing loss is irreversible and may not be prevented by thiamine treatment. The diabetes mellitus is non-type I in nature, with age of onset from infancy to adolescence. Thiamine treatment may reduce insulin requirement and delay onset of diabetes in some individuals.

Diagnosis/testing.

The diagnosis of TRMA is established in a proband with: megaloblastic anemia with normal vitamin B₁₂ / folic acid levels, with or without diabetes or hearing loss, in whom there is a response to oral thiamine; and/or biallelic pathogenic variants in SLC19A2 identified by molecular genetic testing.

Management.

Treatment of manifestations: Lifelong use of pharmacologic doses (50-100 mg/day) of oral thiamine (vitamin B₁) in affected individuals regardless of age. Red blood cell transfusion for severe anemia. Standard treatment for sensorineural hearing loss, diabetes mellitus, and ophthalmologic, cardiovascular, and neurologic manifestations.

Surveillance: At least annual monitoring of the efficacy of the oral thiamine therapy and of disease progression, including: hematologic tests (CBC, reticulocyte count); assessment for glucose intolerance (fasting serum glucose concentration, oral glucose tolerance test, urinalysis); and hearing, ophthalmologic, cardiac, and neurologic evaluations.

Pregnancy management: Good diabetic control prior to and during pregnancy is recommended.

Genetic counseling.

TRMA is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for a pregnancy at increased risk are possible for families in which the SLC19A2 pathogenic variants have been identified in the affected family member.

Suggestive Findings

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

• Megaloblastic anemia occurring between infancy and adolescence:
  • Examination of the bone marrow reveals megaloblastic changes with erythroblasts often containing iron-filled mitochondria (ringed sideroblasts).
  • Vitamin B₁₂ / folic acid levels are normal.
  • The anemia is corrected with pharmacologic doses of thiamine (vitamin B₁) (50-100 mg/day).
  • Even without thiamine supplementation, serum thiamine concentrations are normal; there is no evidence of acidosis or aciduria.
• Progressive sensorineural deafness. Hearing loss generally occurs early and has been detected in toddlers. Whether hearing loss is congenital (prelingual) is unknown. Some affected individuals have signs of megaloblastic anemia and diabetes at an early age, but no hearing loss.
• Diabetes mellitus that is non-type I in nature, with age of onset from infancy to adolescence. Insulin secretion is present but defective [Valerio et al 1998].

Establishing the Diagnosis

The diagnosis of TRMA is established in a proband with: megaloblastic anemia with normal vitamin B₁₂ / folic acid levels, with or without diabetes or hearing loss, in whom there is a response to oral thiamine; and/or biallelic pathogenic (or likely pathogenic) variants in SLC19A2 identified by molecular genetic testing (see Table 1).

Note: Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of TRMA has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Option 2

Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Thiamine-Responsive Megaloblastic Anemia Syndrome

Clinical Description

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 [Ortigoza-Escobar et al 2016, Habeb et al 2018, Zhang et al 2021].

Table 2.

Thiamine-Responsive Megaloblastic Anemia Syndrome: Frequency of Select Features

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. Peripheral blood count shows a pattern of macrocytic anemia with low hemoglobin and high mean corpuscular volume (MCV) in the absence of deficiencies of folate or vitamin B₁₂. Bone marrow shows dysplastic hematopoiesis with numerous megaloblasts. The anemia is corrected with pharmacologic doses of thiamine (vitamin B₁) (50-100 mg/day). However, the red cells remain macrocytic, suggesting a persistent erythropoietic abnormality [Haworth et al 1982, Neufeld et al 1997, Setoodeh et al 2013]; anemia can recur if thiamine therapy is discontinued.

Additional hematologic abnormalities such as thrombocytopenia and neutropenia may be present together with anemia. They can be corrected with pharmacologic doses of thiamine (vitamin B₁) (50-100 mg/day).

Progressive sensorineural deafness. Hearing defects may be present at an early age and in some families may be present at birth [Setoodeh et al 2013]. Progressive sensorineural hearing loss is irreversible and may not be prevented by thiamine treatment. The basis of the sensorineural deafness is obscure; it is not known if the deafness is caused by abnormalities of the cochlea or of the auditory nerve. However, animal studies suggest that selective inner hair cell loss in the cochlea could be the cause of hearing defects in TRMA [Liberman et al 2006].

Non-type I diabetes mellitus has appeared before school age in many (though not all) individuals with glycosuria and hyperglycemia. Diabetic ketoacidosis has been reported in 15% of individuals [Zhang et al 2021]. Initially, affected individuals respond to oral hypoglycemic agents, but most eventually become insulin dependent.

Ophthalmologic manifestations including optic atrophy, when commented on in case reports, appears common. Abnormal appearance of the retina and functional retinal dystrophy have been reported [Meire et al 2000, Kipioti et al 2003, Lagarde et al 2004]. The kindred reported as having DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) by Borgna-Pignatti et al [1989] has in retrospect been shown by genetic analysis to have TRMA. Also, Wu et al [2022] reported an individual with Leber congenital amaurosis who was later found to have molecularly confirmed TRMA.

Cardiovascular abnormalities including sudden death, stroke, high-output heart failure, arrhythmias, atrial standstill, and congenital heart defects such as atrial septal defect or ventricular septal defect have been reported in 20%-30% of individuals with TRMA [Habeb et al 2018, Zhang et al 2021].

Significant neurologic deficits such as stroke, epilepsy, mood disorder, developmental delay, and intellectual disability have been reported during early childhood in 20%-40% of individuals with TRMA [Habeb et al 2018, Zhang et al 2021].

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Nomenclature

The synonym "Rogers syndrome" derives from the first report of the disease in a child with diabetes mellitus, sensorineural deafness, and megaloblastic anemia who responded to thiamine (vitamin B₁) treatment.

Prevalence

Approximately 130 pedigrees are known. TRMA is exceedingly rare outside of consanguineous families or isolated populations. Affected individuals have been observed in various ethnicities including Israeli Arab and Lebanese populations, an Alaskan kindred of native and ethnic Russian descent, and kindreds from Brazil, Japan, Oman, Tunisia, Italy (Venetian and other), Iran, India, and Pakistan, as well as Kashmiri families in Great Britain, ethnic Kurds, persons of northern European heritage, and African Americans [Ortigoza-Escobar et al 2016, Habeb et al 2018, Zhang et al 2021].

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 in Table 4 (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

Treatment of Manifestations

Table 5.

Treatment of Manifestations in Individuals with Thiamine-Responsive Megaloblastic Anemia Syndrome

Surveillance

Table 6.

Recommended Surveillance for Individuals with Thiamine-Responsive Megaloblastic Anemia Syndrome

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of sibs of an affected individual by molecular genetic testing for the SLC19A2 pathogenic variants in the family in order to identify those who would benefit from prompt initiation of treatment and preventive measures.

Supplementation with pharmacologic doses of thiamine (vitamin B₁) (25-100 mg/day compared to US RDA of 1.5 mg/day) is recommended as early as possible for at-risk sibs until their genetic status can be determined.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

While there are no published studies evaluating pregnancy outcome in affected women, good diabetic control prior to and during pregnancy is recommended.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Thiamine-responsive megaloblastic anemia syndrome (TRMA) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for an SLC19A2 pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an SLC19A2 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband [Kang et al 2021].
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for an SLC19A2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with TRMA are obligate heterozygotes (carriers) for a pathogenic variant in SLC19A2.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an SLC19A2 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the SLC19A2 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the SLC19A2 pathogenic variants have been identified in an affected family member, prenatal testing and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Defect of a high-affinity thiamine transporter, SLC19A2, causes thiamine-responsive megaloblastic anemia syndrome (TRMA); however, it is still unclear how the absence of SLC19A2 expression results in the seemingly divergent disorders of megaloblastic anemia, diabetes mellitus, and deafness. Biochemical studies on fibroblasts or erythrocytes from individuals with TRMA showed that absence of the high-affinity component of thiamine transport results in low intracellular thiamine concentrations [Rindi et al 1992, Stagg et al 1999]. Defective RNA ribose synthesis caused by intracellular thiamine deficiency is thought to be the cause of megaloblastic changes in TRMA [Boros et al 2003]. Slc19a2 knockout mouse models have been developed [Oishi et al 2002, Fleming et al 2003]; the animal models manifest megaloblastic changes, diabetes mellitus, and sensorineural deafness (the main features of TRMA) when dietary thiamine levels are decreased [Oishi et al 2002]. While the mechanism of megaloblastic changes is still to be elucidated, these models showed defects in insulin secretion and selective loss of inner hair cells in cochlea [Oishi et al 2002, Liberman et al 2006]. It was demonstrated in cultured human islet cells that SLC19A2 deficiency causes impaired insulin secretion with mitochondrial dysfunction [Jungtrakoon et al 2019].

Studies to demonstrate SLC19A2 variant pathogenicity have all identified severe dysfunction of thiamine transport. These studies described three pathophysiologic mechanisms [Marcé-Grau et al 2019]:

• Reduction of protein expression caused by impaired RNA translation;
• Protein retained within an intracellular segment such as the endoplasmic reticulum;
• Proteins that are able to reach the cell membrane but are functionally impaired.

Questions regarding TRMA disease pathogenesis that still require explanation include why individuals with TRMA do not have manifestations seen in dietary thiamine deficiency [Mandel et al 1984, Poggi et al 1984, Abboud et al 1985] and why the findings in TRMA are organ specific.

Studies have shown that a second high-affinity thiamine transporter, encoded by SLC19A3, has major roles in intestinal thiamine uptake in mice, accounting for the absence of overt thiamine deficiency in persons with TRMA [Reidling et al 2010]. In support of this, two Japanese brothers with a Wernicke-like encephalopathy were reported to have compound heterozygous pathogenic variants in SLC19A3 [Kono et al 2009]. In addition, the difference in distribution of expression of the two thiamine transporters is critical in TRMA: in pancreatic endocrine cells, the expression of SLC19A2 is much higher than that of SLC19A3, and TRMA-associated SLC19A2 mutated alleles disrupt thiamine uptake significantly [Mee et al 2009]. Similarly, it is hypothesized that in TRMA, the other affected tissues (namely, bone marrow and cochlea) do not express or minimally express SLC19A3 [Eudy et al 2000, Rajgopal et al 2001].

Mechanism of disease causation. Loss of function resulting in impaired thiamine uptake. Pathogenic variants result in either a truncated protein from a premature stop codon or aberrantly folded protein caused by missense variants in transmembrane domains.

Author History

George A Diaz, MD, PhD; Icahn School of Medicine at Mount Sinai (2006-2022)
Judith C Fleming, PhD; Children's Hospital and Harvard Medical School (2003-2006)
Ellis J Neufeld, MD, PhD; Children's Hospital and Harvard Medical School (2003-2006)
Kimihiko Oishi, MD (2006-present)
Shuhei Sako, MD (2022-present)
Toshiki Tsunogai, MD (2022-present)

Revision History

• 28 July 2022 (sw) Comprehensive update posted live
• 4 May 2017 (ha) Comprehensive update posted live
• 20 November 2014 (me) Comprehensive update posted live
• 20 September 2012 (me) Comprehensive update posted live
• 8 April 2010 (me) Comprehensive update posted live
• 19 November 2007 (cd) Revision: sequence analysis and prenatal diagnosis available clinically for SCL19A2
• 22 June 2006 (ca) Comprehensive update posted live
• 24 October 2003 (me) Review posted live
• 25 August 2003 (ejn) Original submission

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