Expanding the clinical and molecular spectrum of thiamine pyrophosphokinase deficiency: A treatable neurological disorder caused by TPK1 mutations
Introduction
Thiamine pyrophosphokinase (TPK, EC 2.7.6.2.) transfers a pyrophosphate group from adenosine triphosphate (ATP) to thiamine to produce its active form, thiamine pyrophosphate (TPP) in the cytosol [1]. TPP is a cofactor for enzymes important in a range of fundamental processes such as cellular respiration (pyruvate dehydrogenase and 2-ketoglutarate dehydrogenase) and in providing substrates for synthesis of nucleic acids, nucleotides, fatty acids and steroids (transketolase in the pentose phosphate pathway). It is needed for the catabolism of amino acids (branched-chain α-keto acid dehydrogenase), phytanic acid and 2-hydroxy straight chain fatty acids (2-hydroxyphytanoyl-CoA lyase). A number of defects in thiamine transport and metabolism are now known [2] and TPK1 mutations resulting in episodic encephalopathy type thiamine metabolism dysfunction (THDM5, OMIM 614458) is the most recently described disorder of this group [3]. We present two new patients with TPK1 mutations providing novel clinical and biological insights into the condition.
Section snippets
Case histories
Patient 1 (P1) is a male child born to first cousin parents of Indian origin. He presented at 30 months of age during a viral illness with loss of ability to walk and ataxia. On examination he had brisk deep tendon reflexes. He recovered gradually. At 32 months he presented similarly with chicken pox, followed by development of extra-pyramidal features, upper motor neuron signs and fluctuating hypertonia during recovery. His vocabulary reduced to ten words and he became emotionally labile. At 36
Materials and methods
TPK1 Sanger sequencing, TPP quantification and TPK immunoblotting were performed as described previously [3].
Results
TPK1 Sanger sequencing revealed novel homozygous c.479C>T (p.Ser160Leu) and c.664G>C (p.Asp222His) mutations in P1 and P2 respectively (Fig. 2A). Both mutations affect highly conserved residues (Fig. S1). TPP levels were significantly decreased in patients' blood and muscle samples (Table 1). Activities of the two recombinant mutant TPK enzymes were significantly lower than that of the wild-type TPK (Fig. 2B). Similar to what has been described previously [3] the immunoblot analysis showed
Treatment
500 mg thiamine hydrochloride supplementation was started for P1 after the diagnosis was reached. He has not had further encephalopathic episodes, even with infectious illnesses. He has shown gradual slow developmental progression with improvement in understanding, social interaction, language skills and motor abilities. He does not need the nasogastric tube anymore. He is in mainstream school with extra educational support. He continues to have unclear speech and significant spasticity of all
Discussion
Five disorders of thiamine transport or metabolism are now known. Thiamine responsive megaloblastic anemia syndrome (OMIM 249270) caused by SLC19A2 mutations is characterized by megaloblastic anemia, diabetes mellitus and sensorineural deafness and varying degrees of response to thiamine treatment [6]. Biotin or thiamine responsive basal ganglia disease (OMIM 607483) caused by SLC19A3 mutations is characterized by sub-acute encephalopathy, coma, epilepsy, generalized dystonia and resolution of
Contributions
SB and JAM diagnosed the patients, set up the study and wrote the paper. SB, WS and JAM analyzed data. CdG, AM, BvB, KEC, NK, HS, TM, CM, and OD provided the clinical details. WY performed protein structural analysis. CH and RGF performed biochemical analysis. FAZ performed western blotting. LM and KN performed thiamine quantification and protein expression. VL, HP, and KN performed genetic investigations and cloning. All authors read and approved the manuscript.
Conflicts of interest
None of the authors declare any conflicts of interest.
Acknowledgments
We acknowledge the support of Manchester Biomedical Research Centre. This work was supported by the Marie Curie Initial Training Network MEET supported by the European Union (LM, HP, JAM) and the E-Rare project GENOMIT FWF I 920-B13 (VL, FAZ, RGF, WS).
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