E. Morava

Mitochondrial disease criteria Diagnostic applications in children

Background: Based on a previous prospective clinical and biochemical study, a consensus mitochondrial disease scoring system was established to facilitate the diagnosis in patients with a suspected mitochondrial disorder. Objective: To evaluate the specificity of the diagnostic system, we applied the mitochondrial disease score in 61 children with a multisystem disease and a suspected oxidative phosphorylation disorder who underwent a muscle biopsy and were consecutively diagnosed with a genetic mutation. Methods: We evaluated data of 44 children diagnosed with a disorder in oxidative phosphorylation, carrying a mutation in the mitochondrial or nuclear DNA. We compared them with 17 children who, based on the clinical and metabolic features, also had a muscle biopsy but were finally diagnosed with a nonmitochondrial multisystem disorder by further genetic analysis. Results: All children with a genetically established diagnosis of a primary oxidative phosphorylation disorder had a mitochondrial disease score above 6 (probable mitochondrial disorder), and 73% of the children had a score above 8 (definite mitochondrial disorder) at evaluation of the muscle biopsy. In the nonmitochondrial multisystem disorder group, the score was significantly lower, and no patients reached a score comparable with a definite respiratory chain disorder. Conclusions: The mitochondrial disease criteria system has a high specificity to distinguish between mitochondrial and other multisystem disorders. The method could also be applied in children with a suspected mitochondrial disorder, prior to performing a muscle biopsy.

Major depression in adolescent children consecutively diagnosed with mitochondrial disorder

A higher incidence of major depression has been described in adults with a primary oxidative phosphorylation disease. Intriguingly however, not all patients carrying the same mutation develop symptoms of major depression, pointing out the significance of the interplay of genetic and non-genetic factors in the etiology. In a series of paediatric patients evaluated for mitochondrial dysfunction, out of 35 children with a biochemically and genetically confirmed mitochondrial disorder, we identified five cases presenting with major depression prior to the diagnosis. The patients were diagnosed respectively with mutations in MTTK, MTND1, POLG1, PDHA1 and the common 4977 bp mtDNA deletion. Besides cerebral lactic acidemia protein and glucose concentrations, immunoglobins, anti-gangliosides and neurotransmitters were normal. No significant difference could be confirmed in the disease progression or the quality of life, compared to the other, genetically confirmed mitochondrial patients. In three out of our five patients a significant stress life event was confirmed. We propose the abnormal central nervous system energy metabolism as the underlying cause of the mood disorder in our paediatric patients. Exploring the genetic etiology in children with mitochondrial dysfunction and depression is essential both for safe medication and adequate counselling.

Successful Liver Transplantation and Long-Term Follow-up in a Patient With MPI-CDG

Hepatopathy is the most common feature in the Congenital Disorders of Glycosylation (CDG). More than 70 subtypes have been identified in this growing group of inborn errors. Most defects present as multisystem disease, whereas phosphomannose isomerase deficiency (MPI-CDG) presents with exclusive hepato-intestinal phenotype. MPI-CDG has been considered as one of the very few treatable disorders of glycosylation; several patients showed significant improvement of their life-threatening protein-losing enteropathy and coagulation disorder on oral mannose supplementation therapy. However, patients who have MPI-CDG develop progressive liver insufficiency during a later course of disease. A patient who had MPI-CDG developed progressive liver fibrosis, despite oral mannose supplementation and repeated fractionated heparin therapy. She showed mannose therapy-associated hemolytic jaundice. She developed severe dyspnea and exercise intolerance owing to pulmonary involvement, necessitating liver transplant. After transplantation her physical exercise tolerance, pulmonary functions, and metabolic parameters became fully restored. She is still doing well 2 years after transplantation now. In conclusion, we here report on the first successful liver transplantation in CDG.

Dandy-Walker malformation and polydactyly: a possible expression of hydrolethalus syndrome

Hydrolethalus syndrome consists of hydrocephalus, polydactyly, micrognathia, midcranial malformations, visceral abnormalities and perinatal lethality. It was first described in Finland, and only a few other cases outside Scandinavia are known. We report the first Hungarian patient who displayed many signs of the syndrome but had no cleft lip and visceral abnormalities. This observation suggests the existence of oligosymptomic hydrolethalus syndrome, and suggests that Dandy‐Walker malformation with polydactyly may be a manifestation of the hydrolethalus syndrome.

Infant with MCA and severe cutis laxa due to a de novo duplication 11p of paternal origin

Infant With MCA and Severe Cutis Laxa Due to a De Novo Duplication 11p of Paternal Origin T. Gardeitchik, N. de Leeuw, L. Nijtmans, P. Jira, T. Kozicz, M. Czako, I. van de Burgt, and E. Morava* Department of Pediatrics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands Institute for Genetic and Metabolic Diseases, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands Jeroen Bosch Hospital, s’ Hertogenbosch, The Netherlands Department of Cellular Animal Physiology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, The Netherlands Department of Medical Genetics, University of Pecs, Pecs, Hungary

Stoornissen in de oxidatieve fosforylering: kliniek, diagnostiek en research

SummaryOxidative phosphorylation (oxphos) is one of the most important functions of mitochondria, the power plants of the cell. oxphos is the oxidation of substrates and the production of energy as adenosine-triphosphate (atp). Defects of the oxphos-system form a group of diseases that are known as mitochondrial disorders. Most patients develop symptoms in infancy, especially muscle weakness, exercise intolerance and developmental delay. Lactic acid concentration in body fluids does not have to be elevated. Histopathological and especially biochemical investigations of muscle and fibroblasts are an essential part of the diagnostic process. In this report we describe biochemistry, molecular biology, clinical presentation, diagnostics and therapy of oxphos-system defects. The actual research topics of the Nijmegen Center for Mitochondrial Disorders are highlighted, focussing on complex I.SamenvattingEen belangrijke functie van mitochondriën, de energiefabrieken van de cel, is de oxidatieve fosforylering (oxfos). Hieronder wordt verstaan de oxidatie van brandstoffen en de productie van energie in de vorm van adenosinetrifosfaat (atp). Stoornissen in het oxfos-systeem geven aanleiding tot een groep van ziekten die bekendstaat als mitochondriële ziekten. De meeste patiënten ontwikkelen symptomen op de vroege kinderleeftijd, vooral spierzwakte, beperkt uithoudingsvermogen en retardatie. De lactaatconcentratie in lichaamsvloeistoffen is zeker niet altijd verhoogd. Histopathologisch en met name biochemisch onderzoek van de spier en fibroblasten vormen een essentieel onderdeel van het diagnostisch proces. In dit artikel worden achtereenvolgens biochemie, moleculaire biologie, klinische presentatie, diagnostiek en therapie van defecten van het oxfos-systeem beschreven. Tevens wordt ingegaan op de huidige researchonderwerpen binnen het Nijmegen Centrum voor Mitochondriële Ziekten, waarbij het accent van het onderzoek ligt op complex I.