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Open Access Research article

Mitochondrial mosaics in the liver of 3 infants with mtDNA defects

Frank Roels1*, Patrick Verloo2, François Eyskens3, Baudouin François4, Sara Seneca5, Boel De Paepe2, Jean-Jacques Martin6, Valerie Meersschaut7, Marleen Praet1, Emmanuel Scalais8, Marc Espeel9, Joél Smet2, Gert Van Goethem10 and Rudy Van Coster2*

Author Affiliations

1 Department of Pathology, Ghent University Hospital, block A, De Pintelaan 185, 9000 Gent, Belgium

2 Department of Pediatrics, Division of Pediatric Neurology, Ghent University Hospital, Ghent, Belgium

3 Metabolic Unit, PCMA, Antwerp, Belgium

4 Centre Pinocchio CHC Clinique de l'Espérance, Montegnée, Belgium

5 Center for Medical Genetics, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium

6 Neuropathology, University of Antwerp, Antwerp, Belgium

7 Radiology and Medical Imaging, Ghent University Hospital, Belgium

8 Division of Paediatric Neurology, Centre hospitalier de Luxembourg, Luxembourg

9 Human Anatomy and Embryology, Ghent University, Ghent, Belgium

10 Division of Neurology and Neuromuscular Reference Center, University Hospital of Antwerp, Antwerp, Belgium

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BMC Clinical Pathology 2009, 9:4  doi:10.1186/1472-6890-9-4

Published: 5 June 2009

Abstract

Background

In muscle cytochrome oxidase (COX) negative fibers (mitochondrial mosaics) have often been visualized.

Methods

COX activity staining of liver for light and electron microscopy, muscle stains, blue native gel electrophoresis and activity assays of respiratory chain proteins, their immunolocalisation, mitochondrial and nuclear DNA analysis.

Results

Three unrelated infants showed a mitochondrial mosaic in the liver after staining for COX activity, i.e. hepatocytes with strongly reactive mitochondria were found adjacent to cells with many negative, or barely reactive, mitochondria. Deficiency was most severe in the patient diagnosed with Pearson syndrome. Ragged-red fibers were absent in muscle biopsies of all patients. Enzyme biochemistry was not diagnostic in muscle, fibroblasts and lymphocytes. Blue native gel electrophoresis of liver tissue, but not of muscle, demonstrated a decreased activity of complex IV; in both muscle and liver subcomplexes of complex V were seen. Immunocytochemistry of complex IV confirmed the mosaic pattern in two livers, but not in fibroblasts. MRI of the brain revealed severe white matter cavitation in the Pearson case, but only slight cortical atrophy in the Alpers-Huttenlocher patient, and a normal image in the 3rd. MtDNA in leucocytes showed a common deletion in 50% of the mtDNA molecules of the Pearson patient. In the patient diagnosed with Alpers-Huttenlocher syndrome, mtDNA was depleted for 60% in muscle. In the 3rd patient muscular and hepatic mtDNA was depleted for more than 70%. Mutations in the nuclear encoded gene of POLG were subsequently found in both the 2nd and 3rd patients.

Conclusion

Histoenzymatic COX staining of a liver biopsy is fast and yields crucial data about the pathogenesis; it indicates whether mtDNA should be assayed. Each time a mitochondrial disorder is suspected and muscle data are non-diagnostic, a liver biopsy should be recommended. Mosaics are probably more frequent than observed until now. A novel pathogenic mutation in POLG is reported.

Tentative explanations for the mitochondrial mosaics are, in one patient, unequal partition of mutated mitochondria during mitoses, and in two others, an interaction between products of several genes required for mtDNA maintenance.