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Disorders of fatty acid oxidation and autosomal recessive polycystic kidney disease—different clinical entities and comparable perinatal renal abnormalities

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Abstract

Background

Differential diagnosis of prenatally detected hyperechogenic and enlarged kidneys can be challenging as there is a broad phenotypic overlap between several rare genetic and non-genetic disorders. Metabolic diseases are among the rarest underlying disorders, but they demand particular attention as their prognosis and postnatal management differ from those of other diseases.

Methods

We report two cases of cystic, hyperechogenic and enlarged kidneys detected on prenatal ultrasound images, resulting in the suspected diagnosis of autosomal recessive polycystic kidney disease (ARPKD). Postnatal clinical course and work-up, however, revealed early, neonatal forms of disorders of fatty acid oxidation (DFAO) in both cases, namely, glutaric acidemia type II, based on identification of the novel, homozygous splice-site mutation c.1117-2A > G in the ETFDH gene, in one case and carnitine palmitoyltransferase II deficiency in the other case.

Results

Review of pre- and postnatal sonographic findings resulted in the identification of some important differences that might help to differentiate DFAO from ARPKD. In DFAO, kidneys are enlarged to a milder degree than in ARPKD, and the cysts are located ubiquitously, including also in the cortex and the subcapsular area. Interestingly, recent studies have pointed to a switch in metabolic homeostasis, referred to as the Warburg effect (aerobic glycolysis), as one of the underlying mechanisms of cell proliferation and cyst formation in cystic kidney disease. DFAO are characterized by the inhibition of oxidative phosphorylation, resulting in aerobic glycolysis, and thus they do resemble the Warburg effect. We therefore speculate that this inhibition might be one of the pathomechanisms of renal hyperproliferation and cyst formation in DFAO analogous to the reported findings in ARPKD.

Conclusions

Neonatal forms of DFAO can be differentially diagnosed in neonates with cystic or hyperechogenic kidneys and necessitate immediate biochemical work-up to provide early metabolic management.

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Authors and Affiliations

  1. Pediatric Nephrology, Children’s and Adolescents’ Hospital, University Hospital of Cologne, Kerpener Street 62, 50937, Cologne, Germany

    Agnes Hackl, Max C. Liebau, Lutz T. Weber & Sandra Habbig

  2. Department of Neonatology and Pediatric Intensive Therapy, Children’s and Adolescents’ Hospital, University Hospital of Cologne, Cologne, Germany

    Katrin Mehler & Anne Vierzig

  3. Division of Prenatal Medicine, Department of Obstetrics and Gynecology, University Hospital of Cologne, Cologne, Germany

    Ingo Gottschalk

  4. Department of Pediatric Radiology, Institute for Radiology, University Hospital of Cologne, Cologne, Germany

    Marcus Eydam

  5. Center for Hereditary Breast and Ovarian Cancer and Center for Integrated Oncology (CIO), Medical Faculty, University of Cologne and University Hospital Cologne, Cologne, Germany

    Jan Hauke

  6. Institute for Human Genetics, University Hospital of Cologne, Cologne, Germany

    Bodo B. Beck

  7. Nephrology Research Laboratory, Department II of Internal Medicine, University Hospital of Cologne, Cologne, Germany

    Max C. Liebau

  8. Center for Molecular Medicine, University Hospital of Cologne, Cologne, Germany

    Max C. Liebau

  9. Experimental Pediatrics and Metabolism, Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children’s Hospital, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

    Regina Ensenauer

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  1. Agnes Hackl
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Corresponding author

Correspondence to Agnes Hackl.

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As our study was a retrospective chart review, informed consent was not required.

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Table S1

Synopsis of the novel ETFDH splice mutation found at cDNA position c.1117-2A > G in patient 1 of this study. The variant c.1117-2A > G in ETFDH is predicted to be pathogenic by in silico analysis using the following tools: mutation taster (http://www.mutationtaster.org/) and Alamut software (*containing the splice prediction programmes SpliceSiteFinder-like, MAxEntScan, NNSplice, GeneSplicer, and Human Splicing Finder; http://www.interactive-biosoftware.com/doc/alamutvisual/). Assessment of the ExAC-Browser (containing a data set of ∼60,000 exomes from unrelated individuals sequenced as part of various disease-specific and population genetic studies; [14]) well as the dbSNP database [15] gave no evidence that this variant can also be found in non-affected persons. (DOCX 13 kb)

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Hackl, A., Mehler, K., Gottschalk, I. et al. Disorders of fatty acid oxidation and autosomal recessive polycystic kidney disease—different clinical entities and comparable perinatal renal abnormalities. Pediatr Nephrol 32, 791–800 (2017). https://doi.org/10.1007/s00467-016-3556-5

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  • DOI: https://doi.org/10.1007/s00467-016-3556-5

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