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Utility of Whole Blood Thiamine Pyrophosphate Evaluation in TPK1-Related Diseases

Bugiardini, E; Pope, S; Feichtinger, RG; Poole, OV; Pittman, AM; Woodward, CE; Heales, S; Quinlivan, R; Houlden, H; Mayr, JA; et al. Bugiardini, E; Pope, S; Feichtinger, RG; Poole, OV; Pittman, AM; Woodward, CE; Heales, S; Quinlivan, R; Houlden, H; Mayr, JA; Hanna, MG; Pitceathly, RDS (2019) Utility of Whole Blood Thiamine Pyrophosphate Evaluation in TPK1-Related Diseases. JOURNAL OF CLINICAL MEDICINE, 8 (7). p. 991. ISSN 2077-0383 https://doi.org/10.3390/jcm8070991
SGUL Authors: Pittman, Alan Michael

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Abstract

TPK1 mutations are a rare, but potentially treatable, cause of thiamine deficiency. Diagnosis is challenging given the phenotypic overlap that exists with other metabolic and neurological disorders. We report a case of TPK1-related disease presenting with Leigh-like syndrome and review the diagnostic utility of thiamine pyrophosphate (TPP) blood measurement. The proband, a 35-year-old male, presented at four months of age with recurrent episodes of post-infectious encephalopathy. He subsequently developed epilepsy, learning difficulties, sensorineural hearing loss, spasticity, and dysphagia. There was a positive family history for Leigh syndrome in an older brother. Plasma lactate was elevated (3.51 mmol/L) and brain MRI showed bilateral basal ganglia hyperintensities, indicative of Leigh syndrome. Histochemical and spectrophotometric analysis of mitochondrial respiratory chain complexes I, II+III, and IV was normal. Genetic analysis of muscle mitochondrial DNA was negative. Whole exome sequencing of the proband confirmed compound heterozygous variants in TPK1: c. 426G>C (p. Leu142Phe) and c. 258+1G>A (p.?). Blood TPP levels were reduced, providing functional evidence for the deleterious effects of the variants. We highlight the clinical and bioinformatics challenges to diagnosing rare genetic disorders and the continued utility of biochemical analyses, despite major advances in DNA sequencing technology, when investigating novel, potentially disease-causing, genetic variants. Blood TPP measurement represents a fast and cost-effective diagnostic tool in TPK1-related diseases.

Item Type: Article
Additional Information: © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Keywords: mitochondrial diseases, TPK1, thiamine pyrophosphate, Leigh syndrome, thiamine deficiency
Journal or Publication Title: JOURNAL OF CLINICAL MEDICINE
ISSN: 2077-0383
Dates:
DateEvent
8 July 2019Published
3 July 2019Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
G0601943Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
2012-305121Seventh Framework Programmehttp://dx.doi.org/10.13039/501100004963
MR/S002065/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
Web of Science ID: WOS:000479003300076
URI: https://openaccess.sgul.ac.uk/id/eprint/111339
Publisher's version: https://doi.org/10.3390/jcm8070991

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