PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families,Genetics in Medicine

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PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families
Genetics in Medicine ( IF 8.8 ) Pub Date : 2021-08-16 , DOI: 10.1038/s41436-021-01296-6
Anne Guimier _{1,

2} , Melanie T Achleitner ₃ , Anne Moreau de Bellaing _{1,

4} , Matthew Edwards ₅ , Loïc de Pontual ₁ , Kirti Mittal ₆ , Kyla E Dunn ₇ , Megan E Grove ₈ , Carolyn J Tysoe ₉ , Clémantine Dimartino ₁ , Jessie Cameron ₆ , Anil Kanthi ₁₀ , Anju Shukla ₁₀ , Florence van den Broek ₃ , Diptendu Chatterjee ₆ , Charlotte L Alston ₁₁ , Charlotte V Knowles ₁₁ , Laura Brett ₅ , Jan A Till ₁₂ , Tessa Homfray ₅ , Paul French ₁₃ , Georgia Spentzou _{14,

15} , Noha A Elserafy ₁₆ , Kate S Lichkus ₁₆ , Bindu P Sankaran ₁₆ , Hannah L Kennedy ₁₇ , Peter M George ₁₈ , Alexa Kidd ₁₉ , Saskia B Wortmann _{3,

20} , Dianna G Fisk ₈ , Tamara T Koopmann ₆ , Muhammad A Rafiq ₆ , Jason D Merker _{21,

22} , Sumith Parikh ₂₃ , Priyanka Ahimaz ₁₅ , Robert G Weintraub ₂₄ , Alan S Ma _{25,

26} , Christian Turner ₂₇ , Carolyn J Ellaway _{16,

26} , Liza K Phillips _{28,

29} , David R Thorburn _{30,

31,

32} , Wendy K Chung ₁₅ , Sajel L Kana _{33,

34} , Ona M Faye-Petersen ₃₅ , Michelle L Thompson ₃₆ , Alexandre Janin _{37,

38} , Karen McLeod ₁₄ , Ruth McGowan ₁₃ , Robert McFarland ₁₁ , Katta M Girisha ₁₀ , Deborah J Morris-Rosendahl ₅ , Anna C E Hurst ₃₉ , Claire L S Turner ₄₀ , Robert M Hamilton ₆ , Robert W Taylor ₁₁ , Fanny Bajolle ₄ , Christopher T Gordon ₁ , Jeanne Amiel _{1,

2} , Johannes A Mayr ₃ , Kit Doudney ₄₁

Affiliation

INSERM U1163, Université de Paris, Institut Imagine, Paris, France.
Service de Génétique, Hôpital Necker Enfants Malades, APHP, Paris, France.
Department of Pediatrics, Paracelsus Medical University Salzburg, Salzburg, Austria.
Unité médico-chirurgicale de cardiologie pédiatrique, Hôpital Necker Enfants Malades, APHP, Paris, France.
Clinical Genetics and Genomics Laboratory, Royal Brompton and Harefield NHS Trust, London, UK.
Translational Medicine program and the Genetics & Genome Biology Program, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Canada.
Children's Heart Center, Stanford Children's Health, Palo Alto, CA, USA.
Stanford Medicine Clinical Genomics Program, Stanford, CA, USA.
Exeter Genomics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India.
Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
Paediatric Cardiology, Royal Brompton and Harefield NHS Trust, London, UK.
West of Scotland Centre for Genomic Medicine, Queen Elizabeth University Hospital, Glasgow, UK.
The Royal Hospital for Children, Glasgow, UK.
Department of Pediatrics, Columbia University, New York, NY, USA.
Genetic Metabolic Disorders Service, The Children's Hospital at Westmead, Sydney Children's Hospital Network, Sydney, NSW, Australia.
Department of Psychological Medicine, University of Otago, Christchurch, New Zealand.
Pathogene, Christchurch, New Zealand.
Clinical Genetics New Zealand, Christchurch, New Zealand.
Amalia Children's Hospital, Radboudumc, Nijmegen, The Netherlands.
Department of Pathology, School of Medicine, Stanford, CA, USA.
Departments of Pathology and Laboratory Medicine & Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina School Medicine, Chapel Hill, NC, USA.
Mitochondrial Medicine Center, Neuroscience Institute, Cleveland Clinic, Cleveland, OH, USA.
The Royal Children's Hospital Melbourne, Melbourne, VIC, Australia.
Department of Clinical Genetics, Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, NSW, Australia.
Disciplines of Genomic Medicine and Child and Adolescent Health, University of Sydney, Sydney, Australia.
Heart Centre for Children, The Children's Hospital at Westmead, Sydney, Australia.
SA Pathology, Department of Genetics and Molecular Pathology, Adelaide, SA, Australia.
University of Adelaide, Adelaide, SA, Australia.
Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC, Australia.
Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.
Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC, Australia.
Division of Clinical Genetics and Metabolism, Nicklaus Children's Health System, Miami, FL, USA.
Florida International University, Miami, FL, USA.
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
Hudson Alpha Institute for Biotechnology, Huntsville, AL, USA.
Laboratoire de Cardiogénétique Moléculaire, Service de Biochimie et Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France.
Institut NeuroMyoGène, Université Claude Bernard Lyon 1, Lyon, France.
Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
Department of Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
Centre for Postgraduate Nursing Studies and the Department of Pathology and Biomedical Science, University of Otago Christchurch, Otautahi, New Zealand.

Purpose

Biallelic hypomorphic variants in PPA2, encoding the mitochondrial inorganic pyrophosphatase 2 protein, have been recently identified in individuals presenting with sudden cardiac death, occasionally triggered by alcohol intake or a viral infection. Here we report 20 new families harboring PPA2 variants.

Methods

Synthesis of clinical and molecular data concerning 34 individuals harboring five previously reported PPA2 variants and 12 novel variants, 11 of which were functionally characterized.

Results

Among the 34 individuals, only 6 remain alive. Twenty-three died before the age of 2 years while five died between 14 and 16 years. Within these 28 cases, 15 died of sudden cardiac arrest and 13 of acute heart failure. One case was diagnosed prenatally with cardiomyopathy. Four teenagers drank alcohol before sudden cardiac arrest. Progressive neurological signs were observed in 2/6 surviving individuals. For 11 variants, recombinant PPA2 enzyme activities were significantly decreased and sensitive to temperature, compared to wild-type PPA2 enzyme activity.

Conclusion

We expand the clinical and mutational spectrum associated with PPA2 dysfunction. Heart failure and sudden cardiac arrest occur at various ages with inter- and intrafamilial phenotypic variability, and presentation can include progressive neurological disease. Alcohol intake can trigger cardiac arrest and should be strictly avoided.

中文翻译：

PPA2 相关的心源性猝死：扩展 20 个新家族的临床和等位基因谱

目的

PPA2 中的双等位基因亚型变体，编码线粒体无机焦磷酸酶 2 蛋白，最近已在出现心源性猝死的个体中发现，偶尔由饮酒或病毒感染引发。在这里，我们报告了 20 个含有PPA2变体的新家族。

方法

综合了 34 名个体的临床和分子数据，这些个体携带 5 种先前报道的 PPA2变体和 12 种新变体，其中 11 种具有功能特征。

结果

34人中，只有6人还活着。23 人在 2 岁之前死亡，5 人在 14 至 16 岁之间死亡。在这 28 例中，15 人死于心脏骤停，13 人死于急性心力衰竭。1例产前诊断为心肌病。四名青少年在心脏骤停前饮酒。在 2/6 的幸存者中观察到进行性神经系统体征。对于 11 种变体，与野生型 PPA2 酶活性相比，重组 PPA2 酶活性显着降低且对温度敏感。