Multicenter Study

. 2020 Jan;22(1):199-209.

doi: 10.1038/s41436-019-0613-z. Epub 2019 Aug 29.

The natural history of infantile mitochondrial DNA depletion syndrome due to RRM2B deficiency

Nandaki Keshavan^{1

2}, Jose Abdenur³, Glenn Anderson⁴, Zahra Assouline⁵, Giulia Barcia⁵, Lamia Bouhikbar^{6

7}, Anupam Chakrapani¹, Maureen Cleary¹, Marta C Cohen⁸, François Feillet⁹, Carl Fratter¹⁰, Natalie Hauser¹¹, Tom Jacques⁴, Amanda Lam^{12

13}, Helen McCullagh¹⁴, Rahul Phadke¹³, Agnès Rötig¹⁵, Mark Sharrard⁸, Mariella Simon³, Conrad Smith¹⁰, Ewen W Sommerville^{16

17}, Robert W Taylor¹⁶, Wyatt W Yue¹⁸, Shamima Rahman^{19

20}

Affiliations

¹ Metabolic Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
² Mitochondrial Research Group, UCL Great Ormond Street Institute of Child Health, London, UK.
³ Division of Metabolic Disorders, Children's Hospital of Orange County, Orange, CA, USA.
⁴ Department of Histopathology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
⁵ Department of Genetics, Necker Hospital-Sick Children, Paris, France.
⁶ GOSgene Centre for Translational Omics, UCL Great Ormond Street Institute of Child Health, London, UK.
⁷ NIHR GOSH Biomedical Research Centre, London, UK.
⁸ Sheffield Children's NHS Foundation Trust, Sheffield, UK.
⁹ Reference Centre for Inherited Metabolic Diseases, Nancy, France.
¹⁰ Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
¹¹ Inova Translational Medicine Institute, Falls Church, VA, USA.
¹² Neurometabolic Unit, National Hospital of Neurology and Neurosurgery, London, UK.
¹³ UCL Queen Square Institute of Neurology, London, UK.
¹⁴ Department of Paediatric Neurology, Leeds Children's Hospital, Leeds, UK.
¹⁵ Imagine Institute, Paris, France.
¹⁶ Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
¹⁷ Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
¹⁸ Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
¹⁹ Metabolic Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK. shamima.rahman@ucl.ac.uk.
²⁰ Mitochondrial Research Group, UCL Great Ormond Street Institute of Child Health, London, UK. shamima.rahman@ucl.ac.uk.

PMID: 31462754
DOI: 10.1038/s41436-019-0613-z

Free article

Multicenter Study

The natural history of infantile mitochondrial DNA depletion syndrome due to RRM2B deficiency

Nandaki Keshavan et al. Genet Med. 2020 Jan.

Free article

. 2020 Jan;22(1):199-209.

doi: 10.1038/s41436-019-0613-z. Epub 2019 Aug 29.

Authors

Affiliations

¹ Metabolic Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
² Mitochondrial Research Group, UCL Great Ormond Street Institute of Child Health, London, UK.
³ Division of Metabolic Disorders, Children's Hospital of Orange County, Orange, CA, USA.
⁴ Department of Histopathology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
⁵ Department of Genetics, Necker Hospital-Sick Children, Paris, France.
⁶ GOSgene Centre for Translational Omics, UCL Great Ormond Street Institute of Child Health, London, UK.
⁷ NIHR GOSH Biomedical Research Centre, London, UK.
⁸ Sheffield Children's NHS Foundation Trust, Sheffield, UK.
⁹ Reference Centre for Inherited Metabolic Diseases, Nancy, France.
¹⁰ Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
¹¹ Inova Translational Medicine Institute, Falls Church, VA, USA.
¹² Neurometabolic Unit, National Hospital of Neurology and Neurosurgery, London, UK.
¹³ UCL Queen Square Institute of Neurology, London, UK.
¹⁴ Department of Paediatric Neurology, Leeds Children's Hospital, Leeds, UK.
¹⁵ Imagine Institute, Paris, France.
¹⁶ Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
¹⁷ Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
¹⁸ Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
¹⁹ Metabolic Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK. shamima.rahman@ucl.ac.uk.
²⁰ Mitochondrial Research Group, UCL Great Ormond Street Institute of Child Health, London, UK. shamima.rahman@ucl.ac.uk.

PMID: 31462754
DOI: 10.1038/s41436-019-0613-z

Abstract

Purpose: Mitochondrial DNA (mtDNA) depletion syndrome (MDDS) encompasses a group of genetic disorders of mtDNA maintenance. Mutation of RRM2B is an uncommon cause of infantile-onset encephalomyopathic MDDS. Here we describe the natural history of this disease.

Methods: Multinational series of new genetically confirmed cases from six pediatric centers.

Results: Nine new cases of infantile-onset RRM2B deficiency, and 22 previously published cases comprised a total cohort of 31 patients. Infants presented at a mean of 1.95 months with truncal hypotonia, generalized weakness, and faltering growth. Seizures evolved in 39% at a mean of 3.1 months. Non-neurological manifestations included respiratory distress/failure (58%), renal tubulopathy (55%), sensorineural hearing loss (36%), gastrointestinal disturbance (32%), eye abnormalities (13%), and anemia (13%). Laboratory features included elevated lactate (blood, cerebrospinal fluid (CSF), urine, magnetic resonance (MR), spectroscopy), ragged-red and cytochrome c oxidase-deficient fibers, lipid myopathy, and multiple oxidative phosphorylation enzyme deficiencies in skeletal muscle. Eight new RRM2B variants were identified. Patients with biallelic truncating variants had the worst survival. Overall survival was 29% at 6 months and 16% at 1 year.

Conclusions: Infantile-onset MDDS due to RRM2B deficiency is a severe disorder with characteristic clinical features and extremely poor prognosis. Presently management is supportive as there is no effective treatment. Novel treatments are urgently needed.

Keywords: mitochondrial disease; mtDNA depletion; outcomes; ribonucleotide reductase; treatment.

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References

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The natural history of infantile mitochondrial DNA depletion syndrome due to RRM2B deficiency

Affiliations

The natural history of infantile mitochondrial DNA depletion syndrome due to RRM2B deficiency

Authors

Affiliations

Abstract

References

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding

LinkOut - more resources

Full Text Sources

Medical