Free-thiamine is a potential biomarker of thiamine transporter-2 deficiency: a treatable cause of Leigh syndrome

Abstract

Thiamine transporter-2 deficiency is caused by mutations in the SLC19A3 gene. As opposed to other causes of Leigh syndrome, early administration of thiamine and biotin has a dramatic and immediate clinical effect. New biochemical markers are needed to aid in early diagnosis and timely therapeutic intervention. Thiamine derivatives were analysed by high performance liquid chromatography in 106 whole blood and 38 cerebrospinal fluid samples from paediatric controls, 16 cerebrospinal fluid samples from patients with Leigh syndrome, six of whom harboured mutations in the SLC19A3 gene, and 49 patients with other neurological disorders. Free-thiamine was remarkably reduced in the cerebrospinal fluid of five SLC19A3 patients before treatment. In contrast, free-thiamine was slightly decreased in 15.2% of patients with other neurological conditions, and above the reference range in one SLC19A3 patient on thiamine supplementation. We also observed a severe deficiency of free-thiamine and low levels of thiamine diphosphate in fibroblasts from SLC19A3 patients. Surprisingly, pyruvate dehydrogenase activity and mitochondrial substrate oxidation rates were within the control range. Thiamine derivatives normalized after the addition of thiamine to the culture medium. In conclusion, we found a profound deficiency of free-thiamine in the CSF and fibroblasts of patients with thiamine transporter-2 deficiency. Thiamine supplementation led to clinical improvement in patients early treated and restored thiamine values in fibroblasts and cerebrospinal fluid.

Neuropathological characteristics of the brain in two patients with SLC19A3 mutations related to the biotin-thiamine-responsive basal ganglia disease

“…It is a very rare variant as its minor allele frequency (MAF) reported in the Exome Aggregation Consortium (ExAC) database is 0.000008. It was found up to now in three other families [6,10,12,19] including two with the same c.68G>T/c.68G>T genotype [19] as patient 2. One of them, Yemeni originated, presented first symptoms at the age of 12 months, just like our patient 2.…”

“…Acute, postacute, intermediate and end stage of the disease were specified in that study [6]. Up to now more than 75 patients were reported and natural history of the disease was presented in detail [10]. The clinical course of both presented patients demonstrated the most severe type of the SLC19A3 defect.…”

“…Pathogenic variants in the SLC19A3 [NM_025243.3] coding for thiamine transporter 2 lead to a decrease in the free-thiamine concentration in cells [10]. Brain imaging most commonly shows a basal ganglia involvement of Leigh-like syndrome type [4,5,15] and/or Wernicke encephalopathy features resembling acquired vitamin B 1 deficiency [7].…”

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

“…TPP, which accounts for 80% of total body thiamine, participates in multiple metabolic processes in the cytosol, mitochondria and peroxisome (Figure ). 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 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 . 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.…”