Thiamine-Responsive Megaloblastic Anemia Syndrome

A number sign (#) is used with this entry because of evidence that thiamine-responsive megaloblastic anemia syndrome (TRMA), also known as thiamine metabolism dysfunction syndrome-1 (THMD1), is caused by homozygous mutation in the SLC19A2 (603941) gene, which encodes a thiamine transporter protein, on chromosome 1q24.

Description

Thiamine-responsive megaloblastic anemia syndrome comprises megaloblastic anemia, diabetes mellitus, and sensorineural deafness. Onset is typically between infancy and adolescence, but all of the cardinal findings are often not present initially. The anemia, and sometimes the diabetes, improves with high doses of thiamine. Other more variable features include optic atrophy, congenital heart defects, short stature, and stroke (summary by Bergmann et al., 2009).

Genetic Heterogeneity of Disorders Due to Thiamine Metabolism Dysfunction

See also episodic encephalopathies due to defects in thiamine metabolism: biotin-responsive basal ganglia disease (THMD2; 607483), caused by mutation in the SLC19A3 gene (606152) on chromosome 2q36; Amish lethal microcephaly (THMD3; 607196) and bilateral striatal necrosis and progressive polyneuropathy (THMD4; 613710), both caused by mutation in the SLC25A19 gene (606521) on chromosome 17q25; and THMD5 (614458), caused by mutation in the TPK1 gene (606370) on chromosome 7q35.

Clinical Features

Rogers et al. (1969) described an 11-year-old girl with megaloblastic anemia responsive only to thiamine. She also had diabetes mellitus, amino aciduria, and sensorineural deafness. Viana and Carvalho (1978) described a 6-year-old girl with congenital megaloblastic anemia that responded completely only to pharmacologic doses of thiamine. Relapse occurred twice when thiamine was discontinued. As in the case of Rogers et al. (1969), the child also had latent diabetes mellitus and sensorineural deafness. Situs inversus viscerum totalis was also present. The parents were first cousins and were partially deaf. The syndrome was further delineated and autosomal recessive inheritance corroborated by Haworth et al. (1982), who described affected Pakistani brother and sister. The bone marrow showed megaloblastic erythropoiesis and many ringed sideroblasts, and, by electron microscopy, iron-laden mitochondria in erythroblasts. Autosomal recessive inheritance was demonstrated by the striking pedigree published by Mandel et al. (1984): 2 males and 3 females in 3 related sibships, each with closely related parents, were observed. The proband was the youngest reported case. She presented at age 3 months with severe anemia, diabetes, and deafness, all of which improved with high-dose thiamine treatment. The patient also showed generalized puffiness, hoarseness, and severe cardiac and neurologic disturbances, which also dramatically responded to administration of thiamine in large doses.

The abnormalities in the thiamine-responsive anemia syndrome are consistent with the picture of thiamine-deficient beriberi in childhood (Burgess, 1958). Hyperglycemia has been observed in beriberi, and diabetic glucose-tolerance curves that revert to normal with thiamine replacement are described in rats with experimental thiamine deficiency. The anemia can be megaloblastic, sideroblastic or aplastic.

Abboud et al. (1985) reported 3 brothers with diabetes mellitus, thiamine-responsive megaloblastic anemia, and sensorineural deafness. Two had also congenital septal defects of the heart. In 1 brother the activity of thiamine-dependent enzymes was measured, revealing low alpha-ketoglutarate dehydrogenase activity which might have been responsible for sideroblastic anemia with secondary megaloblastic changes. The anemia responded to thiamine but the diabetes did not.

Borgna-Pignatti et al. (1989) described 2 Italian children, related as first cousins, who developed megaloblastic and sideroblastic anemia, neutropenia, and borderline thrombocytopenia. These authors characterized these children as having DIDMOAD syndrome (222300). In both children, thiamine pyrophosphate in erythrocytes and thiamine pyrophosphokinase activity were lower than the lowest values observed in control subjects. A month after institution of treatment with thiamine, the hematologic findings had returned to normal and insulin requirements had decreased. Withdrawal of thiamine repeatedly induced relapse of the anemia and increase in insulin requirements. However, a later study by Neufeld et al. (1997) determined that the patients reported by Borgna-Pignatti et al. (1989) in fact had thiamine-responsive megaloblastic anemia syndrome, with linkage to chromosome 1q.

Bazarbachi et al. (1998) found reports of 15 patients with the triad of thiamine-responsive anemia, diabetes mellitus, and deafness associated with macrocytic anemia and sometimes moderate thrombocytopenia. Bone marrow aspirates usually showed ringed sideroblasts in addition to the megaloblastic changes. They described 2 new patients who presented with diabetes, deafness, and thiamine-responsive pancytopenia. Bone marrow aspirate and biopsy were typical of trilineage myelodysplasia. The findings suggested that thiamine may have a role in the regulation of hemopoiesis at the stem cell level. They proposed the designation 'thiamine-responsive myelodysplasia' for this disorder.

Villa et al. (2000) reported the case of a 20-year-old girl with TRMA associated with diabetes mellitus and bilateral sensorineural deafness. Megaloblastic anemia was diagnosed at 7 months and was successfully treated with multiple vitamin preparations. Diabetes was diagnosed at age 2 years and was treated with insulin for 6 months at a dose of 0.5 IU/kg BW. The diagnosis of TRMA was clinically confirmed when bilateral sensorineural deafness was detected. Thereafter, thiamine treatment was started (50 mg/day), and insulin was discontinued because of frequent episodes of hypoglycemia. At age 17 years, because of secondary amenorrhea and echographic findings of small ovarian cysts, the patient was diagnosed as having polycystic ovary syndrome and was treated with estro-progestins (12 cycles/yr of ciproterone, ethinyl estradiol). One year later, at age 18 years, the patient developed motor seizures initially involving the left leg, then rapidly extending to the whole body, followed by unconsciousness. Brain MRI and angiography showed severely reduced blood flow in the right middle cerebral artery, with a large ischemic area in the corresponding territory, absence of flow in the distal internal carotid arteries, and slight compensatory hypertrophy of the basilar artery. X-ray digital arteriography confirmed MRI findings and showed narrowing of the left superficial femoral and popliteal arteries.

Bergmann et al. (2009) reported 8 patients from 7 families with genetically confirmed TRMA. The patients were of various ethnic origin, including Korean, Indian, Lebanese, Honduran, Italian, Caucasian, and Portuguese. All had megaloblastic anemia, often with ringed sideroblasts, diabetes mellitus, which was often insulin-dependent, and deafness. Onset of anemia occurred between 11 months and 11 years of age; onset of diabetes between ages 1.5 years and 11 years; and onset of deafness between ages 8 months and 6 years in 6 patients and at age 30 in 1 patient. One patient had normal hearing at age 15 years. Treatment with high-dose thiamine resulted in improvement in the anemia and, in some cases, amelioration of the diabetes phenotype.

Clinical Management

The patient of Poggi et al. (1984) no longer needed insulin after the start of thiamine treatment. Poggi et al. (1989) and Rindi et al. (1992) reported further studies of the proband, a 5-year-old girl at the time of diagnosis, and her affected brother. Rindi et al. (1992) reported that with daily administration of a lipophilic form of thiamine with enhanced bioavailability, the girl was 'still well controlled as far as anaemia and deafness are concerned. During the last 3 years, her diabetes has required insulin therapy.' The boy was well controlled as far as anemia, deafness, and diabetes were concerned, but had developed progressive optic atrophy during the previous 2 years. Rindi et al. (1992) concluded that the cells from TRMA patients contain low levels of thiamine compounds, probably due to their inability to take up and retain physiologic concentrations of thiamine.

Mapping

Neufeld et al. (1997, 1997) performed homozygosity mapping and linkage mapping in 4 large kindreds of native Alaskan and Italian origin with TRMA. Strong evidence for linkage was found to a single marker on 1q23.2-q23.3; maximum lod = 3.7 for D1S1679. Sixteen markers spanning the region were examined in the Alaskan kindred, plus 2 additional consanguineous kindreds of Arab-Israeli origin. These results confirmed the putative disease gene interval, suggesting genetic homogeneity. Linkage analysis generated the highest combined lod score, 8.1 at theta = 0.0, with marker D1S2779. The Italian and Alaskan patients shared no haplotypes with each other nor with the Arab-Israeli families, suggesting that the disease arose independently on 3 different genetic backgrounds. Several heterozygous parents had diabetes mellitus, deafness, or megaloblastic anemia, raising the possibility that mutations at this locus predispose carriers to these manifestations.

Based on genetic recombination, homozygosity mapping, and linkage disequilibrium (highest lod score of 12.5 at D1S2799, at a recombination fraction of 0), Raz et al. (1998) further narrowed the TRMA interval to 4 cM. They analyzed an additional 7 families of diverse ethnic origin and confirmed homogeneity of the disease.

Banikazemi et al. (1999) narrowed the location of the TRMA locus to a 1.4-cM interval on 1q23.3. Using a P1-derived artificial chromosome (PAC) contig spanning the TRMA candidate region, Labay et al. (1999) clarified the order of genetic markers across the TRMA locus, provided 9 new polymorphic markers, and narrowed the locus to an approximately 400-kb region.

Molecular Genetics

By positional cloning, Labay et al. (1999) identified the SLC19A2 gene, which they called THTR1, within the critical TRMA locus region. In all affected members of 6 families segregating TRMA, they identified homozygous mutations in the SLC19A2 gene, which encodes a putative transmembrane protein homologous to the reduced folate carrier proteins. Labay et al. (1999) suggested that a defective thiamine transporter protein underlies the TRMA syndrome. They noted that studies by Rindi et al. (1994) and by Stagg et al. (1999) had suggested that deficiency in a high-affinity thiamine transporter may cause this disorder.

Scharfe et al. (2000) reported a girl with a trp358-to-ter mutation (603941.0009) in the SLC19A2 gene. In addition to TRMA, the girl had short stature, hepatosplenomegaly, retinal degeneration, and a brain MRI lesion. Biochemical analyses of muscle and skin biopsies revealed a severe deficiency of pyruvate dehydrogenase and complex I of the respiratory chain. These biochemical abnormalities responded to thiamine supplementation.