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

## TL;DR

Thiamine metabolism dysfunction syndrome 5 is a rare genetic disorder with a wide range of symptoms, from mild to severe, and treatment with a specific form of thiamine can be effective.

## Contribution

The paper reviews the diverse clinical spectrum of TMDS5 and highlights treatment effectiveness based on symptom severity.

## Key findings

- TMDS5 caused by TPK1 variants leads to a wide range of clinical manifestations, from mild ataxia to severe Leigh syndrome.
- Phosphorylated thiamine (TPP) treatment is more effective for milder ataxia cases when administered promptly.
- Further research is needed to identify biomarkers and understand variant-specific treatment responses.

## 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.