Unveiling long-standing low-molecular-weight proteinuria: A proximal tubular mitochondrial enzyme impairment caused...

The energy requirement of renal proximal tubular cells depends on mitochondrial fatty acid β-oxidation. Enoyl-CoA hydratase-l-3-hydroxyacyl-CoA dehydrogenase (EHHADH) is a crucial enzyme in mitochondrial fatty acid oxidation, and mutations in EHHADH reportedly cause Fanconi syndrome. Here, we report the case of a 28-year-old Japanese woman with a long-term history of low-molecular-weight proteinuria (LMWP) who exhibited a missense mutation in the EHHADH gene. She was diagnosed with LMWP at 4 years of age. The search for the CLCN5 gene was unremarkable, and kidney biopsy revealed no significant tubulointerstitial changes. The LMWP persisted, and glucosuria gradually developed thereafter. Unexpectedly, next-generation sequencing identified a heterozygous missense mutation in the EHHADH gene. Her father, who harbored LMWP, also had the same mutation. Furthermore, immunostaining of the stored kidney specimens showed decreased immunoreactivity for cytochrome c oxidase subunit 4 in the proximal tubules, suggesting an underlying mitochondrial impairment.