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Case Reports
. 2019 Jul 8;8(7):991.
doi: 10.3390/jcm8070991.

Utility of Whole Blood Thiamine Pyrophosphate Evaluation in TPK1-Related Diseases

Enrico Bugiardini  1   2 , Simon Pope  3 , René G Feichtinger  4 , Olivia V Poole  1   2 , Alan M Pittman  2 , Cathy E Woodward  5 , Simon Heales  3 , Rosaline Quinlivan  1   2   6 , Henry Houlden  1   2 , Johannes A Mayr  4 , Michael G Hanna  1   2 , Robert D S Pitceathly  7   8
Affiliations
Case Reports

Utility of Whole Blood Thiamine Pyrophosphate Evaluation in TPK1-Related Diseases

Enrico Bugiardini et al. J Clin Med. .

Abstract

TPK1 mutations are a rare, but potentially treatable, cause of thiamine deficiency. Diagnosis is challenging given the phenotypic overlap that exists with other metabolic and neurological disorders. We report a case of TPK1-related disease presenting with Leigh-like syndrome and review the diagnostic utility of thiamine pyrophosphate (TPP) blood measurement. The proband, a 35-year-old male, presented at four months of age with recurrent episodes of post-infectious encephalopathy. He subsequently developed epilepsy, learning difficulties, sensorineural hearing loss, spasticity, and dysphagia. There was a positive family history for Leigh syndrome in an older brother. Plasma lactate was elevated (3.51 mmol/L) and brain MRI showed bilateral basal ganglia hyperintensities, indicative of Leigh syndrome. Histochemical and spectrophotometric analysis of mitochondrial respiratory chain complexes I, II+III, and IV was normal. Genetic analysis of muscle mitochondrial DNA was negative. Whole exome sequencing of the proband confirmed compound heterozygous variants in TPK1: c. 426G>C (p. Leu142Phe) and c. 258+1G>A (p.?). Blood TPP levels were reduced, providing functional evidence for the deleterious effects of the variants. We highlight the clinical and bioinformatics challenges to diagnosing rare genetic disorders and the continued utility of biochemical analyses, despite major advances in DNA sequencing technology, when investigating novel, potentially disease-causing, genetic variants. Blood TPP measurement represents a fast and cost-effective diagnostic tool in TPK1-related diseases.

Keywords: Leigh syndrome; TPK1; mitochondrial diseases; thiamine deficiency; thiamine pyrophosphate.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Brain MRI. (A) Axial image demonstrates bilateral, symmetrical T2-weighted high signal intensities within the corpus striatum (arrows). (B) Sagittal image shows cerebellar atrophy (asterisk).
Figure 2
Figure 2
Domain and amino acid conservation for the c.426G>C; p.Leu142Phe variant, and segregation studies and impact on thiamine pyrophosphokinase 1 (TPK1) protein steady state levels of both TPK1 variants. (A) Conservation of hTPK1 amino acid sequence between species. The L142 residue is highly conserved and resides within the catalytic domain of the protein. (B) Family pedigree and segregation analysis. NDUFA1 variant: c.94G>C. TPK1 variants (bold): c.426G>C and c.258+1G>A. (C) Steady state hTPK1 protein levels in patient fibroblasts. Abbreviations: GPI, glucose-6-phosphate isomerase (loading control); C, healthy control; D1 and D2, positive controls—previously reported as P2 and P5, respectively (Mayr et al., 2011) [6]; PT, proband in present study.
Figure 3
Figure 3
Thiamine structure and pathways. (A) Structure of different thiamine species and enzymatic pathways. Thiamine is phosphorylated to thiamine pyrophosphate (TPP) by thiamine pyrophosphokinase 1 (hTPK1). It can be further phosphorylated to thiamine triphosphate (TTP) by mitochondrial thiamine triphosphosphate synthase (ThTP synthase). It can also be dephosphorylated by thiamine phosphatase (Th phosphatase) to thiamine monophosphate (TMP) and thiamine. (B) Thiamine is absorbed in the small intestine and enters the cells using two transporters (encoded by SLC19A2/SLC19A3) where it is pyrophosphorylated to the active form (TPP) by hTPK1. TPP is transported into mitochondria by the SLC25A19 encoded carrier where it acts as a cofactor for three distinct dehydrogenases: (1) pyruvate dehydrogenase complex (PDHC); (2) branched-chain alfa keto acid dehydrogenase (BCKDH); and (3) alpha-ketoglutarate dehydrogenase (α-KGDH). Outside of mitochondria, TPP acts a cofactor for Transketolase and 2-hydroxyacyl-Coa Lyase 1 (HACL1).
Figure 4
Figure 4
High performance liquid chromatography (HPLC) after 24 months of supplementation with thiamine. Red line: patient. Blue line: control. In patient there is a prominent peak for thiamine monophosphate (TMP) and unphosphorylated thiamine (thiamine) compared to control. These are caused by a reduced conversion of thiamine and TMP to thiamine diphosphate/pyrophosphate (TPP) for a deficient hTPK1 activity.
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