Treatment of genetic defects of thiamine transport and metabolism

Abstract

We conducted a literature review of all reported cases with these genetic defects, and focused our paper on treatment efficacy and safety, adverse effects, dosing and treatment monitoring. Expert commentary: Doses of thiamine vary according to the genetic defect: for SLC19A2, the usual dose is 25-200 mg/day (1-4 mg/kg per day), for SLC19A3, 10-40 mg/kg per day, and for TPK1, 30 mg/kg per day. Thiamine supplementation in SLC19A3-mutated patients restores CSF and intracellular thiamine levels, resulting in successful clinical benefits. In conclusion, evidence collected so far suggests that the administration of thiamine improves outcome in SLC19A-2, SLC19A3- and TPK1-mutated patients, so most efforts should be aimed at early diagnosis of these disorders.

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

“…Thiamine doses are very variable but generally within the range of 10 to 40 mg/kg/day . Toxicity studies reported minor adverse reactions after endovenous administration such as transient local irritation, and only one major reaction consisting of generalized pruritus .…”

“…7,[44][45][46][47][48] More than 100 cases have been reported, all of them presenting with symptoms in childhood or adolescence. 2,3 Diabetes and anemia can appear as early as the neonatal period and require the administration of insulin and multiple blood transfusions. Deafness is usually the last manifestation to develop and requires cochlear implantation or hearing aids, 49 reported 32 individuals harboring SLC19A2 mutations.…”

“…This deficiency can be used as a biomarker for diagnosis and monitoring of treatment. 2,3 Brain MRI is abnormal in all symptomatic cases and presents symmetrically distributed brain lesions in caudate nuclei, putamen, and medial thalami and, less frequently, cerebral cortex, brainstem and cerebellum. 4,72,74,76 The changes are hyperintense on T2 and Fluid-attenuated inversion recovery (FLAIR) images, and when MRI is performed in the acute phase, they generally exhibit a swelling appearance and diffuse restriction on Apparent diffusion coefficient (ADC) maps.…”

“…In the cytosol, it is involved in the pentose phosphate pathway, as a cofactor of transketolase enzyme. 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.…”

“…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). Thiamine absorption takes place through passive diffusion, at high concentration, or through different carriers: SLC19A2 (thiamine transporter-1); SLC19A3 (thiamine transporter-2); SLC19A1 (folate carrier); SLC22A1 (OCT1, organic cation transporter 1); SLC35F3 (solute carrier) and SLC44A44 (human TPP carrier).…”