Thiamine deficiency in childhood with attention to genetic causes: Survival and outcome predictors

Abstract

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.

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

“…In the cytosol, it is involved in the pentose phosphate pathway, as a cofactor of transketolase enzyme . In the mitochondria, TPP is a cofactor of several complexes: (a) pyruvate dehydrogenase complex, which catalyzes the conversion of pyruvate into acetyl‐CoA; (b) oxoglutarate dehydrogenase complex, which catalyzes the decarboxylation of alpha‐ketoglutarate in the Krebs cycle; and (c) branched‐chain alpha‐ketoacid dehydrogenase complex, which catalyzes the decarboxylation of branched, short‐chain alpha‐ketoacids . In the peroxisome, TPP acts as a cofactor of 2‐hydroxyacyl‐CoA lyase (HACL1) which has a role in fatty acids degradation .…”

“…While SLC19A2 defects lead to diabetes mellitus, megaloblastic anemia and sensory‐neural hearing loss, SLC19A3 , SLC25A19 , and TPK1 genetic defects cause severe encephalopathy in patients with otherwise normal systemic metabolism. Clinical, radiological, and biochemical diagnosis criteria for inherited defects in thiamine transport and metabolism with prominent neurological involvement are stated in Table …”

“…Patients with bilateral striatal degeneration and progressive polyneuropathy show T2‐hyperintensities restricted to the caudate and putamen . Progression to cavitation is characteristic, described as T2‐hyperintensity and T1‐hypointensity in the neostriatum …”

“…[39][40][41][42] A minority of children presents with the triad of ataxia, ophthalmoplegia and decreased consciousness. 4 Most commonly, mental status changes are present in isolation at the beginning of symptoms. Uncommon presenting symptoms include hypotension and tachycardia, related to a defect in efferent sympathetic outflow; hypothermia, caused by involvement of the hypothalamic regions; and seizures, resulting from excessive glutamatergic activity.…”

“…2,3 In the mitochondria, TPP is a cofactor of several complexes: (a) pyruvate dehydrogenase complex, which catalyzes the conversion of pyruvate into acetyl-CoA; (b) oxoglutarate dehydrogenase complex, which catalyzes the decarboxylation of alpha-ketoglutarate in the Krebs cycle; and (c) branched-chain alpha-ketoacid dehydrogenase complex, which catalyzes the decarboxylation of branched, short-chain alpha-ketoacids. 4,5 In the peroxisome, TPP acts as a cofactor of 2-hydroxyacyl-CoA lyase (HACL1) which has a role in fatty acids degradation. 2,3,6 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 thiamine monophosphate (TMP, purple balls), thiamine pyrophosphate (TPP, green balls) and thiamine triphosphate (TTP, brown balls).…”