Thiamine-Responsive Megaloblastic Anemia Syndrome

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2021-01-18
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Summary

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is corrected with thiamine treatment, but the red cells remain macrocytic, and anemia can recur when treatment is withdrawn. Progressive sensorineural hearing loss has generally been 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 delay onset of diabetes in some individuals.

Diagnosis/testing.

The diagnosis of TRMA is established in a proband (with or without diabetes or hearing loss):

  • With megaloblastic anemia and normal vitamin B12/folic acid levels in whom there is a response to oral thiamine; and/or
  • By identification of biallelic pathogenic variants in SLC19A2 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.

Prevention of secondary complications: Complications secondary to poor glycemic control for diabetes or chronic anemia may occur. Ongoing management of the primary disease is essential.

Surveillance: At least yearly 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, OGTT, urine analysis); and hearing, ophthalmologic, and cardiac 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.

Diagnosis

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). However, the red cells remain macrocytic, suggesting a persistent erythropoietic abnormality [Haworth et al 1982, Neufeld et al 1997]; anemia can recur when thiamine is withdrawn.
    • Even without thiamine supplementation, serum thiamine concentrations are normal; there is no evidence of acidosis or aciduria.
  • Progressive sensorineural deafness. Hearing loss is generally 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 identification of biallelic pathogenic variants in SLC19A2 by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

  • Single-gene testing. Sequence analysis of SLC19A2 is performed first and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
  • A multigene panel that includes SLC19A2 and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene varies by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). 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

Gene 1MethodProportion of Probands with Pathogenic Variants 2 Detectable by Method
SLC19A2Sequence analysis 3Nearly 100% 4
Gene-targeted deletion/duplication analysis 5Very rare; observed in 1 family to date 6
1.

See Table A. Genes and Databases for chromosome locus and protein.

2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Nearly all individuals with the diagnostic phenotypic triad evaluated by sequence analysis have identifiable pathogenic variants in SLC19A2. To date, more than 40 families with 33 distinct pathogenic variants have been identified [Diaz et al 1999, Raz et al 2000, Scharfe et al 2000, Gritli et al 2001, Neufeld et al 2001, Ozdemir et al 2002, Lagarde et al 2004, Ricketts et al 2006, Bergmann et al 2009, Onal et al 2009, Pichler et al 2012, Shaw-Smith et al 2012, Yilmaz Agladioglu et al 2012]. Homozygosity by descent has been the most common finding. Seven individuals from six families were compound heterozygotes with distinct pathogenic variants from each parent [Bergmann et al 2009, Pichler et al 2012, Shaw-Smith et al 2012].

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

Beshlawi et al [2014]

Clinical Characteristics

Clinical Description

Thiamine-responsive megaloblastic anemia syndrome (TRMA) is characterized by megaloblastic anemia, progressive sensorineural hearing loss, and diabetes mellitus.

  • The earliest findings of significant bone marrow problems (see Suggestive Findings) have been in the first year of life and the latest in 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.
  • Hearing defects may be present at an early age and in some families may even 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 a few cases [Kurtoğlu et al 2008, Pomahačová et al 2017]. Initially, patients respond to oral hypoglycemic agents but most become insulin dependent in the long term.

In addition to the triad of clinical features that characterize TRMA, other findings have been observed, each in only a subset of individuals:

  • 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; optic atrophy was not known to be a finding of TRMA at the time (see Differential Diagnosis).
  • Cardiovascular abnormalities including sudden death, stroke, high-output heart failure, paroxysmal atrial tachycardia, atrial standstill, and congenital heart defects such as atrial septal defect or ventricular septal defect have been reported in 27% of individuals with TRMA [Villa et al 2000, Lorber et al 2003, Lagarde et al 2004, Aycan et al 2011, Shaw-Smith et al 2012].
  • Significant neurologic deficit including stroke and focal or generalized epilepsy has been reported during early childhood in 27% of individuals with TRMA [Shaw-Smith et al 2012].

Genotype-Phenotype Correlations

No genotype-phenotype correlation has been discerned.

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.

One case report suggests "thiamine-responsive myelodysplasia" as an alternative name for the syndrome [Bazarbachi et al 1998].

Prevalence

Approximately 50 pedigrees are known.

TRMA is exceedingly rare outside of consanguineous families or isolated populations. Cases 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 [Raz et al 2000, Neufeld et al 2001, Lagarde et al 2004, Bergmann et al 2009, Pichler et al 2012, Shaw-Smith et al 2012, Yilmaz Agladioglu et al 2012].

Differential Diagnosis

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 metabolic 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.

Phenotypic overlap exists between TRMA and Wolfram syndrome, or DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness), including diabetes mellitus, optic atrophy, and deafness. Notably missing in Wolfram syndrome are megaloblastic anemia and thiamine responsiveness. Wolfram syndrome is caused by pathogenic variants in WFS1. The encoded protein is a novel transmembrane glycoprotein of 100 kd located in the endoplasmic reticulum, where it is thought to play a role in membrane trafficking, protein processing, or regulation of calcium homeostasis.

The combination of diabetes mellitus and deafness calls to mind mitochondrial disorders [Fischel-Ghodsian 1999], but the macrocytic anemia, megaloblastic bone marrow, and response to thiamine distinguish TRMA from these disorders (see Mitochondrial Disease Overview). Inheritance in TRMA is unequivocally autosomal recessive, which sets it apart from disorders with apparent maternal transmission and mitochondrial inheritance.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with thiamine-responsive megaloblastic anemia syndrome (TRMA), the following evaluations are recommended if they have not already been completed:

  • Peripheral blood count and bone marrow analysis for evidence of megaloblastic anemia
  • Serum folate concentration, serum vitamin B12 concentration, and serum iron studies to exclude other entities
  • Hearing test
  • Fasting serum glucose concentration, oral glucose tolerance test (OGTT), and urinalysis to diagnose diabetes mellitus
  • Ophthalmologic evaluation
  • Cardiac evaluation, including echocardiography
  • Neuroimaging including brain MRI when clinically indicated
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Thiamine

Management focuses on lifelong use of pharmacologic doses (50-100 mg/day) of oral thiamine (vitamin B1) in affected individuals regardless of age.

High-dose thiamine supplementation:

  • Invariably improves the hematologic picture;
  • Did not prevent the development of hearing loss in infants with TRMA in some studies [Borgna-Pignatti et al 2009, Akın et al 2011]. The efficacy of high-dose thiamine in improving hearing or delaying hearing loss has been difficult to study and remains unclear.
  • May delay onset of diabetes mellitus, and may ameliorate diabetes mellitus in the short term and perhaps even for decades [Valerio et al 1998]. Insulin requirements are reduced with thiamine therapy in some cases [Neufeld et al 1997].
  • Has not been evaluated as a treatment for optic atrophy, cardiovascular abnormalities, or neurologic abnormalities associated with TRMA.

Additional Treatment

Red blood cell transfusion for severe anemia is indicated.

See Deafness and Hereditary Hearing Loss Overview for treatment strategies for hearing loss. Treatment has included cochlear implant [Hagr 2014].

Diabetes, cardiovascular abnormalities, and neurologic disorders should be treated in the standard manner.

Prevention of Primary Manifestations

See Treatment of Manifestations.

Prevention of Secondary Complications

Complications secondary to poor glycemic control for diabetes or chronic anemia may occur. Ongoing management of the primary disease is essential.

Surveillance

The following are recommended at least yearly to monitor the efficacy of the oral thiamine therapy as well as disease progression:

  • Hematologic tests (CBC, reticulocyte count)
  • Hearing test
  • Assessment for glucose intolerance (fasting serum glucose concentration, OGTT, urinalysis)
  • Ophthalmologic evaluation
  • Cardiac evaluation
  • Neurologic evaluation

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of sibs of an affected individual by molecular genetic testing of 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) (25-75 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.