Expanding the clinical and molecular spectrum of thiamine pyrophosphokinase deficiency: A treatable neurological disorder caused by TPK1 mutations

https://doi.org/10.1016/j.ymgme.2014.09.010Get rights and content

Highlights

  • TPK deficiency can present as episodic encephalopathy or Leigh syndrome like early-onset global developmental delay.

  • MRI changes in TPK deficiency can be either fleeting or progressive and can affect either white or gray matter.

  • 2-ketoglutaric aciduria is a good marker for TPK deficiency but may need to be repeated on several occasions.

  • TPK activity and TPP quantification assays in frozen muscle and blood can confirm the diagnosis of TPK deficiency.

  • Thiamine supplementation rescues TPK enzyme activity in vitro and improves outcome in affected patients.

Abstract

Thiamine pyrophosphokinase (TPK) produces thiamine pyrophosphate, a cofactor for a number of enzymes, including pyruvate dehydrogenase and 2-ketoglutarate dehydrogenase. Episodic encephalopathy type thiamine metabolism dysfunction (OMIM 614458) due to TPK1 mutations is a recently described rare disorder. The mechanism of the disease, its phenotype and treatment are not entirely clear.

We present two patients with novel homozygous TPK1 mutations (Patient 1 with p.Ser160Leu and Patient 2 with p.Asp222His). Unlike the previously described phenotype, Patient 2 presented with a Leigh syndrome like non-episodic early-onset global developmental delay, thus extending the phenotypic spectrum of the disorder. We, therefore, propose that TPK deficiency may be a better name for the condition. The two cases help to further refine the neuroradiological features of TPK deficiency and show that MRI changes can be either fleeting or progressive and can affect either white or gray matter. We also show that in some cases lactic acidosis can be absent and 2-ketoglutaric aciduria may be the only biochemical marker. Furthermore, we have established the assays for TPK enzyme activity measurement and thiamine pyrophosphate quantification in frozen muscle and blood. These tests will help to diagnose or confirm the diagnosis of TPK deficiency in a clinical setting.

Early thiamine supplementation prevented encephalopathic episodes and improved developmental progression of Patient 1, emphasizing the importance of early diagnosis and treatment of TPK deficiency. We present evidence suggesting that thiamine supplementation may rescue TPK enzyme activity.

Lastly, in silico protein structural analysis shows that the p.Ser160Leu mutation is predicted to interfere with TPK dimerization, which may be a novel mechanism for the disease.

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).

References (14)

There are more references available in the full text version of this article.

Cited by (47)

  • Product inhibition of mammalian thiamine pyrophosphokinase is an important mechanism for maintaining thiamine diphosphate homeostasis

    2022, Biochimica et Biophysica Acta - General Subjects
    Citation Excerpt :

    They result in Leigh disease-like phenotypes with acute encephalopathy, ataxia, dystonia, seizures and elevated lactate and oxoglutarate plasma and cerebrospinal concentrations. In some cases, when a significant enzyme activity remains, as reported for the TPK1 mutation affecting the dimerization of monomers, a thiamine therapy can give promising results [28], emphasizing the importance of an early diagnosis. Indeed, early age intervention is an important factor for improving the outcome after thiamine supplementation and whole blood ThDP measurements could be helpful for diagnosis and biochemical monitoring following thiamine supplementation [29,30].

  • Eleven novel mutations and clinical characteristics in seven Chinese patients with thiamine metabolism dysfunction syndrome

    2020, European Journal of Medical Genetics
    Citation Excerpt :

    Thiamine metabolism dysfunction syndrome (THMD), which results from a deficiency of thiamine metabolism, comprises a group of rare, clinically and genetically heterogeneous encephalopathies with autosomal recessive inheritance (Banka et al., 2014).

  • The mitochondrial epilepsies

    2020, European Journal of Paediatric Neurology
View all citing articles on Scopus
View full text