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Review
. 2025 Apr 4;20(1):160.
doi: 10.1186/s13023-025-03665-9.

The wide phenotypic spectrum of thiamine metabolism dysfunction syndrome 5 and its treatment

Alice Dallan #  1   2 , Giuseppe Reynolds #  1   2 , Carlotta Canavese  3 , Diana Carli  4 , Maria Luca  4 , Andrea Gazzin  2   5 , Marco Spada  2   6 , Francesco Porta  2   6 , Alessandro Mussa  7   8   9
Affiliations
Review

The wide phenotypic spectrum of thiamine metabolism dysfunction syndrome 5 and its treatment

Alice Dallan et al. Orphanet J Rare Dis. .

Abstract

Thiamine metabolism dysfunction syndrome 5 (TMDS5) is a rare inborn error of metabolism caused by variants in TPK1, leading to reduced TPK levels. This enzyme is crucial for the production of thiamine pyrophosphate, the active form of thiamine, a vital coenzyme in numerous metabolic pathways. The clinical presentation exhibits a diverse range of manifestations. In this review, we explore reported cases in the literature and present two cases representing the extremes of the clinical spectrum: recurrent ataxia and Leigh syndrome. The former phenotype follows a milder course. The second one is characterized by early onset and severe symptoms, including dystonia, epilepsy, and developmental regression, progressing rapidly to severe disability with high mortality. Typically, children exposed to infectious or traumatic triggers display episodes marked by ataxia and dystonia, with periods of good health or only mild disabilities in between. Treatment with the phosphorylated thiamine active bioform, TPP, is more effective in the recurrent ataxia form, especially when initiated promptly at symptom onset. Further studies are needed to identify available biomarkers and establish correlations between different variants, severity, and treatment response.

Keywords: TPK1; Leigh syndrome; Recurring ataxia; Thiamine; Thiamine metabolism dysfunction syndrome 5.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The ethical approval was obtained from the Intercompany Ethics Committee of A.O.U. Città della Salute e della Scienza di Torino, A.O. Ordine Mauriziano di Torino and A.S.L. Città di Torino, with application number 256/2022, protocol number 17/06/2022. Informed consent was obtained from parents of participants prior to their inclusion in the study and archived by authors according to the local ethics committee’s policy. The study was conducted in accordance with the ethical principles enshrined in the Helsinki Declaration. Consent for publication: Written consent for publication of the clinical details and any accompanying images was obtained from parents of participants and archived by authors according to the local ethics committee’s policy. Competing interests: All the authors declare no conflicts of interest.

Figures

Image 1
Image 1
Thiamine pathways: (A) Thiamine undergoes phosphorylation to produce thiamine pyrophosphate (TPP) through the action of thiamine pyrophosphokinase 1 (hTPK1). Further phosphorylation by mitochondrial thiamine triphosphosphate synthase results in thiamine triphosphate (TTP). Thiamine can be dephosphorylated to thiamine monophosphate (TMP) and thiamine by thiamine phosphatase. (B) The absorption of thiamine in the small intestine and its entry into cells involve transporters encoded by SLC19A2/SLC19A3. Inside cells, thiamine is pyrophosphorylated to its active form (TPP) by hTPK1. TPP serves as a cofactor for three dehydrogenases in mitochondria: (1) pyruvate dehydrogenase complex (PDHC), (2) branched-chain alfa-keto acid dehydrogenase (BCKDH), and (3) alpha-ketoglutarate dehydrogenase (α-KGDH). Outside of mitochondria, TPP functions as a cofactor for Transketolase and 2-hydroxyacyl-CoA Lyase 1 (HACL1)
Image 2
Image 2
Magnetic Resonance Imaging (MRI) performed at 4 years of age in Patient 2 revealing parenchymal depletion with enlargement of subarachnoid spaces (A), alterations in the putamen, striatum, and caudate nuclei (B, C)
See this image and copyright information in PMC

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