Thiamine Pyrophosphokinase Deficiency in Encephalopathic Children with Defects in the Pyruvate Oxidation Pathway

Abstract

Thiamine pyrophosphate (TPP) is an essential cofactor of the cytosolic transketolase and of three mitochondrial enzymes involved in the oxidative decarboxylation of either pyruvate, α-ketoglutarate or branched chain amino acids. Thiamine is taken up by specific transporters into the cell and converted to the active TPP by thiamine pyrophosphokinase (TPK) in the cytosol from where it can be transported into mitochondria. Here, we report five individuals from three families presenting with variable degrees of ataxia, psychomotor retardation, progressive dystonia, and lactic acidosis. Investigation of the mitochondrial energy metabolism showed reduced oxidation of pyruvate but normal pyruvate dehydrogenase complex activity in the presence of excess TPP. A reduced concentration of TPP was found in the muscle and blood. Mutation analysis of TPK1 uncovered three missense, one splice-site, and one frameshift mutation resulting in decreased TPK protein levels.

A framework for exhaustively mapping functional missense variants

“…We applied the higher‐throughput TileSeq approach, coupled with yeast complementation, to a diverse set of genes: SUMO1, for which heterozygous null variants are associated with cleft palate (Andreou et al , 2007); thiamine pyrophosphokinase 1 (TPK1), associated with vitamin B1 metabolism dysfunction (Mayr et al , 2011); and CALM1, CALM2, and CALM3, associated with cardiac arrhythmias (long‐QT syndrome (Crotti et al , 2013) and catecholaminergic polymorphic ventricular tachycardia (Nyegaard et al , 2012)). Because the three calmodulin genes encode the same polypeptide sequence, performing DMS for CALM1 also provided maps for CALM2 and CALM3.…”

“…The majority of these variants were scored as deleterious (Appendix Fig S9A). Thiamine metabolism dysfunction syndrome, reported to be caused by variants in TPK1, is a severe disease to which patients succumb in childhood (Mayr et al , 2011). Although GnomAD attempted to exclude subjects with severe pediatric disease, the abundance of rare predicted‐deleterious variants may be understood by the disease's recessive inheritance pattern.…”

Major Contribution of Genomic Copy Number Variation in Syndromic Congenital Heart Disease: The Use of MLPA as the First Genetic Test

“…It is known that mutations in this gene are inherited in a recessive mode. In general, affect- ed individuals present with acute encephalopathy, resulting in progressive neurological dysfunction [Mayr et al, 2011]. Since this defect is rare, and this gene has low expression in the heart, it was not possible to determine a clear correlation between this duplication and CHD of the patient.…”

Leigh syndrome: One disorder, more than 75 monogenic causes

“…[65][66][67] PDHc deficiency due to mutations in genes associated with TPP availability (TPK1, SLC19A3, and SLC25A19) can be missed because of the presence of TPP in routine PDHc enzymatic assays, but may be identifiable when measuring PDHc activity in the absence of TPP. 68,69 Mutations in the thiamine transporter SLC19A3 are well known to cause biotin/thiamineresponsive basal ganglia disease (BTBGD; MIM 607483), which phenocopies LS as a progressive encephalopathy with similar neuroimaging and episodic decline. 70 Unlike typical LS, patients with BTBGD can show significant clinical and neuroradiological improvement following administration of thiamine and high-dose biotin, particularly when commenced early in the disease course.…”