Thiamine responsive megaloblastic anemia: The puzzling phenotype

Beshlawi, Ismail; Zadjali, Shoaib Al; Bashir, Wafa; Elshinawy, Mohamed; Al‐Rawas, Abdulhakim; Wali, Yasser

doi:10.1002/pbc.24849

Cited by 23 publications

(13 citation statements)

References 17 publications

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“…Oxoglutarate dehydrogenase complex intervenes in the production of succinyl‐coenzyme A, which is the substrate of the enzyme delta‐aminolevulinate synthase 2, an enzyme that catalyzes the first step of the synthesis of the heme group. The role of TPP as a cofactor of this enzyme complex may explain the megaloblastic anemia that is observed in Rogers syndrome …”

Section: Biochemistry Of Thiamine In Humansmentioning

confidence: 99%

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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Section: Biochemistry Of Thiamine In Humansmentioning

confidence: 99%

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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“…Megaloblastic changes and the presence of more than 10% sideroblasts in the bone marrow aspiration leads to the diagnosis of TRMA. 11 Beshlawi et al, 5 reported that response to thiamine was variable, hemoglobin level can reach normal values and insulin dose decreased after one month with thiamine therapy (100 mg/ day). Two patients were stopped using insulin after thiamine dose reached 200 mg/day.…”

Section: Discussionmentioning

confidence: 99%

“…Two patients were stopped using insulin after thiamine dose reached 200 mg/day. 3,5 Alzahrani et al informed that high dose thiamine therapy in TRMA patients can improve the disease symptoms, correct the anemia and reduce or discontinue the need for exogenous insulin. 12 Our patient was diagnosed non-autoimmune diabetes mellitus at age of 3 months.…”

Section: Discussionmentioning

confidence: 99%

“…In a few cases, it was reported that insulin requirements decreased with thiamine treatment. 2,3,5 It is thought that megaloblastic anemia, another classic sign of the syndrome, occurs as a result of intracellular thiamine deficiency due to a defective nucleic acid synthesis. 6 Megaloblastic anemia starts at almost the same age when signs of hyperglycemia occur.…”

Section: Introductionmentioning

confidence: 99%

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Infantile-onset thiamine responsive megaloblastic anemia syndrome with SLC19A2 mutation: a case report

et al. 2017

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Background. Thiamine-responsive megaloblastic anemia syndrome (TRMA), also known as Rogers syndrome, is characterized by megaloblastic anemia, sensorineural hearing loss, and diabetes mellitus. Disturbances of the thiamine transport into the cells results from homozygous or compound heterozygous mutations in the SLC19A2 gene. Case presentation. We report a girl which presented with sensorineural deafness treated with a hearing prosthesis, insulin requiring diabetes, macrocytic anemia, treated with thiamine (100 mg/day). Hemoglobin level improved to 12.1 g/dl after dose of thiamine therapy increased up to 200 mg/day. Conclusion. Patients with TRMA must be evaluated for megaloblastic anemia, sensorineural hearing loss, and diabetes mellitus. They must be followed for response of hematologic and diabetic after thiamine therapy. It should be kept in mind that dose of thiamine therapy may be increased according to the clinical response. Genetic counseling should be given.

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“…28,56 Because deafness was the earliest symptoms diagnosed in the disease, reflecting the fact that hearing loss is more recognizable than anemia and diabetes, the results of newborn hearing tests could aid in the differential diagnosis of SLC19A2 deficiency among patients with PNDM to permit an earlier diagnosis, proper treatment, and less mortality. 52,60,61 It has been shown that despite thiamine treatment, insulin dependency can relapse after adolescence in some SLC19A2-deficient patients. 18,44,45 Considering that thiamine can be passively transported into cells at higher concentration, the reason for disease recurrence is probably the result of relatively insufficient thiamine supplementation (maximum 300 mg daily in the literature; see Table S2) when the patients grew up.…”

Section: Discussionmentioning

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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Thiamine responsive megaloblastic anemia: The puzzling phenotype

Abstract: TRMA is a disease of expanding phenotypic spectrum with poor genotype-phenotype correlation.

Cited by 23 publications

References 17 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

Infantile-onset thiamine responsive megaloblastic anemia syndrome with SLC19A2 mutation: a case report

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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