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

被引：22

作者：

Keshavan, Nandaki ^{[1
,2
]}

Abdenur, Jose ^{[3
]}

Anderson, Glenn ^{[4
]}

Assouline, Zahra ^{[5
]}

Barcia, Giulia ^{[5
]}

Bouhikbar, Lamia ^{[6
,7
]}

Chakrapani, Anupam ^{[1
]}

Cleary, Maureen ^{[1
]}

Cohen, Marta C. ^{[8
]}

Feillet, Francois ^{[9
]}

Fratter, Carl ^{[10
]}

Hauser, Natalie ^{[11
]}

Jacques, Tom ^{[4
]}

Lam, Amanda ^{[12
,13
]}

McCullagh, Helen ^{[14
]}

Phadke, Rahul ^{[13
]}

Rotig, Agnes ^{[15
]}

Sharrard, Mark ^{[8
]}

Simon, Mariella ^{[3
]}

Smith, Conrad ^{[10
]}

Sommerville, Ewen W. ^{[16
,17
]}

Taylor, Robert W. ^{[16
]}

Yue, Wyatt W. ^{[18
]}

Rahman, Shamima ^{[1
,2
]}

机构：

[1] Great Ormond St Hosp Children NHS Fdn Trust, Metab Unit, London, England

[2] UCL Great Ormond St Inst Child Hlth, Mitochondrial Res Grp, London, England

[3] Childrens Hosp Orange Cty, Div Metab Disorders, Orange, CA 92668 USA

[4] Great Ormond St Hosp Children NHS Fdn Trust, Dept Histopathol, London, England

[5] Necker Hosp Sick Children, Dept Genet, Paris, France

[6] UCL Great Ormond St Inst Child Hlth, GOSgene Ctr Translat Omics, London, England

[7] NIHR GOSH Biomed Res Ctr, London, England

[8] Sheffield Childrens NHS Fdn Trust, Sheffield, S Yorkshire, England

[9] Reference Ctr Inherited Metab Dis, Nancy, France

[10] Oxford Univ Hosp NHS Fdn Trust, Oxford Med Genet Labs, Oxford, England

[11] Inova Translat Med Inst, Falls Church, VA USA

[12] Natl Hosp Neurol & Neurosurg, Neurometabol Unit, London, England

[13] UCL Queen Sq Inst Neurol, London, England

[14] Leeds Childrens Hosp, Dept Paediat Neurol, Leeds, W Yorkshire, England

[15] Imagine Inst, Paris, France

[16] Newcastle Univ, Inst Neurosci, Wellcome Ctr Mitochondrial Res, Newcastle Upon Tyne, Tyne & Wear, England

[17] Cardiff Univ, Div Psychol Med & Clin Neurosci, Cardiff, Wales

[18] Univ Oxford, Nuffield Dept Med, Struct Genom Consortium, Oxford, England

来源：

GENETICS IN MEDICINE | 2020年 / 22卷 / 01期

基金：

英国医学研究理事会; 英国工程与自然科学研究理事会;

关键词：

mitochondrial disease; mtDNA depletion; ribonucleotide reductase; treatment; outcomes; MUTATIONS; MTDNA; P53R2;

D O I：

10.1038/s41436-019-0613-z

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：199 / 209

页数：11

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