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View of Cryostat Section; Islet of Stained Cells Sur- Liver:Figure Ultrastructure 8 and Reaction for Cytochrome Oxidase Rounded by Unstained Parenchyma

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View of Cryostat Section; Islet of Stained Cells Sur- Liver:Figure Ultrastructure 8 and Reaction for Cytochrome Oxidase Rounded by Unstained Parenchyma BMC Clinical Pathology BioMed Central Research article Open Access Mitochondrial mosaics in the liver of 3 infants with mtDNA defects Frank Roels*1, 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 Coster*2 Address: 1Department of Pathology, Ghent University Hospital, block A, De Pintelaan 185, 9000 Gent, Belgium, 2Department of Pediatrics, Division of Pediatric Neurology, Ghent University Hospital, Ghent, Belgium, 3Metabolic Unit, PCMA, Antwerp, Belgium, 4Centre Pinocchio CHC Clinique de l'Espérance, Montegnée, Belgium, 5Center for Medical Genetics, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium, 6Neuropathology, University of Antwerp, Antwerp, Belgium, 7Radiology and Medical Imaging, Ghent University Hospital, Belgium, 8Division of Paediatric Neurology, Centre hospitalier de Luxembourg, Luxembourg, 9Human Anatomy and Embryology, Ghent University, Ghent, Belgium and 10Division of Neurology and Neuromuscular Reference Center, University Hospital of Antwerp, Antwerp, Belgium Email: Frank Roels* - [email protected]; Patrick Verloo - [email protected]; François Eyskens - [email protected]; Baudouin François - [email protected]; Sara Seneca - [email protected]; Boel De Paepe - [email protected]; Jean- Jacques Martin - [email protected]; Valerie Meersschaut - [email protected]; Marleen Praet - [email protected]; Emmanuel Scalais - [email protected]; Marc Espeel - [email protected]; Joél Smet - [email protected]; Gert Van Goethem - [email protected]; Rudy Van Coster* - [email protected] * Corresponding authors Published: 5 June 2009 Received: 9 July 2008 Accepted: 5 June 2009 BMC Clinical Pathology 2009, 9:4 doi:10.1186/1472-6890-9-4 This article is available from: http://www.biomedcentral.com/1472-6890/9/4 © 2009 Roels et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 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. Page 1 of 12 (page number not for citation purposes) BMC Clinical Pathology 2009, 9:4 http://www.biomedcentral.com/1472-6890/9/4 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. Background Enzymes and metabolites of oxidative phosphorylation Mitochondrial heterogeneity after cytochrome oxidase were measured in liver, cultured fibroblasts, lymphocytes staining has often been visualized in muscle [1-15]. or muscle. Whether this is caused by varying proportions of mutant and/or depleted versus wildtype mtDNA, has not (com- Blue native PAGE was performed on liver or muscle pletely) been elucidated. Müller-Höcker [16] using COX homogenate as described [26]. MtDNA was analysed by histochemistry demonstrated a mosaic in the liver of an RT-PCR in muscle or leucocytes or liver according to infant with encephalopathy, cholestatic giant cell hepati- [27]The nuclear gene POLG encoding polymerase gamma tis and mtDNA depletion of unknown origin. was sequenced as described [28]. Pearson syndrome (PS) (moderate psychomotor retarda- For immunocytochemistry cytospins of cultured fibrob- tion, pancytopenia and pancreatic insufficiency; MIM lasts were prepared and stained as described [29]. Of liver 557000) and Alpers-Huttenlocher syndrome (AHS) tissue 8 μm paraffin sections were deparaffinized in (myoclonal epilepsy, liver and brain disease; MIM xylene and rehydrated in ethanol solutions. After blocking 203700) are known to harbour defects of mitochondrial with 2.5% BSA in PBS for 30 min, sections were incubated function [17-19], but mitochondrial mosaics in the liver with primary antibodies in the same solution during 2 have not been described. hours at room temperature. For the detection of each of the five complexes of the oxidative phosphorylation, We report on a 2.5 year old girl with PS, a 1-year old boy monoclonal antibodies were selected that were directed with AHS, and a 3-year old girl with mtDNA depletion; all against the gene products of NDUFS7, SDHB, UQCRC2, show mosaics in their liver parenchyma. In contrast non- MTCO1 and ATP5A1 (Invitrogen). Immunodetection was parenchymal cells appear microscopically normal. accomplished with the alkaline phosphatase labelled EnVision polymer (Dako) and fast red chromogen. Nuclei Partial results were published in abstract form [20]. were counterstained with hematoxylin and slides were mounted with aquatex. Methods Muscle stains included Gomori-trichrome, fiber typing by Ethical issues: all tests and investigations reported in this ATP-ase after preincubation at pH 4.6, and localisation of paper were carried out for diagnostic purposes in the COX-and NADH-TR activities according to standard reci- interest of the patients, and under the authority of the uni- pes [21]. In the liver cytochrome oxidase activity was vis- versity hospitals involved. In particular the parents gave ualized with diaminobenzidine according to Seligman et approval for the muscle and liver biopsies, as well as for al [22], as modified by Novikoff & Goldfischer [23]. publication. Briefly, liver samples were prefixed in 1% cold buffered glutaraldehyde for 2 hrs in order to preserve ultrastruc- Results ture. After rinsing, cryostat sections were incubated in Patients open vials at 37° in a DAB medium at pH 6 in acetate Patient 1, the daughter of non-consanguineous parents, buffer containing 0.005 M MnCl2, with and without presents with slight pancytopenia (hemoglobin 9 g/dL, added cytochrome c (1 mg/10 ml) for 2 and 4 hrs. DAB leucocytes 3–5000/ml) and exocrine pancreatic dysfunc- staining of mitochondria was shown to be both O2 and tion (lipase up to 700 U/L but amylase normal). In addi- cytochrome c dependent [24,25]. For light microscopy tion there is moderate psychomotor retardation; at 3 y she (LM) 7 μm sections were mounted in aquamount; for is not walking, and talks little. A diagnosis of Pearson syn- electron microscopy 60 μm sections were postfixed in 1% drome is proposed. MRI shows bilateral cavities in the OsO4. Semithin sections were also examined by LM. frontal white matter and right occipital lobe (figures 1a, b, Page 2 of 12 (page number not for citation purposes) BMC Clinical Pathology 2009, 9:4 http://www.biomedcentral.com/1472-6890/9/4 a b c d PatientFigure 2,2 brain MRI Patient 2, brain MRI. 2a: T2 weighted; mild tot moderate PatientFigure 1,1 brain MRI dilatation of ventricles and peripheral liquor spaces suggest- Patient 1, brain MRI. 1a: TRACE sequence shows cyto- ing cerebral atrophy. 2b: TRACE sequence shows cytotoxic toxic oedema in frontoparietal white matter bilaterally, and oedema in cortex of right central gyrus. 2c: 3 months later. in right occipital. 1b: FLAIR sequence, right occipital and Focal cortical atrophy of central gyrus bilaterally. 2d: 2 years bilateral frontoparietal lesions; compare to fig 1a. 1c: 5 later. Focal cortical atrophy of central gyrus bilaterally. months later. T1 weighted without iv contrast. Bifrontal white matter loss with lacunae, small lacuna in right occipital. 1d: Coronal section;
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