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Thiamine-responsive megaloblastic anemia syndrome
Thiamine-responsive megaloblastic anemia (TRMA) is characterized by a triad of megaloblastic anemia, non-type I diabetes mellitus, and sensorineural deafness.
TRMA syndrome has been reported in less than 80 cases worldwide. Its prevalence and incidence are unknown.
TRMA can present at any age between infancy and adolescence, although often not all key features are manifested at onset. TRMA is typically characterized by the triad of megaloblastic anemia responding to thiamine, sensorineural deafness, and non-type I diabetes mellitus. Clinical megaloblastic anemia manifestations may comprise hyporexia, lethargy, cephalalgia, pallor, diarrhea, and parasthesia in hands and feet. Other variable clinical signs include retinal dystrophy and optic nerve atrophy; short stature; cardiovascular abnormalities including congenital heart defects such as atrial and/or ventricular septal defect and arrhythmia/conduction anomalies; seizures and strokes. The variable phenotypic presentation of TRMA syndrome may cause a significant delay between the onset of symptoms and an accurate diagnosis.
TRMA is an autosomal recessive disorder caused by heterogeneous mutations in the high-affinity transporter SLC19A2, located to chromosome 1q23.3. Nearly all patients identified are homozygous for the SLC19A2 mutations, but a small number of heterozygous mutations have been reported.
Diagnosis of TRMA is based on clinical findings and can be confirmed by a bone marrow assessment showing megaloblastic anemia in association with erythroblasts with iron-filled mitochondria (ringed sideroblasts) and by molecular genetic analysis of the SLC19A2 gene. Affected individuals have normal thiamine serum levels. Newborns should be screened by distortion-product otoacoustic emissions (DPOAE) and brainstem evoked response audiometry (BERA).
Differential diagnosis includes Wolfram syndrome, mitochondrial disorders such as Kearns-Sayre syndrome and Pearson syndrome (see these terms), as well as dietary vitamin B12 or folate deficiency.
Prenatal diagnosis is possible by amniocentesis or chorionic villus sampling and specific gene analysis.
The SLC19A2 mutation is transmitted as an autosomal recessive trait. Genetic counseling should be offered to affected individuals and their families informing them of the possibilities of carrier testing for at-risk family members and the genetic risk for transmission to their children. Many patients are from consanguineous families, so it is difficult to ascertain whether all of the clinical features reported in some families are solely associated with the SLC19A2 mutation.
Management and treatment
Treatment is symptomatic and includes daily significant doses of thiamine (vitamin B1; 25-75 mg per day) to alleviate anemia and to possibly improve diabetes mellitus short-term and long-term outcome. Hearing loss appears irremediable and has a variable timeframe. There is still debate on whether prenatal and early thiamine treatment in affected individuals significantly delays the onset and reduces the hearing defect; several patients diagnosed at a young age have preserved hearing with thiamine treatment since a young age. Hearing aids and palliative care are recommended. Management includes regular hematological monitoring, glucose tolerance, urine, hearing, ophthalmologic and cardiac assessment.
Prognosis is variable. Once hearing is lost, it cannot be restored, whereas the anemia is generally reversible and the diabetes is often ameliorated for some time, and to some degree, with treatment. For patients with appropriate treatment and regular follow-up normal life expectancy should be achievable.