Abstract

Hereditary, isolated Fanconi syndrome has been described a handful of times in the literature, displaying variable Mendelian patterns of inheritance. Some cases segregate as autosomal dominant and may or may not be associated with renal failure, whilst other kindreds show recessive and X-linked recessive inheritance. In 2001, Lichter-Konecki, et al. identified the locus (chromosome 15q15.3) in a kindred with autosomal dominant Fanconi syndrome. In 2014, Klootwijk, et al. found a causal mutation in EHHADH, a gene involved in peroxisomal beta-oxidation resulting in dominant Fanconi syndrome with preserved renal function in a black family. We applied whole exome sequencing technology to a Caucasian boy presenting with sporadic, idiopathic Fanconi syndrome. We identified a de novo mutation in EHHADH, the same variant as previously described by Klootwijk, et al. This mutation has been observed to cause the protein encoded by EHHADH to mislocalize to the mitochondria, where it interferes with mitochondrial beta-oxidation, the primary source of energy in renal proximal tubular cells. Aberrant mitochondrial beta-oxidation starves the renal tubule cells of energy required to maintain electrochemical gradients, essential for solute reabsorption. We describe the use of whole exome sequencing to determine the cause of Fanconi syndrome where the family history was compatible with a variety of different modes of inheritance. Our patient is the first Caucasian patient with a de novo mutation in EHHADH causing isolated Fanconi syndrome. This finding allows both informed prognostic discussion and genetic counselling.

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