Neuropediatrics 2017; 48(04): 309-314
DOI: 10.1055/s-0037-1603776
Review Article
Georg Thieme Verlag KG Stuttgart · New York

A Guideline for the Diagnosis of Pediatric Mitochondrial Disease: The Value of Muscle and Skin Biopsies in the Genetics Era

Saskia B. Wortmann
1  Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria
2  Institute of Human Genetics, Technical University Munich, Munich, Germany
3  Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany
,
Johannes A. Mayr
1  Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria
,
Jean Marc Nuoffer
4  University Institute of Clinical Chemistry, Bern University Hospital, Bern, Switzerland
,
Holger Prokisch
2  Institute of Human Genetics, Technical University Munich, Munich, Germany
3  Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany
,
Wolfgang Sperl
1  Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria
› Author Affiliations
Further Information

Publication History

16 March 2017

03 May 2017

Publication Date:
09 June 2017 (eFirst)

Abstract

Mitochondrial diseases are highly heterogeneous on the clinical, biochemical, and genetic level. In the traditional diagnostic approach (“biopsy first”) the evaluation of the affected individual and his body fluids, combined with the analysis of the respiratory chain enzymes in muscle based the subsequent Sanger sequencing of single candidate genes (“from function to gene”). Within the past few years, next-generation sequencing techniques of leucocyte-derived DNA (e.g., exome sequencing), with a diagnostic yield of more than 40%, have become the first line routine technology. This implicates that the invasive muscle biopsy is performed less often, especially in children. Furthermore, in this “genetics-first” approach the detection of new candidate genes precedes functional evaluations (“from gene to function”) leading to reverse phenotyping of affected individuals. Here, we line out the value of muscle and other tissue biopsies in this “genetics-first” era. We describe when and why it is still needed. We create awareness of pitfalls in the genetic diagnostics of mitochondrial diseases still necessitating tissue biopsies. Finally, we discuss why tissue biopsies are required for confirmatory diagnostics, or for getting a biochemical diagnosis in patients with hidden variants not detectable by standard genetics.

Note

The study was financially supported by the E-Rare project GENOMIT (01GM1207 to H.P., Austrian Science Fonds [FWF]: I 2741-B26 to J.A.M.), the Vereinigung zur Förderung pädiatrischer Forschung und Fortbildung Salzburg.


Supplementary Material