Novel nonsense mutation (p.Ile411Metfs*12) in the SLC19A2 gene causing Thiamine Responsive Megaloblastic Anemia in an Indian patient

Manimaran, Paramasivam; Subramanian, Veedamali S.; Karthi, Sellamuthu; Gandhimathi, Krishnan; Varalakshmi, Perumal; Ganesh, Ramaswamy; Rathinavel, Andiappan; Said, Hamid M.; Ashokkumar, Balasubramaniem

doi:10.1016/j.cca.2015.11.002

Cited by 9 publications

(7 citation statements)

References 20 publications

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“…Several studies have been done to demonstrate variants pathogenicity . All of them proved a severe impairment of thiamine cell uptake.…”

Section: Inborn Errors Of Metabolism Leading To Thiamine Dysfunction mentioning

confidence: 99%

“…These experiments concluded that transmembrane backbone and NH 2 -terminal residues are relevant for protein trafficking to the cell membrane instead of N-glycosylation positions or C-terminal region 66 Several studies have been done to demonstrate variants pathogenicity. 66,[68][69][70] All of them proved a severe impairment of thiamine cell uptake. Moreover, RNA and protein expression and cell localization studies have been also analyzed by some authors 66,69,70 describing three pathophysiological mechanism causing thiamine transport dysfunction: (a) variants impairing RNA translation resulting in the absence or infraexpression of the protein (c.277G>C, c.1074G>A, and c.1147delGT); (b) variants retaining the protein within intracellular compartments such as endoplasmic reticulum (c.473C>G); and (c) variants which enable proteins to get cell membrane but resulting in a functional impairment (c.428C>T, c.515G>A, c.152C>T, and c.1232delT).…”

Section: Slc19a2: Genetic Defects and Functional Studiesmentioning

confidence: 99%

“…Finally, latest bioinformatics software have been used to model variant effects on protein structure in comparison to wild-type THTR-1 in order to infer functional consequences. 69,71 3.2 | Thiamine metabolism dysfunction syndrome 2 (biotin-or thiamine-responsive encephalopathy type) (OMIM 607483)…”

Section: Slc19a2: Genetic Defects and Functional Studiesmentioning

confidence: 99%

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Genetic defects of thiamine transport and metabolism: A review of clinical phenotypes, genetics, and functional studies

Marcé‐Grau

Martí-Sánchez

Baide‐Mairena

et al. 2019

J of Inher Metab Disea

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Thiamine is a crucial cofactor involved in the maintenance of carbohydrate metabolism and participates in multiple cellular metabolic processes within the cytosol, mitochondria, and peroxisomes. Currently, four genetic defects have been described causing impairment of thiamine transport and metabolism: SLC19A2 dysfunction leads to diabetes mellitus, megaloblastic anemia and sensory‐neural hearing loss, whereas SLC19A3, SLC25A19, and TPK1‐related disorders result in recurrent encephalopathy, basal ganglia necrosis, generalized dystonia, severe disability, and early death. In order to achieve early diagnosis and treatment, biomarkers play an important role. SLC19A3 patients present a profound decrease of free‐thiamine in cerebrospinal fluid (CSF) and fibroblasts. TPK1 patients show decreased concentrations of thiamine pyrophosphate in blood and muscle. Thiamine supplementation has been shown to improve diabetes and anemia control in Rogers' syndrome patients due to SLC19A2 deficiency. In a significant number of patients with SLC19A3, thiamine improves clinical outcome and survival, and prevents further metabolic crisis. In SLC25A19 and TPK1 defects, thiamine has also led to clinical stabilization in single cases. Moreover, thiamine supplementation leads to normal concentrations of free‐thiamine in the CSF of SLC19A3 patients. Herein, we present a literature review of the current knowledge of the disease including related clinical phenotypes, treatment approaches, update of pathogenic variants, as well as in vitro and in vivo functional models that provide pathogenic evidence and propose mechanisms for thiamine deficiency in humans.

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“…Several studies have been done to demonstrate variants pathogenicity . All of them proved a severe impairment of thiamine cell uptake.…”

Section: Inborn Errors Of Metabolism Leading To Thiamine Dysfunction mentioning

confidence: 99%

Section: Slc19a2: Genetic Defects and Functional Studiesmentioning

confidence: 99%

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Genetic defects of thiamine transport and metabolism: A review of clinical phenotypes, genetics, and functional studies

Marcé‐Grau

Martí-Sánchez

Baide‐Mairena

et al. 2019

J of Inher Metab Disea

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“…To date, more than 40 different SLC19A2 mutations have been identified in less than 60 families [18][19][20][21][22][23]. The majority of these have been described in individual case reports or small series and the focus has been mainly on the haematological manifestations of the condition.…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenomics in diabetes: outcomes of thiamine therapy in TRMA syndrome

et al. 2018

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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 . At presentation, three individuals had isolated diabetes and 12 had asymptomatic hyperglycaemia. Followup 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 A list of the members of the International Neonatal Diabetes Consortium is included in the electronic supplementary material (ESM).Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00125-018-4554-x) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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“…Age of onset of symptoms of thiamine-responsive megaloblastic anemia among patients with solute carrier family 19 member 2 (SLC19A2) mutations2,[4][5][6][7]10,12,[14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][31][32][33][34][35][36]39,41,43,45,[49][50][51]53,54,[56][57][58][59][60][61][62][65][66][67] Data are given as the median (interquartile range). *P-values were determined using the Mann-Whitney test.LONG (Children's Hospital of Fudan University) for generous help with the diagnosis and management of the patient.…”

mentioning

confidence: 99%

Recovered insulin production after thiamine administration in permanent neonatal diabetes mellitus with a novel solute carrier family 19 member 2 (SLC19A2) mutation

Sun

Zhou

Zhang

et al. 2017

Journal of Diabetes

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Background: Solute carrier family 19 member 2 (SLC19A2) gene deficiency is one of the causes of permanent neonatal diabetes mellitus (PNDM) and can be effectively managed by thiamine supplementation. Herein we report on a male patient with a novel SLC19A2 mutation and summarize the clinical characteristics of patients with SLC19A2 deficiency. Methods: The genetic diagnosis of the patient with PNDM was made by sequencing and quantitative polymerase chain reaction. The clinical characteristics of PNDM were summarized on the basis of a systematic review of the literature. Results: The patient with PNDM had c.848G>A (p.W283X) homozygous mutation in SLC19A2. His father had a wild-type SLC19A2 (c.848G) and his mother was c.848G/A heterozygous. The patient and his father both had a diploid genotype (c.848A/A and c.848G/G). After oral thiamine administration, the patient's fasting C-peptide levels increased gradually, and there was a marked decrease in insulin requirements. A search of the literature revealed that thiamine treatment was effective and improved diabetes in 63% of patients with SLC19A2 deficiency. Conclusions: A novel SLC19A2 mutation (c.848G>A; p.W283X) was identified, which was most likely inherited as segmental uniparental isodisomy. Insulin insufficiency in PNDM caused by SLC19A2 deficiency can be corrected by thiamine supplementation. The differential diagnosis of SLC19A2 deficiency should be considered in children with PNDM accompanied by anemia or hearing defects to allow for early treatment.

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Novel nonsense mutation (p.Ile411Metfs*12) in the SLC19A2 gene causing Thiamine Responsive Megaloblastic Anemia in an Indian patient

Cited by 9 publications

References 20 publications

Genetic defects of thiamine transport and metabolism: A review of clinical phenotypes, genetics, and functional studies

Genetic defects of thiamine transport and metabolism: A review of clinical phenotypes, genetics, and functional studies

Pharmacogenomics in diabetes: outcomes of thiamine therapy in TRMA syndrome

Recovered insulin production after thiamine administration in permanent neonatal diabetes mellitus with a novel solute carrier family 19 member 2 (SLC19A2) mutation

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