SLC25A19 – Leigh syndrome

A homozygous missense variant in SLC25A19 was identified in a Tunisian child with clinical and neuroimaging hallmarks of Leigh syndrome. Targeted sequencing of 281 nuclear genes revealed c.454C>G (p.Pro152Ala) in SLC25A19 in one patient, consistent with autosomal recessive inheritance and a thiamine transporter defect ([PMID:36093993]). No segregation data or additional unrelated cases have yet been reported.

Functional studies of SLC25A19 variants in thiamine metabolism dysfunction syndrome 4 (THMD4) demonstrate that missense changes disrupt mitochondrial thiamine pyrophosphate transport in cellular models, supporting a loss-of-function mechanism ([PMID:34587972]; [PMID:31506564]). However, LS-specific functional assays and further case reports are needed to confirm the pathogenic role of SLC25A19 in Leigh syndrome. Key take-home: SLC25A19 should be included in genetic panels for Leigh syndrome, with potential consideration of thiamine supplementation as a targeted therapy.

References

• Bioscience Reports • 2022 • Next-generation sequencing of Tunisian Leigh syndrome patients reveals novel variations: impact for diagnosis and treatment. PMID:36093993
• Orphanet Journal of Rare Diseases • 2021 • Identification and functional analysis of novel SLC25A19 variants causing thiamine metabolism dysfunction syndrome 4. PMID:34587972
• Journal of Human Genetics • 2019 • Functional analysis of the third identified SLC25A19 mutation causative for the thiamine metabolism dysfunction syndrome 4. PMID:31506564

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