TRMA syndrome with a severe phenotype, cerebral infarction, and novel compound heterozygous SLC19A2 mutation: a case report

Thiamine-responsive megaloblastic anemia (TRMA, OMIM 249270)—also called Rogers Syndrome—was first described by Rogers LE et al. [1] in 1969. It is caused by mutations in the SLC19A2 gene (solute carrier family 19 member 2), which is located on the chromosome 1q23.2–23.3 (OMIM 603941), and encodes the high affinity thiamine transporter-1 (THTR-1) [2]. Patients with TRMA are characterized by diabetes, megaloblastic anemia, and progressive sensorineural hearing loss during early childhood [3], and oral thiamine administration can effectively alleviate the symptoms of diabetes and anemia [4]. To date, only 100 cases of TRMA syndrome have been reported worldwide [5]. Here, we introduce the clinical features, diagnosis, and treatment of a Chinese boy with a typical TRMA syndrome.

Thiamine, also known as vitamin B1, is widely found in the skeletal muscle, cardiac muscle, liver, kidney, and brain. Under physiological concentrations, thiamine is transported into the cell mainly by saturable, high affinity and low adhesion transporters THTR-1 and THTR-2, which are encoded by the SLC19A2 and SLC19A3 genes, respectively. After entering the cell, thiamine is converted to thiamine diphosphate (TDP). In the cytoplasm, TDP functions in the pentose phosphate pathway with transketolase (TK); in the mitochondria, it functions in the tricarboxylic acid cycle with α-ketoglutarate dehydrogenase (α -KGDH) and pyruvate dehydrogenase complex (PDHC). The SLC19A2 gene is highly expressed in the inner ear cells, β-islet cells, and hematopoietic stem cells; therefore, these cells are extremely affected by the lack of THTR-1. Consequently, the typical clinical triad of TRMA manifests: diabetes, megaloblastic anemia, and sensorineural hearing loss. Besides the clinical triad, patients with TRMA have been reported to have additional symptoms, such as visual impairment, congenital heart disease (organic change and/or arrhythmia), short stature, cerebrovascular events, thrombocytopenia, and leukopenia [5].

The β-islet cells in patients with TRMA cannot transport thiamine, and therefore cannot carry out aerobic metabolism effectively. This results in β-cell loss and reduction in insulin secretion, leading to type I diabetes even though the patient does not have β-cell autoimmunity. In some patients, C-peptide levels are maintained for a long time [6]. Thiamine therapy enables most patients to stop insulin administration or reduce the dosage [7]. Nevertheless, some patients may need insulin administration during puberty because of accelerated apoptosis of β-cells, necessitating long-term follow-ups [8]. Development of diabetes into ketoacidosis is rare in patients with TRMA; however, in thiamine shortage, ketoacidosis may also appear before puberty [9].

The activity of transketolase in hematopoietic cells in the bone marrow decreases in patients with TRMA syndrome due to the lack of thiamine. This, in turn, can cause several cellular abnormalities, such as disorders in ribosomal and DNA synthesis, immature nucleus formation, and hypertrophy of the cell. Consequently, blood cell formation decreases, leading to anemia. Additionally, thiamine shortage can also affect the synthesis of ferroprotoporphyrin and result in the formation of ring sideroblasts [10‐12]. Hitherto, only one case without anemia has been reported [13]. Hemoglobin levels of most patients with TRMA syndrome can return to normal levels following thiamine treatment.

Patients with TRMA syndrome are usually congenitally deaf or have hearing loss, which gradually worsens. Liberman et al. [14] found in rats that low thiamine diet (2 mg thiamine/kg) could be detrimental to cochlear inner hair cells (IHCs) and cause their atrophy. This observation supports the hypothesis that early intervention with thiamine treatment may antagonize progression of deafness in patients with TRMA syndrome. However, according to Akin et al. [15], such treatment does not suffice to stop the hearing loss. In fact, the majority of the patients with TRMA syndrome still had deafness, even with thiamine therapy. Therefore, it is generally believed that thiamine therapy cannot alleviate deafness. Nevertheless, it is necessary to test whether increased doses of thiamine, or an earlier onset of the treatment can prevent hearing loss altogether or decelerate its progression.

In his 2016 review, Ortigoza-Escobar et al. [5] list several other symptoms observed in addition to the clinical triad, such as visual impairment (retinitis pigmentosa [16], optic atrophy [17], photoreceptor degeneration [18], macular lesions [4] and nystagmus [19]), congenital heart disease (atrial arrhythmia, or atrial septal defect [5] are frequent), short stature [5] [20], cerebrovascular disorders (stroke and epilepsy [4]), thrombocytopenia, and leukopenia. Furthermore, these authors also mention that only one TRMA patient presented 1–2 symptoms in addition to the triad despite he had a homozygous mutation, whereas three patients had all the symptoms mentioned above. Notably, the patient we describe here had all the symptoms mentioned above, even though he had a heterozygous mutation. His clinical presentation was more severe than the previously reported cases, For instance, he had ketoacidosis at the early age of 6 years old, and presented all the known symptoms. Furthermore, he had cerebral infarction, paralysis of his left arm, and ventricular premature beat (VPB) when he was 9 months old, This is the first time such phenotype has been reported.

Currently, 45 different mutations are documented in the SLC19A2 gene from TRMA patients according to the HGMD database, most of which are from consanguineous backgrounds [5]. Most of these mutations are missense/nonsense mutations, which introduce a premature stop codon, or frameshift mutations. Only a few are missense mutations, which change the amino acid residue, causing abnormalities in the protein structure [4, 12]. The patient presented here was found to have a novel compound heterozygote mutation in the SLC19A2 gene, comprising a duplication (c.405dupA) on one allele, and a single nucleotide deletion (c.903delG) on the other allele. Alamut functional software predicted that the mutation could lead to premature translational termination, which can cause formation of a truncated protein, and thus, the mutation was classified as a “pathogenic variation.”

Thiamine supplementation is the main treatment of TRMA syndrome. In most reported cases, thiamine therapy alleviated diabetes and anemia [4], except for only one case in which diabetes did not improve [20]. However, Some patients again became diabetic and anemic after stopping thiamine therapy [19, 21]. Lifelong therapeutic use of thiamine at the range of 25–75 mg/day was usually recommended, with earlier start of the therapy being more effective [7]. In all the reported cases, the dosage was increased up to 300 mg/day [5]. In the case presented here, the dose was only 30 mg/day, and the follow-up exams showed that diabetes, anemia, and arrhythmia of the patient were ameliorated.