Siblings of FBXL4-related mitochondrial DNA depletion syndrome, leading to fatal fulminant pneumonia

TL;DR

Two siblings with a rare mitochondrial disease caused by FBXL4 gene variants died from severe pneumonia, suggesting the condition may impair the body's ability to fight lung infections.

Contribution

Identifies a novel clinical manifestation of FBXL4-MTDPS as increased susceptibility to fatal pneumonia.

Findings

Two siblings with FBXL4-MTDPS died from fulminant pneumonia in infancy.

Autopsy showed severe bacterial lung infection as the cause of death.

FBXL4-MTDPS may impair pulmonary infection defense mechanisms.

Abstract

The F-box and leucine-rich repeat protein 4 (FBXL4) is a nuclear encoded mitochondrial protein essential for mitochondrial DNA (mtDNA) maintenance. Biallelic variants in FBXL4 cause FBXL4-related mitochondrial DNA depletion syndrome (FBXL4-MTDPS), characterized by lactic acidosis and developmental delay. We report two siblings diagnosed with FBXL4-MTDPS who died of fulminant pneumonia in infancy; autopsy revealed extensive pulmonary inflammation consistent with severe bacterial infection. FBXL4-MTDPS may involve intrinsic defects in pulmonary infection defense, increasing susceptibility to fatal infection such as pneumonia.

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