Thiamine Deficiency in Childhood with Attention to Genetic Causes: Survival and Outcome Predictors

Thiamine Deficiency Study Group, Siddharth Banka

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Primary and secondary conditions leading to thiamine deficiency have overlapping features in children, presenting with acute episodes of encephalopathy, bilateral symmetric brain lesions, and high excretion of organic acids that are specific of thiamine-dependent mitochondrial enzymes, mainly lactate, alpha-ketoglutarate, and branched chain keto-acids. Undiagnosed and untreated thiamine deficiencies are often fatal or lead to severe sequelae. Herein, we describe the clinical and genetic characterization of 79 patients with inherited thiamine defects causing encephalopathy in childhood, identifying outcome predictors in patients with pathogenic SLC19A3 variants, the most common genetic etiology. We propose diagnostic criteria that will aid clinicians to establish a faster and accurate diagnosis so that early vitamin supplementation is considered. Ann Neurol 2017;82:317–330
Thiamine or vitamin B1 is a critical cofactor involved in energy metabolism and in the synthesis of nucleic acids, antioxidants, lipids, and neurotransmitters.[1, 2] Thiamine is a water-soluble essential nutrient obtained from cereals, meat, eggs, legumes, and vegetables. In the absence of adequate thiamine intake, limited tissue storage may be depleted in 4 to 6 weeks.[3] Thiamine requires specific transporters for the absorption in the small intestine and for cellular and mitochondrial uptake (thiamine transporter-1, encoded by SLC19A2, thiamine transporter-2, encoded by SLC19A3, and mitochondrial thiamine diphosphate carrier, encoded by SLC25A19). Within the cellular compartment, thiamine is converted into thiamine diphosphate by thiamine phosphokinase (TPK1), the metabolically active form of thiamine, which acts as a cofactor of several thiamine-dependent enzymes in the cytosol, peroxisomes, and mitochondria (Fig 1). Specifically, in the mitochondria, thiamine diphosphate (TDP) acts as a cofactor of the PDHc (pyruvate dehydrogenase complex), OGDHC (oxoglutarate dehydrogenase complex), and BCODC (branched chain 2-oxo acid dehydrogenase complex).
Original languageEnglish
JournalAnnals of Neurology
Issue number3
Early online date18 Jul 2017
Publication statusPublished - 2017


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