Deoxyguanosine kinase deficiency: natural history and liver transplant outcome

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Autosomal recessive pathogenetic variants in the DGUOK gene cause deficiency of deoxyguanosine kinase activity and mitochondrial deoxynucleotides pool imbalance, consequently, leading to quantitative and/or qualitative impairment of mitochondrial DNA synthesis. Typically, patients present early-onset liver failure with or without neurological involvement and a clinical course rapidly progressing to death.

This is an international multicentre study aiming to provide a retrospective natural history of deoxyguanosine kinase deficient patients. A systematic literature review from January 2001 to June 2023 was conducted. Physicians of research centres or clinicians all around the world caring for previously reported patients were contacted to provide followup information or additional clinical, biochemical, histological/histochemical, and molecular genetics data for unreported cases with a confirmed molecular diagnosis of deoxyguanosine kinase deficiency.

A cohort of 202 genetically confirmed patients, 36 unreported, and 166 from a systematic literature review, were analyzed. Patients had a neonatal onset (≤ 1 month) in 55.7% of cases, infantile (>1 month and ≤ 1 year) in 32.3%, pediatric (>1 year and ≤18 years) in 2.5% and adult (>18 years) in 9.5%. Kaplan-Meier analysis showed statistically different survival rates ( P < 0.0001) among the four age groups with the highest mortality for neonatal onset. Based on the clinical phenotype, we defined four different clinical subtypes: hepatocerebral (58.8%), isolated hepatopathy (21.9%), hepatomyoencephalopathy (9.6%), and isolated myopathy (9.6%). Muscle involvement was predominant in adult-onset cases whereas liver dysfunction causes morbidity and mortality in early-onset patients with a median survival of less than 1 year. No genotype–phenotype correlation was identified. Liver transplant significantly modified the survival rate in 26 treated patients when compared with untreated. Only six patients had additional mild neurological signs after liver transplant.

In conclusion, deoxyguanosine kinase deficiency is a disease spectrum with a prevalent liver and brain tissue specificity in neonatal and infantile-onset patients and muscle tissue specificity in adult-onset cases. Our study provides clinical, molecular genetics and biochemical data for early diagnosis, clinical trial planning and immediate intervention with liver transplant and/or nucleoside supplementation.

Abstract

Manzoni et al. demonstrated Deoxyguanosine kinase deficiency as a tissue-specific mitochondrial DNA maintenance defect manifesting with rapidly progressive liver disease in early-onset patients and mild myopathy in adults. Early recognition is essential for immediate intervention with a Liver transplant, showing evidence of efficacy in the analysed cohort, and/or nucleoside supplementation.

Graphical Abstract

Graphical abstract

Related collections

Most cited references 76

Record: found
Abstract: found
Article: not found

Use of whole-exome sequencing to determine the genetic basis of multiple mitochondrial respiratory chain complex deficiencies.

Robert W. Taylor, Angela Pyle, Helen Griffin … (2014)

Mitochondrial disorders have emerged as a common cause of inherited disease, but their diagnosis remains challenging. Multiple respiratory chain complex defects are particularly difficult to diagnose at the molecular level because of the massive number of nuclear genes potentially involved in intramitochondrial protein synthesis, with many not yet linked to human disease. To determine the molecular basis of multiple respiratory chain complex deficiencies. We studied 53 patients referred to 2 national centers in the United Kingdom and Germany between 2005 and 2012. All had biochemical evidence of multiple respiratory chain complex defects but no primary pathogenic mitochondrial DNA mutation. Whole-exome sequencing was performed using 62-Mb exome enrichment, followed by variant prioritization using bioinformatic prediction tools, variant validation by Sanger sequencing, and segregation of the variant with the disease phenotype in the family. Presumptive causal variants were identified in 28 patients (53%; 95% CI, 39%-67%) and possible causal variants were identified in 4 (8%; 95% CI, 2%-18%). Together these accounted for 32 patients (60% 95% CI, 46%-74%) and involved 18 different genes. These included recurrent mutations in RMND1, AARS2, and MTO1, each on a haplotype background consistent with a shared founder allele, and potential novel mutations in 4 possible mitochondrial disease genes (VARS2, GARS, FLAD1, and PTCD1). Distinguishing clinical features included deafness and renal involvement associated with RMND1 and cardiomyopathy with AARS2 and MTO1. However, atypical clinical features were present in some patients, including normal liver function and Leigh syndrome (subacute necrotizing encephalomyelopathy) seen in association with TRMU mutations and no cardiomyopathy with founder SCO2 mutations. It was not possible to confidently identify the underlying genetic basis in 21 patients (40%; 95% CI, 26%-54%). Exome sequencing enhances the ability to identify potential nuclear gene mutations in patients with biochemically defined defects affecting multiple mitochondrial respiratory chain complexes. Additional study is required in independent patient populations to determine the utility of this approach in comparison with traditional diagnostic methods.

0 comments Cited 157 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Loss-of-function mutations in MGME1 impair mtDNA replication and cause multisystemic mitochondrial disease.

Dario Ronchi, Maurizio Moggio, Gábor Zsurka … (2013)

Known disease mechanisms in mitochondrial DNA (mtDNA) maintenance disorders alter either the mitochondrial replication machinery (POLG, POLG2 and C10orf2) or the biosynthesis pathways of deoxyribonucleoside 5'-triphosphates for mtDNA synthesis. However, in many of these disorders, the underlying genetic defect has yet to be discovered. Here, we identify homozygous nonsense and missense mutations in the orphan gene C20orf72 in three families with a mitochondrial syndrome characterized by external ophthalmoplegia, emaciation and respiratory failure. Muscle biopsies showed mtDNA depletion and multiple mtDNA deletions. C20orf72, hereafter MGME1 (mitochondrial genome maintenance exonuclease 1), encodes a mitochondrial RecB-type exonuclease belonging to the PD-(D/E)XK nuclease superfamily. We show that MGME1 cleaves single-stranded DNA and processes DNA flap substrates. Fibroblasts from affected individuals do not repopulate after chemically induced mtDNA depletion. They also accumulate intermediates of stalled replication and show increased levels of 7S DNA, as do MGME1-depleted cells. Thus, we show that MGME1-mediated mtDNA processing is essential for mitochondrial genome maintenance.

0 comments Cited 87 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Clinical and genetic spectrum of mitochondrial neurogastrointestinal encephalomyopathy.

Michio Hirano, Caterina Garone, Saba Tadesse (2011)

Mitochondrial neurogastrointestinal encephalomyopathy is a rare multisystemic autosomic recessive disorder characterized by: onset typically before the age of 30 years; ptosis; progressive external ophthalmoplegia; gastrointestinal dysmotility; cachexia; peripheral neuropathy; and leucoencephalopathy. The disease is caused by mutations in the TYMP gene encoding thymidine phosphorylasethymine phosphorylase. Anecdotal reports suggest that allogeneic haematopoetic stem cell transplantation may be beneficial for mitochondrial neurogastrointestinal encephalomyopathy, but is associated with a high mortality. After selecting patients who fulfilled the clinical criteria for mitochondrial neurogastrointestinal encephalomyopathy and had severe thymidine phosphorylase deficiency in the buffy coat ( G in Europe and c.518T>G in the Dominican Republic, that could guide genetic screening in each location. Although the sequence of clinical manifestations in the disease varied, half of the patients initially had gastrointestinal symptoms. We confirmed anecdotal reports of intra- and inter-familial clinical variability and absence of genotype-phenotype correlation in the disease, suggesting genetic modifiers, environmental factors or both contribute to disease manifestations. Acute medical events such as infections often provoked worsening of symptoms, suggesting that careful monitoring and early treatment of intercurrent illnesses may be beneficial. We observed endocrine/exocrine pancreatic insufficiency, which had not previously been reported. Kaplan-Meier analysis revealed significant mortality between the ages of 20 and 40 years due to infectious or metabolic complications. Despite increasing awareness of this illness, a high proportion of patients had been misdiagnosed. Early and accurate diagnosis of mitochondrial neurogastrointestinal encephalomyopathy, together with timely treatment of acute intercurrent illnesses, may retard disease progression and increase the number of patients eligible for allogeneic haematopoetic stem cell transplantation.

0 comments Cited 74 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Eleonora Manzoni

Sara Carli:

ORCID: https://orcid.org/0000-0001-8130-5364

Pauline Gaignard

Lea Dewi Schlieben

Michio Hirano

Dario Ronchi

Emmanuel Gonzales

Masaru Shimura

Kei Murayama:

ORCID: https://orcid.org/0000-0002-3923-8636

Yasushi Okazaki

Ivo Barić

Danijela Petkovic Ramadza

Daniela Karall

Johannes Mayr

Diego Martinelli:

ORCID: https://orcid.org/0000-0002-9324-2871

Chiara La Morgia

Guido Primiano:

ORCID: https://orcid.org/0000-0001-7616-7008

René Santer

Serenella Servidei

Céline Bris

Aline Cano

Francesca Furlan

Serena Gasperini

Nolwenn Laborde

Costanza Lamperti

Dominic Lenz

Michelangelo Mancuso

Vincenzo Montano

Francesca Menni

Olimpia Musumeci

Victoria Nesbitt

Elena Procopio

Cécile Rouzier:

ORCID: https://orcid.org/0000-0002-2969-1904

Christian Staufner

Jan-Willem Taanman

Galit Tal

Chiara Ticci

Duccio Maria Cordelli

Valerio Carelli

Vincent Procaccio

Holger Prokisch

Caterina Garone:

ORCID: https://orcid.org/0000-0003-4928-1037

Journal

Journal ID (nlm-ta): Brain Commun

Journal ID (iso-abbrev): Brain Commun

Journal ID (publisher-id): braincomms

Title: Brain Communications

Publisher: Oxford University Press (UK )

ISSN (Electronic): 2632-1297

Publication date Collection: 2024

Publication date (Electronic): 06 May 2024

Publication date PMC-release: 06 May 2024

Volume: 6

Issue: 3

Electronic Location Identifier: fcae160

Affiliations

Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna , Bologna 40138, Italy

IRCCS Istituto delle Scienze Neurologiche, UO Neuropsichiatria dell’età Pediatrica di Bologna , Bologna 40124, Italy

Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna , Bologna 40138, Italy

Department of Biochemistry, Bicêtre Hospital, Reference Center for Mitochondrial Disease, University of Paris-Saclay, Assistance Publique-Hôpitaux de Paris , Paris 94275, France

School of Medicine, Institute of Human Genetics, Technical University of Munich , Munich, 80333 Germany

Institute of Neurogenomics, Computational Health Center, Helmholtz Zentrum München , Neuherberg 80333, Germany

H. Houston Merritt Neuromuscular Research Center, Department of Neurology, Columbia University Irving Medical Center , New York, NY 10033, USA

Dino Ferrari Center, Department of Pathophysiology and Transplantation, University of Milan , Milan 20122, Italy

Pediatric Hepatology and Pediatric Liver Transplantation Unit, Bicêtre Hospital, Reference Center for Mitochondrial Disease, University of Paris-Saclay, Assistance Publique-Hôpitaux de Paris , Paris 94270, France

Center for Medical Genetics, Department of Metabolism, Chiba Children’s Hospital , Chiba 260-0842, Japan

Diagnostics and Therapeutic of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University , Tokyo 113-8421, Japan

Department of Pediatrics, University Hospital Centre Zagreb and University of Zagreb, School of Medicine , Zagreb 10000, Croatia

Clinic for Pediatrics, Division of Inherited Metabolic Disorders, Medical University of Innsbruck , 6020 Innsbruck, Austria

University Children’s Hospital, Paracelsus Medical University (PMU) , 5020 Salzburg, Austria

Division of Metabolism, Bambino Gesù Children’s Hospital IRCCS , Rome 00165, Italy

Department of Biomedical and Neuromotor Sciences, University of Bologna , Bologna 40123, Italy

IRCCS Istituto di Scienze Neurologiche di Bologna, Programma di Neurogenetica , Bologna 40124, Italy

Dipartimento di Neuroscienze, Organi di Senso e Torace -Fondazione Policlinico Universitario Agostino Gemelli IRCCS , Rome 00136, Italy

Dipartimento Di Neuroscienze, Università Cattolica del Sacro Cuore , Rome 00168, Italy

Department of Pediatrics, University Medical Center Eppendorf , Hamburg 20246, Germany

Dipartimento di Neuroscienze, Organi di Senso e Torace -Fondazione Policlinico Universitario Agostino Gemelli IRCCS , Rome 00136, Italy

Dipartimento Di Neuroscienze, Università Cattolica del Sacro Cuore , Rome 00168, Italy

University Angers, Angers Hospital, INSERM, CNRS, MITOVASC, SFR ICAT , Angers F-49000, France

Centre de référence des maladies héréditaires du métabolisme, CHU la Timone Enfants , Marseille 13005, France

Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Regional Clinical Center for Expanded Newborn Screening , Milan 20122, Italy

Department of Pediatrics, Fondazione IRCCS San Gerardo dei Tintori , 20900 Monza, Italy

Unité de Gastroentérologie, Hépatologie, Nutrition et Maladies Héréditaires du Métabolisme, Hôpital des Enfants, CHU de Toulouse , Toulouse 31300, France

Division of Medical Genetics and Neurogenetics, Fondazione IRCCS Neurological Institute ‘C. Besta’ , Milan 20133, Italy

Division of Neuropaediatrics and Paediatric Metabolic Medicine, Center for Paediatric and Adolescent Medicine, University Hospital Heidelberg , Heidelberg 69120, Germany

Department of Clinical and Experimental Medicine, Neurological Institute, University of Pisa & AOUP , Pisa 56126, Italy

Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Regional Clinical Center for Expanded Newborn Screening , Milan 20122, Italy

Unit of Neurology and Neuromuscular Disorders, Department of Clinical and Experimental Medicine, University of Messina , Messina 98125, Italy

Department of Paediatrics, Medical Sciences Division, Oxford University , Oxford OX3 9DU, UK

Metabolic Unit, Meyer Children’s Hospital IRCCS , Florence 50139, Italy

Centre de référence des Maladies Mitochondriales, Service de Génétique Médicale, CHU de Nice, Université Côte d’Azur, CNRS, INSERM, IRCAN , Nice 06000, France

Division of Neuropaediatrics and Paediatric Metabolic Medicine, Center for Paediatric and Adolescent Medicine, University Hospital Heidelberg , Heidelberg 69120, Germany

Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG, UK

Metabolic Clinic, Ruth Rappaport Children's Hospital, Rambam Health Care Campus , Haifa 3109601, Israel

The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology , Haifa 3109601, Israel