title: Expanding the clinical and molecular spectrum of thiamine pyrophosphokinase deficiency: a treatable neurological disorder caused by TPK1 mutations.
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.
authors.affiliation: 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.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Banka
authors.affiliation: Department of Paediatric Neurology, Royal Preston Hospital, Preston, UK.
authors.forename: Christian
authors.initials: C
authors.lastname: de Goede
authors.affiliation: Structural Genomics Consortium, Old Road Campus Research Building, University of Oxford, Oxford, UK.
authors.forename: Wyatt W
authors.initials: WW
authors.lastname: Yue
authors.affiliation: Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, MAHSC, Manchester, UK.
authors.forename: Andrew A M
authors.initials: AA
authors.lastname: Morris
authors.affiliation: Department of Paediatrics, Royal Blackburn Hospital, Blackburn, UK.
authors.forename: Beate
authors.initials: B
authors.lastname: von Bremen
authors.affiliation: Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, MAHSC, Manchester, UK.
authors.forename: Kate E
authors.initials: KE
authors.lastname: Chandler
authors.affiliation: Department of Paediatrics, Paracelsus Medical University, Salzburg, Austria.
authors.forename: René G
authors.initials: RG
authors.lastname: Feichtinger
authors.affiliation: Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, MAHSC, Manchester, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Hart
authors.affiliation: Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, MAHSC, Manchester, UK.
authors.forename: Nasaim
authors.initials: N
authors.lastname: Khan
authors.affiliation: Department of Paediatrics, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Verena
authors.initials: V
authors.lastname: Lunzer
authors.affiliation: Department of Paediatrics, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Lavinija
authors.initials: L
authors.lastname: Mataković
authors.affiliation: Department of General Paediatrics, University Children's Hospital Münster, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Marquardt
authors.affiliation: Department of Paediatrics, Technische Universität München, Munich, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Makowski
authors.affiliation: Institute of Human Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.affiliation: Clemenshospital, Children's Hospital, Münster, Germany.
authors.forename: Otfried
authors.initials: O
authors.lastname: Debus
authors.affiliation: Department of Chemistry, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nosaka
authors.affiliation: Department of Radiology, Royal Preston Hospital, Preston, UK.
authors.forename: Hemant
authors.initials: H
authors.lastname: Sonwalkar
authors.affiliation: Department of Paediatrics, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Franz A
authors.initials: FA
authors.lastname: Zimmermann
authors.affiliation: Department of Paediatrics, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sperl
authors.affiliation: Department of Paediatrics, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Mayr
mesh_terms: D000140:Acidosis, Lactic; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D009422:Nervous System Diseases / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011487:Protein Conformation; D055503:Protein Multimerization; D013836:Thiamin Pyrophosphokinase / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D013831:Thiamine / Q000008:administration & dosage / Q000627:therapeutic use; D013835:Thiamine Pyrophosphate / Q000378:metabolism
chemical_list: D013836:Thiamin Pyrophosphokinase; D013835:Thiamine Pyrophosphate; D013831:Thiamine
keywords: Episodic encephalopathy type thiamine metabolism dysfunction; TPK deficiency; TPK1; Thiamine; Thiamine pyrophosphokinase