Aims
/
hypothesis
Diabetes is one of the cardinal features of thiamine-responsive megaloblastic anaemia (TRMA) syndrome. Current knowledge of this rare monogenic diabetes subtype is limited. We ...investigated the genotype, phenotype and response to thiamine (vitamin B
1
) in a cohort of individuals with TRMA-related diabetes.
Methods
We studied 32 individuals with biallelic
SLC19A2
mutations identified by Sanger or next generation sequencing. Clinical details were collected through a follow-up questionnaire.
Results
We identified 24 different mutations, of which nine are novel. The onset of the first TRMA symptom ranged from birth to 4 years (median 6 months interquartile range, IQR 3–24) and median age at diabetes onset was 10 months (IQR 5–27). At presentation, three individuals had isolated diabetes and 12 had asymptomatic hyperglycaemia. Follow-up data was available for 15 individuals treated with thiamine for a median 4.7 years (IQR 3–10). Four patients were able to stop insulin and seven achieved better glycaemic control on lower insulin doses. These 11 patients were significantly younger at diabetes diagnosis (
p
= 0.042), at genetic testing (
p
= 0.01) and when starting thiamine (
p
= 0.007) compared with the rest of the cohort. All patients treated with thiamine became transfusion-independent and adolescents achieved normal puberty. There were no additional benefits of thiamine doses >150 mg/day and no reported side effects up to 300 mg/day.
Conclusions/interpretation
In TRMA syndrome, diabetes can be asymptomatic and present before the appearance of other features. Prompt recognition is essential as early treatment with thiamine can result in improved glycaemic control, with some individuals becoming insulin-independent.
Data availability
SLC19A2
mutation details have been deposited in the Decipher database (
https://decipher.sanger.ac.uk/
).
There has been major progress in recent years uncovering the genetic causes of diabetes presenting in the first year of life. Twenty genes have been identified to date. The most common causes ...accounting for the majority of cases are mutations in the genes encoding the two subunits of the ATP-sensitive potassium channel (K
ATP
),
KCNJ11
and
ABCC8
, and the insulin gene (
INS
), as well as abnormalities in chromosome 6q24. Patients with activating mutations in
KCNJ11
and
ABCC8
can be treated with oral sulfonylureas in lieu of insulin injections. This compelling example of personalized genetic medicine leading to improved glucose regulation and quality of life may—with continued research—be repeated for other forms of neonatal diabetes in the future.
Thiamine-responsive megaloblastic anemia (TRMA) syndrome is a rare autosomal recessive disorder characterized by a cardinal triad consisting of megaloblastic anemia, sensorineural deafness, and ...diabetes mellitus. TRMA is caused by mutations in the gene SLC19A2 encoding a high-affinity thiamine transporter, which disturbs the active thiamine uptake into cells. We report here on a 1-year and 9-month-old female baby with megaloblastic anemia, thrombocytopenia, and diabetes mellitus. Our patient had significant sensorineural hearing loss that was late to appear. Diagnosis was based on clinical features and dramatic response of anemia, thrombocytopenia, and glycemic control to thiamine therapy. In view of the clinical history of the patient, targeted gene sequencing of genes causing monogenic diabetes was performed. The genes selected comprised 40 gene loci and were sequenced by Illumina sequencing platform. We found a novel homozygous deletion mutation of complete exon 2 of the SLC19A2 gene (ENST00000236137), which we believe has not been described to be associated with TRMA. Exon 2 of SLC19A2 gene includes amino acid from 69 to 269. Thiamine resulted in rapid normalization of the hemoglobin level with improvement in glycemic control. TRMA syndrome should be kept in mind in the differential diagnosis of megaloblastic anemia, deafness, and diabetes mellitus. Early introduction of high-dose thiamine can reverse anemia and allow more glycemic control for diabetes. We conclude that genetic analysis confirms the diagnosis of TRMA. As exogenous thiamine is shown to reverse some of the clinical features of the disease, a genetic diagnosis of TRMA syndrome is extremely important.
Thiamine-responsive megaloblastic anemia (TRMA), an autosomal recessive disorder, is caused by mutations in SLC19A2 gene encodes a high affinity thiamine transporter (THTR-1). The occurrence of TRMA ...is diagnosed by megaloblastic anemia, diabetes mellitus, and sensorineural deafness. Here, we report a female TRMA patient of Indian descent born to 4th degree consanguineous parents presented with retinitis pigmentosa and vision impairment, who had a novel homozygous mutation (c.1232delT/ter422; p.Ile411Metfs*12) in 5th exon of SLC19A2 gene that causes premature termination of hTHTR-1. PROSITE analysis predicted to abrogate GPCRs family-1 signature motif in the variant by this mutation c.1232delT/ter422, suggesting uncharacteristic rhodopsin function leading to cause RP clinically. Thiamine transport activity by the clinical variant was severely inhibited than wild-type THTR-1. Confocal imaging had shown that the variant p.I411Mfs*12 is targeted to the cell membrane and showed no discrepancy in membrane expression than wild-type. Our findings are the first report, to the best of our knowledge, on this novel nonsense mutation of hTHTR-1 causing TRMA in an Indian patient through functionally impaired thiamine transporter activity.
•We analyzed the SLC19A2 gene in a TRMA patient of Indian descent.•A novel nonsense mutation was identified in the SLC19A2 gene for the first time.•GPCR motif ablation in variant suggesting a role in vision impairment of patient.•Thiamine transport activity by the variant was completely disrupted.
Here we report a 5-month-old boy with thiamine Responsive Megaloblastic Anemia syndrome (TRMA syndrome) with several attacks of stroke, admitted to Mofid Children's Hospital, Tehran, Iran, in 2016. ...In addition to the cardinal clinical manifestations of the syndrome, other manifestations comprise thiamine-responsive megaloblastic anemia, diabetes mellitus, and sensor neural hearing loss. The patient showed the ischemic attack of stroke. Megaloblastic anemia and diabetes were diagnosed at 8 months and was successfully treated with vitamin and insulin prescription. After treatment of thiamine, diabetes was controlled and insulin was discontinued. In spite of the thiamine administration, the second stroke as hemorrhagic stroke occurred in the patient after a few months. TRAMA is inherited in an autosomal recessive manner. TRMA was confirmed by mutation in SLC19A2. A homozygous splice site variant was detected in SLC19A2 gene. Stroke was not reported in this syndrome (only in one report about one attack in an adult patient) but in this patient, several attacks of stroke were reported before and after thiamin administration.
Thiamine-responsive megaloblastic anemia (TRMA) is an autosomal recessive syndrome characterized by early-onset anemia, diabetes, and hearing loss caused by mutations in the SLC19A2 gene. We studied ...the genetic cause and clinical features of this condition in patients from the Persian population. A clinical and molecular investigation was performed in four patients from three families and their healthy family members. All had the typical diagnostic criteria. The onset of hearing loss in three patients was at birth and one patient also had a stroke and seizure disorder. Thiamine treatment effectively corrected the anemia in all of our patients but did not prevent hearing loss. Diabetes was improved in one patient who presented at the age of 8months with anemia and diabetes after 2months of starting thiamine. The coding regions of SLC19A2 were sequenced in all patients. The identified mutation was tested in all members of the families. Molecular analyses identified a homozygous nonsense mutation c.697C>T (p.Gln233*) as the cause of the disease in all families. This mutation was previously reported in a Turkish patient with TRMA and is likely to be a founder mutation in the Persian population.
► A non-sense SLC19A2 in four patients with TRMA indicating its high frequency in Persian population. ► Most patients with this mutation had short stature. ► This study expands the knowledge about the of genotype–phenotype correlations in TRMA. ► The results have implications for genetic counseling in other affected families.
Methylation of tRNA on the four canonical bases adds structural complexity to the molecule, and improves decoding specificity and efficiency. While many tRNA methylases are known, detailed insight ...into the catalytic mechanism is only available in a few cases. Of interest among all tRNA methylases is the structural basis for nucleotide selection, by which the specificity is limited to a single site, or broadened to multiple sites. General themes in catalysis include the basis for rate acceleration at highly diverse nucleophilic centers for methyl transfer, using
S-adenosylmethionine as a cofactor. Studies of tRNA methylases have also yielded insights into molecular evolution, particularly in the case of enzymes that recognize distinct structures to perform identical reactions at the same target nucleotide.
To report on 5-year multimodal imaging of ocular findings in a patient with thiamine-responsive megaloblastic anemia.
Observational case report.
A 20-year-old-man with a history of ...thiamine-responsive megaloblastic anemia demonstrated a symmetric bull's eye maculopathy. Spectral domain optical coherence tomography revealed disruption of the parafoveal ellipsoid zone, fundus autofluorescence demonstrated foveal hypoautofluorescence, and full-field electroretinogram testing revealed a decreased photopic and scotopic response consistent with cone-rod dystrophy. His best-corrected visual acuity remained stable over 5 years at 20/50 in the right eye and 20/40 in the left eye, and visual field testing remained stable over time.
Ocular manifestations in thiamine-responsive megaloblastic anemia are uncommon and variable. In this case, multimodal imaging and electroretinogram findings are consistent with cone-rod degeneration. The patient is taking daily thiamine supplementation, and visual acuity, funduscopic examination, spectral domain optical coherence tomography, and autofluorescence remained stable over a 5-year period.
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