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

• Published in: Molecular genetics and metabolism 2014-12, Vol.113 (4), p.301-306
• Main Authors: Banka, Siddharth, de Goede, Christian, Yue, Wyatt W., Morris, Andrew A.M., von Bremen, Beate, Chandler, Kate E., Feichtinger, René G., Hart, Claire, Khan, Nasaim, Lunzer, Verena, Mataković, Lavinija, Marquardt, Thorsten, Makowski, Christine, Prokisch, Holger, Debus, Otfried, Nosaka, Kazuto, Sonwalkar, Hemant, Zimmermann, Franz A., Sperl, Wolfgang, Mayr, Johannes A.
• Format: Article
• Language: English
• Subjects: Acidosis, Lactic; Amino Acid Sequence; Child; Child, Preschool; Episodic encephalopathy type thiamine metabolism dysfunction; Female; Humans; Magnetic Resonance Imaging; Male; Models, Molecular; Mutation; Nervous System Diseases - drug therapy; Nervous System Diseases - genetics; Nervous System Diseases - metabolism; Nervous System Diseases - pathology; Phenotype; Protein Conformation; Protein Multimerization; Thiamin Pyrophosphokinase - chemistry; Thiamin Pyrophosphokinase - deficiency; Thiamin Pyrophosphokinase - genetics; Thiamin Pyrophosphokinase - metabolism; Thiamine; Thiamine - administration & dosage; Thiamine - therapeutic use; Thiamine Pyrophosphate - metabolism; Thiamine pyrophosphokinase; TPK deficiency; TPK1
• ISSN: 1096-7192; 1096-7206
• DOI: 10.1016/j.ymgme.2014.09.010

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. •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.