Expanded phenotype of AARS1-related white matter disease,Genetics in Medicine

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Expanded phenotype of AARS1-related white matter disease
Genetics in Medicine ( IF 6.6 ) Pub Date : 2021-08-27 , DOI: 10.1038/s41436-021-01286-8
Guy Helman _{1,

2} , Marisa I Mendes ₃ , Francesco Nicita ₄ , Lama Darbelli _{5,

6,

7,

8} , Omar Sherbini ₉ , Travis Moore _{5,

6} , Alexa Derksen _{5,

6} , Amy Pizzino ₉ , Rosalba Carrozzo ₄ , Alessandra Torraco ₄ , Michela Catteruccia ₄ , Chiara Aiello ₄ , Paola Goffrini ₁₀ , Sonia Figuccia ₁₀ , Desiree E C Smith ₃ , Kinga Hadzsiev ₁₁ , Andreas Hahn ₁₂ , Saskia Biskup ₁₃ , Ines Brösse ₁₄ , Urania Kotzaeridou ₁₄ , Darja Gauck ₁₅ , Theresa A Grebe ₁₆ , Frances Elmslie ₁₇ , Karen Stals ₁₈ , Rajat Gupta ₁₉ , Enrico Bertini ₄ , Isabelle Thiffault _{20,

21,

22} , Ryan J Taft ₂₃ , Raphael Schiffmann ₂₄ , Ulrich Brandl ₂₅ , Tobias B Haack ₁₅ , Gajja S Salomons ₃ , Cas Simons _{1,

2} , Geneviève Bernard _{5,

6,

7,

8} , Marjo S van der Knaap _{26,

27} , Adeline Vanderver _{9,

28} , Ralf A Husain ₂₅

Affiliation

Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, VIC, Australia.
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
Metabolic Unit, Department of Clinical Chemistry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
Department of Neurosciences, Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
Department of Pediatrics, McGill University, Montreal, QC, Canada.
Department of Human Genetics, McGill University, Montreal, QC, Canada.
Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy.
Department of Medical Genetics, University of Pécs, Pécs, Hungary.
Department of Child Neurology, Justus-Liebig-University, Giessen, Germany.
Praxis fuer Humangenetik and CeGaT GmbH, Tuebingen, Germany.
Division of Child Neurology and Inherited Metabolic Diseases, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany.
Division of Genetics and Metabolism, Department of Child Health, Phoenix Children's Hospital, University of Arizona College of Medicine, Phoenix, AZ, USA.
South West Thames Regional Genetics Service, St George's University Hospital, London, UK.
Molecular Genetics Department, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
Department of Neurology, Birmingham Children's Hospital, Birmingham, UK.
Children's Mercy Kansas City, Center for Pediatric Genomic Medicine, Kansas City, MO, USA.
Department of Pathology and Laboratory Medicine, Children's Mercy Hospitals, Kansas City, MO, USA.
School of Medicine, University of Missouri-Kansas City, Kansas City, MO, USA.
Illumina, Inc, San Diego, CA, USA.
Baylor Scott & White Research Institute, Dallas, TX, USA.
Department of Neuropediatrics, Jena University Hospital, Jena, Germany.
Department of Child Neurology, Emma Children's Hospital, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam and Amsterdam Neuroscience, Amsterdam, The Netherlands.
Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, The Netherlands.
Department of Neurology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.

Purpose

Recent reports of individuals with cytoplasmic transfer RNA (tRNA) synthetase-related disorders have identified cases with phenotypic variability from the index presentations. We sought to assess phenotypic variability in individuals with AARS1-related disease.

Methods

A cross-sectional survey was performed on individuals with biallelic variants in AARS1. Clinical data, neuroimaging, and genetic testing results were reviewed. Alanyl tRNA synthetase (AlaRS) activity was measured in available fibroblasts.

Results

We identified 11 affected individuals. Two phenotypic presentations emerged, one with early infantile–onset disease resembling the index cases of AARS1-related epileptic encephalopathy with deficient myelination (n = 7). The second (n = 4) was a later-onset disorder, where disease onset occurred after the first year of life and was characterized on neuroimaging by a progressive posterior predominant leukoencephalopathy evolving to include the frontal white matter. AlaRS activity was significantly reduced in five affected individuals with both early infantile–onset and late-onset phenotypes.

Conclusion

We suggest that variants in AARS1 result in a broader clinical spectrum than previously appreciated. The predominant form results in early infantile–onset disease with epileptic encephalopathy and deficient myelination. However, a subgroup of affected individuals manifests with late-onset disease and similarly rapid progressive clinical decline. Longitudinal imaging and clinical follow-up will be valuable in understanding factors affecting disease progression and outcome.

中文翻译：

AARS1 相关白质疾病的扩展表型

目的

最近关于患有细胞质转移 RNA (tRNA) 合成酶相关疾病的个体的报告已经从指数表现中确定了具有表型变异性的病例。我们试图评估AARS1相关疾病个体的表型变异性。

方法

对AARS1中具有双等位基因变异的个体进行了横断面调查。审查了临床数据、神经影像学和基因检测结果。在可用的成纤维细胞中测量丙氨酰 tRNA 合成酶 (AlaRS) 活性。

结果

我们确定了 11 名受影响的个人。出现了两种表型表现，一种是早期婴儿发病的疾病，类似于AARS1相关的有髓鞘缺乏的癫痫性脑病的指示病例（n = 7）。第二种 ( n = 4) 是一种迟发性疾病，疾病发作发生在出生后的第一年，其神经影像学特征为进行性后部为主的白质脑病演变为包括额叶白质。在具有早期婴儿发病和迟发表型的五个受影响个体中，AlaRS 活性显着降低。