Frank Roels

Publications (25)69.04 Total impact

• Article: Polymerase gamma deficiency (POLG): clinical course in a child with a two stage evolution from infantile myocerebrohepatopathy spectrum to an Alpers syndrome and neuropathological findings of Leigh's encephalopathy.

  Emmanuel Scalais, Baudouin Francois, Patrick Schlesser, Rene Stevens, Christian Nuttin, Jean-Jacques Martin, Rudy Van Coster, Sara Seneca, Frank Roels, Gert Van Goethem, Ann Löfgren, Linda De Meirleir
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  ABSTRACT: Description of the clinical course in a child compound heterozygous for POLG1 mutations, neuropathology findings and results of dietary treatment based on fasting avoidance and long chain triglycerides (LCT) restriction. At 3(1/2) months of age the patient presented with severe hypoglycemia, hyperlactatemia, moderate ketosis and hepatic failure. Fasting hypoglycemia occurred 8 h after meals. The hypoglycemia did not respond to glucagon. She was supplemented with IV glucose and/or frequent feedings, but developed liver insufficiency which was reversed by long-chain triglyceride (LCT) restriction. Alpha-foeto-protein (AFP) levels were elevated and returned to low values after dietary treatment. Liver biopsy displayed cirrhosis, bile ductular proliferation, steatosis, isolated complex IV defect in part of the liver mitochondria, and mitochondrial DNA depletion (27% of control values). Two heterozygous mutations (p. [Ala467Thr] + p. [Gly848Ser]) were found in the POLG1 gene. At 3 years of age she progressively developed refractory mixed type seizures including a focal component and psychomotor regression which fulfilled the criteria of Alpers syndrome (AS) although the initial presentation was compatible with infantile myocerebrohepatopathy spectrum (MCHS). She died at 5 years of age of respiratory insufficiency. Neuropathologic investigation revealed lesions in the right striatal area and the inferior colliculi typical for Leigh's encephalopathy. The present patient showed an evolution from infantile MCHS to AS, and dietary treatment seemed to slow the progression of liver failure. In spite of the late clinical features of AS, it extends the neuropathological spectrum of AS and polymerase gamma deficiency (POLG) to Leigh syndrome lesions.
  European journal of paediatric neurology: EJPN: official journal of the European Paediatric Neurology Society 02/2012; 16(5):542-8. · 2.01 Impact Factor
• Source

  Available from: Gert van goethem

  Article: Mitochondrial mosaics in the liver of 3 infants with mtDNA defects.

  Frank Roels, Patrick Verloo, François Eyskens, Baudouin François, Sara Seneca, Boel De Paepe, Jean-Jacques Martin, Valerie Meersschaut, Marleen Praet, Emmanuel Scalais, Marc Espeel, Joél Smet, Gert Van Goethem, Rudy Van Coster
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  ABSTRACT: In muscle cytochrome oxidase (COX) negative fibers (mitochondrial mosaics) have often been visualized. 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. 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. 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.
  BMC Clinical Pathology 07/2009; 9:4.
• Source

  Available from: Stéphane Savary

  Article: Phenylbutyrate up-regulates the adrenoleukodystrophy-related gene as a nonclassical peroxisome proliferator.

  Catherine Gondcaille, Marianne Depreter, Stéphane Fourcade, Maria Rita Lecca, Sabrina Leclercq, Pascal G P Martin, Thierry Pineau, Françoise Cadepond, Martine ElEtr, Nathalie Bertrand, Alain Beley, Sandrine Duclos, Dirk De Craemer, Frank Roels, Stéphane Savary, Maurice Bugaut
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  ABSTRACT: X-linked adrenoleukodystrophy (X-ALD) is a demyelinating disease due to mutations in the ABCD1 (ALD) gene, encoding a peroxisomal ATP-binding cassette transporter (ALDP). Overexpression of adrenoleukodystrophy-related protein, an ALDP homologue encoded by the ABCD2 (adrenoleukodystrophy-related) gene, can compensate for ALDP deficiency. 4-Phenylbutyrate (PBA) has been shown to induce both ABCD2 expression and peroxisome proliferation in human fibroblasts. We show that peroxisome proliferation with unusual shapes and clusters occurred in liver of PBA-treated rodents in a PPARalpha-independent way. PBA activated Abcd2 in cultured glial cells, making PBA a candidate drug for therapy of X-ALD. The Abcd2 induction observed was partially PPARalpha independent in hepatocytes and totally independent in fibroblasts. We demonstrate that a GC box and a CCAAT box of the Abcd2 promoter are the key elements of the PBA-dependent Abcd2 induction, histone deacetylase (HDAC)1 being recruited by the GC box. Thus, PBA is a nonclassical peroxisome proliferator inducing pleiotropic effects, including effects at the peroxisomal level mainly through HDAC inhibition.
  The Journal of Cell Biology 05/2005; 169(1):93-104. · 10.26 Impact Factor
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  Available from: Jo Vandesompele

  Article: No evidence for involvement of SDHD in neuroblastoma pathogenesis.

  Katleen De Preter, Jo Vandesompele, Jasmien Hoebeeck, Caroline Vandenbroecke, Jöel Smet, Annick Nuyts, Geneviève Laureys, Valérie Combaret, Nadine Van Roy, Frank Roels, Rudy Van Coster, Marleen Praet, Anne De Paepe, Frank Speleman
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  ABSTRACT: Deletions in the long arm of chromosome 11 are observed in a subgroup of advanced stage neuroblastomas with poor outcome. The deleted region harbours the tumour suppressor gene SDHD that is frequently mutated in paraganglioma and pheochromocytoma, which are, like neuroblastoma, tumours originating from the neural crest. In this study, we sought for evidence for involvement of SDHD in neuroblastoma. SDHD was investigated on the genome, transcriptome and proteome level using mutation screening, methylation specific PCR, real-time quantitative PCR based homozygous deletion screening and mRNA expression profiling, immunoblotting, functional protein analysis and ultrastructural imaging of the mitochondria. Analysis at the genomic level of 67 tumour samples and 37 cell lines revealed at least 2 bona-fide mutations in cell lines without allelic loss at 11q23: a 4bp-deletion causing skip of exon 3 resulting in a premature stop codon in cell line N206, and a Y93C mutation in cell line NMB located in a region affected by germline SDHD mutations causing hereditary paraganglioma. No evidence for hypermethylation of the SDHD promotor region was observed, nor could we detect homozygous deletions. Interestingly, SDHD mRNA expression was significantly reduced in SDHD mutated cell lines and cell lines with 11q allelic loss as compared to both cell lines without 11q allelic loss and normal foetal neuroblast cells. However, protein analyses and assessment of mitochondrial morphology presently do not provide clues as to the possible effect of reduced SDHD expression on the neuroblastoma tumour phenotype. Our study provides no indications for 2-hit involvement of SDHD in the pathogenesis of neuroblastoma. Also, although a haplo-insufficient mechanism for SDHD involvement in advanced stage neuroblastoma could be considered, the present data do not provide consistent evidence for this hypothesis.
  BMC Cancer 09/2004; 4:55. · 3.01 Impact Factor
• Article: Human peroxisomal disorders.

  Marianne Depreter, Marc Espeel, Frank Roels
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  ABSTRACT: Peroxisomes are single membrane-bound cell organelles performing numerous metabolic functions. The present article aims to give an overview of our current knowledge about inherited peroxisomal disorders in which these organelles are lacking or one or more of their functions are impaired. They are multiorgan disorders and the nervous system is implicated in most. After a summary of the historical names and categories, each having distinct symptoms and prognosis, microscopic pathology is reviewed in detail. Data from the literature are added to experience in the authors' laboratory with 167 liver biopsy and autopsy samples from peroxisomal patients, and with a smaller number of chorion samples for prenatal diagnosis, adrenal-, kidney-, and brain samples. Various light and electron microscopic methods are used including enzyme- and immunocytochemistry, polarizing microscopy, and morphometry. Together with other laboratory investigations and clinical data, this approach continues to contribute to the diagnosis and further characterization of peroxisomal disorders, and the discovery of novel variants. When liver specimens are examined, three main groups including 9 novel variants (33 patients) are distinguished: (1) absence or (2) presence of peroxisomes, and (3) mosaic distribution of cells with and without peroxisomes (10 patients). Renal microcysts, polarizing trilamellar inclusions, and insoluble lipid in macrophages in liver, adrenal cortex, brain, and in interstitial cells of kidney are also valuable for classification. On a genetic basis, complementation of fibroblasts has classified peroxisome biogenesis disorders into 12 complementation groups. Peroxisome biogenesis genes (PEX), knock-out-mice, and induction of redundant genes are briefly reviewed, including some recent results with 4-phenylbutyrate. Finally, regulation of peroxisome expression during development and in cell cultures, and by physiological factors is discussed.
  Microscopy Research and Technique 07/2003; 61(2):203-23. · 1.79 Impact Factor
• Article: Peroxisomes during development and in distinct cell types.

  Frank Roels, Marianne Depreter, Marc Espeel, Katharina D'Herde, Ingrid Kerckaert, Joseph Vamecq, Christiane Van den Branden
  Advances in experimental medicine and biology 02/2003; 544:39-54. · 1.09 Impact Factor
• Article: Resolution of the molecular defect in a patient with peroxisomal mosaicism in the liver.

  Jeannette Gootjes, Hanna Mandel, Petra A W Mooijer, Frank Roels, Hans R Waterham, Ronald J A Wanders
  Advances in experimental medicine and biology 02/2003; 544:107-11. · 1.09 Impact Factor
• Article: Why study regulation of genes in inherited disorders?

  Frank Roels
  Advances in experimental medicine and biology 02/2003; 544:1-8. · 1.09 Impact Factor
• Article: Evaluation of the preventive effect of glyceryl trioleate-trierucate ("Lorenzo's oil") therapy in X-linked adrenoleukodystrophy: results of two concurrent trials.

  Hugo W Moser, Gerald V Raymond, Wolfgang Koehler, Piotr Sokolowski, Folker Hanefeld, Georg Christoph Korenke, Anne Green, Daniel J Loes, Donald H Hunneman, Richard O Jones, Shou-En Lu, Graziella Uziel, Marisa L Giros, Frank Roels
  Advances in experimental medicine and biology 02/2003; 544:369-87. · 1.09 Impact Factor
• Article: Regulation of peroxisomal genes by DHEA and vitamin D.

  Marianne Depreter, Jo Vandesompele, Sacha Ferdinandusse, Frank Speleman, Frank Roels
  Advances in experimental medicine and biology 02/2003; 544:237-42. · 1.09 Impact Factor
• Article: Modified peroxisomes in primary hepatocyte cultures.

  Marianne Depreter, Tracy Walker, Sonja Beken, Karen De Smet, Peggy Papeleu, Tom Tytgat, Marc Espeel, Vera Rogiers, Frank Roels
  Advances in experimental medicine and biology 02/2003; 544:255-64. · 1.09 Impact Factor
• Source

  Available from: Stéphane Savary

  Article: Pharmacological induction of redundant genes for a therapy of X-ALD: phenylbutyrate and other compounds.

  Maurice Bugaut, Stephane Fourcade, Catherine Gondcaille, Fabien Gueugnon, Marianne Depreter, Frank Roels, Angela Netik, Johannes Berger, Pascal Martin, Thierry Pineau, Francoise Cadepond, Martine El Etr, Stephane Savary
  Advances in experimental medicine and biology 02/2003; 544:281-91. · 1.09 Impact Factor
• Article: Peroxisome mosaics.

  Frank Roels, Jean-Marie Saudubray, Marisa Giros, Hanna Mandel, François Eyskens, Nieves Saracibar, Begoña Atares Pueyo, Jose M Prats, Betty De Prest, Kathleen De Preter, Mercedes Pineda, Pierre Krystkowiak, Jeannette Gootjes, Ronald J A Wanders, Marc Espeel, Bwee Tien Poll-The
  Advances in experimental medicine and biology 02/2003; 544:97-106. · 1.09 Impact Factor
• Source

  Available from: ncbi.nlm.nih.gov

  Article: A PEX6-defective peroxisomal biogenesis disorder with severe phenotype in an infant, versus mild phenotype resembling Usher syndrome in the affected parents.

  Annick Raas-Rothschild, Ronald J A Wanders, Petra A W Mooijer, Jeannette Gootjes, Hans R Waterham, Alisa Gutman, Yasuyuki Suzuki, Nobuyuki Shimozawa, Naomi Kondo, Gideon Eshel, Marc Espeel, Frank Roels, Stanley H Korman
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  ABSTRACT: Sensorineural deafness and retinitis pigmentosa (RP) are the hallmarks of Usher syndrome (USH) but are also prominent features in peroxisomal biogenesis defects (PBDs); both are autosomal recessively inherited. The firstborn son of unrelated parents, who both had sensorineural deafness and RP diagnosed as USH, presented with sensorineural deafness, RP, dysmorphism, developmental delay, hepatomegaly, and hypsarrhythmia and died at age 17 mo. The infant was shown to have a PBD, on the basis of elevated plasma levels of very-long- and branched-chain fatty acids (VLCFAs and BCFAs), deficiency of multiple peroxisomal functions in fibroblasts, and complete absence of peroxisomes in fibroblasts and liver. Surprisingly, both parents had elevated plasma levels of VLCFAs and BCFAs. Fibroblast studies confirmed that both parents had a PBD. The parents' milder phenotypes correlated with relatively mild peroxisomal biochemical dysfunction and with catalase immunofluorescence microscopy demonstrating mosaicism and temperature sensitivity in fibroblasts. The infant and both of his parents belonged to complementation group C. PEX6 gene sequencing revealed mutations on both alleles, in the infant and in his parents. This unique family is the first report of a PBD with which the parents are themselves affected individuals rather than asymptomatic carriers. Because of considerable overlap between USH and milder PBD phenotypes, individuals suspected to have USH should be screened for peroxisomal dysfunction.
  The American Journal of Human Genetics 05/2002; 70(4):1062-8. · 10.60 Impact Factor
• Article: Chondrodysplasia punctata with multiple congenital anomalies: a new syndrome?

  G. R. Mortier, Ludwine M. Messiaen, Marc Espeel, Koen J. Smets, Bart D. Vanzieleghem, Frank Roels, Anne M. De Paepe
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  ABSTRACT: We report a male neonate with craniofacial dysmorphic features, multiple congenital anomalies and an unusual form of chondrodysplasia punctata. Radiographic examination revealed punctate epiphyses and coronal clefting of the thoracic spine. The hand radiographs showed some similarities to the brachytelephalangic type of chondrodysplasia punctata. However, the disorder did not fit well with any known entity of chondrodysplasia punctata or other condition characterized by punctate epiphyses.
  Pediatric Radiology 09/1998; 28(10):790-793. · 1.67 Impact Factor
• Article: Peroxisome mosaicism in the livers of peroxisomal deficiency patients

  Marc Espeel, Hanna Mandel, Florence Poggi, Jan A. M. Smeitink, Ronald J. A. Wanders, Ingrid Kerckaert, Rudolf B. H. Schutgens, Jean-Marie Saudubray, Bwee-Tien Poll-The, PhD Frank Roels MD, Frank Roels
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  ABSTRACT: Peroxisomal deficiency disorders, which are genetically transmitted, are assumed to be expressed in all cells, and the use of cultured skin fibroblasts for diagnosis and research is based on this assumption. We describe three patients with clinical, biochemical, and microscopic evidence of a peroxisomal disorder. However, their liver displays mosaicism, i.e., parenchymal cells with peroxisomes are adjacent to cells without peroxisomes. Ten percent (volume), 8%, and less than 1% of the parenchyma possessed peroxisomes that can be identified in immunocytochemical tests for six matrix and membrane proteins performed by light and electron microscopy. In the bulk of the parenchyma, catalase is localized in the cytoplasm, and in such cells no peroxisomes are evident by electron microscopy and immunolabeling for the 43-kd peroxisomal membrane protein (PMP) in two patients; in the third case, peroxisomal membrane ghosts are present. Immunoblots of peroxisomal β-oxidation enzymes show a pattern similar to that from patients with a generalized peroxisomal deficiency. In contrast to the clinical and biochemical signs of peroxisomal dysfunction and hepatic histopathology, cultured fibroblasts from two patients demonstrate normal peroxisomal functions, including very-long-chain fatty acid oxidation and plasmalogen synthesis. (Hepatology 1995; 22:497–504.)
  Hepatology 07/1995; 22(2):497 - 504. · 11.66 Impact Factor
• Article: Peroxisomes in liver, kidney and duodenum of nude mice bearing xenografts of human pancreatic adenocarcinomas

  Dirk De Craemer, Marina Pauwels, André Vergeylen, Frank Roels, Christiane Van den Branden
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  ABSTRACT: In the liver, kidney and duodenum of nude mice with xenografts of two human pancreatic adenocarcinomas differing in growth rate, catalase activity was assayed and peroxisomes were studied using catalase cytochemistry and light and electron microscopy. Hepatic and duodenal catalase activity were significantly decreased in tumour-bearing mice. Renal catalase activity was unchanged. At light microscopic level, a decrease in peroxisomal staining was evident in all duodenums and most livers of tumour-bearing mice. Only minor changes were observed in the kidneys. Ultrastructural morphometry of the hepatocellular peroxisomes revealed a decrease in size, volume density and surface density only in mice with fast-growing xenografts. These observations indicate that the two pancreatic adenocarcinomas exerted a different effect on the hepatic peroxisomes, and that catalase activity and peroxisomes in liver and duodenum are more affected than in kidney.
  Virchows Archiv B Cell Pathology 04/1993; 64(1):7-12.
• Article: Peroxisomes in cirrhosis of the human liver: A cytochemical, ultrastructural and quantitative study

  Dirk De Craemer, Marina Pauwels, Frank Roels
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  ABSTRACT: Hepatocellular peroxisomes in 32 patients with cirrhosis were studied by means of catalase cytochemical and morphometric analysis. Seven normal human livers were used as controls. The severity of the cirrhosis was determined with the Child-Turcotte criteria. Under the light microscope, a decrease in catalase staining was observed in 12 livers. Staining showed a weak inverse correlation with severity of the cirrhotic process. Peroxisomes revealed a perinuclear configuration in 24 patients. Morphometric analysis of peroxisomes was performed on 14 cirrhotic livers and revealed a near doubling of the number of organelles, with a compensatory decrease in mean peroxisomal diameter: no appreciable change in total volume of the peroxisome compartment was found. Cytoplasmic invaginations, protrusions and gastruloid cisternae were sparse. Apparently, peroxisomal proliferation in liver cells appeared early in the cirrhotic process. In all 10 livers with a perinuclear configuration of the peroxisomes that were processed for electron microscopy, a morphometrically confirmed increase in the number of peroxisomes was observed. Peroxisomes frequently showed transparent matrical spots and angular profiles. In two patients nucleoid-containing peroxisomes were observed. Although variation between individual patients was high, peroxisomal changes were observed in each cirrhotic liver. No relationship between morphological or morphometric alterations in peroxisomal compartment on one side and the severity of the disease or the type of cirrhotic nodules on the other side was observed. (HEPATOLOGY 1993;17:404–410.)
  Hepatology 02/1993; 17(3):404 - 410. · 11.66 Impact Factor
• Article: Hepatic peroxisomes in adrenoleukodystrophy and related syndromes: Cytochemical and morphometric data

  Frank Roels, Marina Pauwels, Bwee Tien Poll-Thé, Jacques Scotto, Hélène Ogier, Patrick Aubourg, Jean-Marie Saudubray
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  ABSTRACT: Peroxisomes were visualized by cytochemical staining for catalase or/and electron microscopy in liver biopsies of two boys with childhood adrenoleukodystrophy (ALD), and of two girls with autopsy confirmed neonatal adrenoleukodystrophy (NALD). In a third patient previously described as NALD, unusual organelles were seen which may be large abnormal microbodies. Enlarged peroxisomes (determined by morphometry) were also present in the livers of the other two NALD patients. In the ALD patient whose clinical disease was more severe, peroxisomes were larger than in the older ALD case. Catalase staining was diminished and markedly heterogeneous. Additional unusual features such as a separate population of tubular forms, contact with fat droplets, marginal plate and invaginations containing glycogen were seen in the neonatal cases. These data are compared to the enlarged or elongated peroxisomes and heterogeneous staining in the thiolase-deficient pseudo-Zellweger patient (Goldfischer et al. 1986) and in 2 siblings with acylCoA oxidase deficiency (Poll-Th et al. 1986, 1988). Enlarged peroxisomes are a common feature in this group of patients with peroxisomal deficiency disorders, suggesting that increased size and lowered metabolic capacity are associated. Nevertheless a marked morphopathological heterogeneity of peroxisomes thus exists in syndromes described as NALD including previously published cases. Most likely this heterogeneity reflects different enzymatic deficiencies, as confirmed by the biochemical data available. Clinically similar syndromes cover divergent microscopical and enzymatic peroxisomal patterns, and naming of the disease should be adapted to reflect such data. Cytochemical studies are urged in every suspected patient.
  Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 06/1988; 413(4):275-285. · 2.49 Impact Factor
• Article: Cytochemical discrimination between catalases and peroxidases using diaminobenzidine

  Frank Roels, Eddie Wisse, Betty Prest, Jannes Meulen
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  ABSTRACT: The influence on diaminobenzidine staining of four variables: prefixation in aldehyde, temperature and pH of incubation, and H2O2 concentration, was investigated in catalase-, as well as in peroxydase-containing material. Catalase from five different sources and five types of peroxidase were examine. It is conclude: (a) when cells are incubated without prior fixation, in a DAB medium at room temperature and pH 7.3 with 0.003% H2O2, peroxidases produce a visible cytochemical stain, while catalases do not; (b) the cytochemical reaction elicited by catalases is stimulated by prior aldehyde fixation in specified conditions, and incubation at 45 C and pH 9.7 with 0.06% H2O2; (c) under the latter circumstances several peroxidases also stain. Ultrastructural preservation is satisfactory in tissues incubated prior toxation.
  Histochemie 11/1975; 41(4):281-312. · 2.59 Impact Factor