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

Mol Genet Metab. 2014 Dec;113(4):301-6. doi: 10.1016/j.ymgme.2014.09.010.

Siddharth Banka ¹, Christian de Goede ², Wyatt W Yue ³, Andrew A M Morris ⁴, Beate von Bremen ⁵, Kate E Chandler ⁴, René G Feichtinger ⁶, Claire Hart ⁴, Nasaim Khan ⁴, Verena Lunzer ⁶, Lavinija Mataković ⁶, Thorsten Marquardt ⁷, Christine Makowski ⁸, Holger Prokisch ⁹, Otfried Debus ¹⁰, Kazuto Nosaka ¹¹, Hemant Sonwalkar ¹², Franz A Zimmermann ⁶, Wolfgang Sperl ⁶, Johannes A Mayr ⁶

Affiliations

1 Faculty of Medical and Human Sciences, Manchester Centre for Genomic Medicine, Institute of Human Development, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Manchester, UK; Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, MAHSC, Manchester, UK. Electronic address: Siddharth.Banka@manchester.ac.uk.
2 Department of Paediatric Neurology, Royal Preston Hospital, Preston, UK.
3 Structural Genomics Consortium, Old Road Campus Research Building, University of Oxford, Oxford, UK.
4 Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, MAHSC, Manchester, UK.
5 Department of Paediatrics, Royal Blackburn Hospital, Blackburn, UK.
6 Department of Paediatrics, Paracelsus Medical University, Salzburg, Austria.
7 Department of General Paediatrics, University Children's Hospital Münster, Germany.
8 Department of Paediatrics, Technische Universität München, Munich, Germany.
9 Institute of Human Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.
10 Clemenshospital, Children's Hospital, Münster, Germany.
11 Department of Chemistry, Hyogo College of Medicine, Nishinomiya, Japan.
12 Department of Radiology, Royal Preston Hospital, Preston, UK.

PMID: 25458521 DOI: 10.1016/j.ymgme.2014.09.010

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.

Keywords

Episodic encephalopathy type thiamine metabolism dysfunction; TPK deficiency; TPK1; Thiamine; Thiamine pyrophosphokinase.

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