Predominant and novel de novo variants in 29 individuals with ALG13 deficiency: Clinical description, biomarker status, biochemical analysis, and treatment suggestions.,Journal of Inherited Metabolic Disease

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Predominant and novel de novo variants in 29 individuals with ALG13 deficiency: Clinical description, biomarker status, biochemical analysis, and treatment suggestions.
Journal of Inherited Metabolic Disease ( IF 4.2 ) Pub Date : 2020-07-18 , DOI: 10.1002/jimd.12290
Bobby G Ng ₁ , Erik A Eklund _{1,

2} , Sergey A Shiryaev ₁ , Yin Y Dong ₃ , Mary-Alice Abbott ₄ , Carla Asteggiano _{5,

6} , Michael J Bamshad _{7,

8} , Eileen Barr ₉ , Jonathan A Bernstein _{10,

11} , Shabeed Chelakkadan ₁₂ , John Christodoulou _{13,

14,

15} , Wendy K Chung _{16,

17} , Michael A Ciliberto ₁₈ , Janice Cousin ₁₉ , Fiona Gardiner ₂₀ , Suman Ghosh ₂₁ , William D Graf ₂₂ , Stephanie Grunewald ₂₃ , Katherine Hammond ₂₄ , Natalie S Hauser ₂₅ , George E Hoganson ₂₆ , Kimberly M Houck ₂₇ , Jennefer N Kohler _{10,

28} , Eva Morava ₂₉ , Austin A Larson ₃₀ , Pengfei Liu _{31,

32} , Sujana Madathil ₁₈ , Colleen McCormack _{10,

28} , Naomi J L Meeks ₃₀ , Rebecca Miller ₂₅ , Kristin G Monaghan ₃₃ , Deborah A Nickerson ₈ , Timothy Blake Palculict ₃₃ , Gabriela Magali Papazoglu ₅ , Beth A Pletcher ₃₄ , Ingrid E Scheffer _{20,

35} , Andrea Beatriz Schenone ₃₆ , Rhonda E Schnur ₃₃ , Yue Si ₃₃ , Leah J Rowe ₃₀ , Alvaro H Serrano Russi _{37,

38} , Rossana Sanchez Russo ₉ , Farouq Thabet ₃₉ , Allysa Tuite ₃₄ , María Mercedes Villanueva ₃₆ , Raymond Y Wang _{40,

41} , Richard I Webster _{42,

43} , Dorcas Wilson _{44,

45} , Alice Zalan ₂₆ , , Lynne A Wolfe ₄₆ , Jill A Rosenfeld _{31,

32} , Lindsay Rhodes ₃₃ , Hudson H Freeze ₁

Affiliation

Human Genetics Program, Sanford Children's Health Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
Department of Clinical Sciences, Lund, Pediatrics, Lund University, Lund, Sweden.
Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
Department of Pediatrics, Baystate Children's Hospital, University of Massachusetts Medical School - Baystate, Springfield, Massachusetts, USA.
CEMECO-CONICET, Children Hospital, School of Medicine, National University of Cordoba, Cordoba, Argentina.
Chair of Pharmacology, Catholic University of Cordoba, Cordoba, Argentina.
Department of Pediatrics, University of Washington, Seattle, Washington, USA.
Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
Department of Human Genetics, Emory University, Atlanta, Georgia, USA.
Stanford University School of Medicine, Stanford, California, USA.
Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, California, USA.
Monash Children's Hospital, Melbourne, Australia.
Brain and Mitochondrial Research Group, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia.
Department of Paediatrics, University of Melbourne, Melbourne, Australia.
Discipline of Child and Adolescent Health, Sydney Medical School, University of Sydney, Sydney, Australia.
Department of Pediatrics, Columbia University, New York, New York, USA.
Department of Medicine, Columbia University, New York, New York, USA.
Department of Pediatrics, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA.
Section of Human Biochemical Genetics, National Human Genome Research Institute, Bethesda, Maryland, USA.
University of Melbourne, Austin Health, Melbourne, Australia.
Department of Pediatrics Division of Pediatric Neurology, University of Florida College of Medicine, Gainesville, Florida, USA.
Division of Pediatric Neurology, Department of Pediatrics, Connecticut Children's; University of Connecticut, Farmington, Connecticut, USA.
Metabolic Medicine Department, Great Ormond Street Hospital, Institute of Child Health University College London, NIHR Biomedical Research Center, London, UK.
Division of Pediatric Neurology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Inova Translational Medicine Institute Division of Medical Genomics Inova Fairfax Hospital Falls Church, Virginia, USA.
Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois, USA.
Department of Pediatrics, Section of Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, Texas, USA.
Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota, USA.
Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
Baylor Genetics Laboratories, Houston, Texas, USA.
GeneDx, Inc. Laboratory, Gaithersburg, Maryland, USA.
Department of Pediatrics, Rutgers New Jersey Medical School, Newark, New Jersey, USA.
University of Melbourne, Royal Children's Hospital, Florey and Murdoch Institutes, Melbourne, Australia.
Laboratorio de Neuroquimica "Dr. N. A. Chamoles"-FESEN, Buenos Aires, Argentina.
Division of Medical Genetics Children's Hospital Los Angeles, University of Southern California, Los Angeles, California, USA.
Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
MercyOne Pediatric Neurology, Des Moines, Iowa, USA.
Division of Metabolic Disorders, Children's Hospital of Orange County, Orange, California, USA.
Department of Pediatrics, University of California-Irvine, Orange, California, USA.
T.Y. Nelson Department of Neurology and Neurosurgery, The Children's Hospital, Westmead, Australia.
Kids Neuroscience Centre, The Children's Hospital, Westmead, Australia.
Netcare Sunninghill Hospital, Sandton, South Africa.
Nelson Mandela Children's Hospital, Johannesburg, South Africa.
Undiagnosed Diseases Program, Common Fund, National Institutes of Health, Bethesda, Maryland, USA.

Asparagine‐linked glycosylation 13 homolog (ALG13) encodes a nonredundant, highly conserved, X‐linked uridine diphosphate (UDP)‐N‐acetylglucosaminyltransferase required for the synthesis of lipid linked oligosaccharide precursor and proper N‐linked glycosylation. De novo variants in ALG13 underlie a form of early infantile epileptic encephalopathy known as EIEE36, but given its essential role in glycosylation, it is also considered a congenital disorder of glycosylation (CDG), ALG13‐CDG. Twenty‐four previously reported ALG13‐CDG cases had de novo variants, but surprisingly, unlike most forms of CDG, ALG13‐CDG did not show the anticipated glycosylation defects, typically detected by altered transferrin glycosylation. Structural homology modeling of two recurrent de novo variants, p.A81T and p.N107S, suggests both are likely to impact the function of ALG13. Using a corresponding ALG13‐deficient yeast strain, we show that expressing yeast ALG13 with either of the highly conserved hotspot variants rescues the observed growth defect, but not its glycosylation abnormality. We present molecular and clinical data on 29 previously unreported individuals with de novo variants in ALG13. This more than doubles the number of known cases. A key finding is that a vast majority of the individuals presents with West syndrome, a feature shared with other CDG types. Among these, the initial epileptic spasms best responded to adrenocorticotropic hormone or prednisolone, while clobazam and felbamate showed promise for continued epilepsy treatment. A ketogenic diet seems to play an important role in the treatment of these individuals.

中文翻译：

29 名 ALG13 缺陷患者的主要和新型从头变异：临床描述、生物标志物状态、生化分析和治疗建议。

Asparagine-linked glycosylation 13 homolog ( ALG13 ) 编码一个非冗余的、高度保守的 X-linked 尿苷二磷酸 (UDP) -N-乙酰氨基葡萄糖转移酶，这是合成脂质连接的寡糖前体和正确的 N-连接糖基化所必需的。ALG13 中的从头变体它是一种称为 EIEE36 的早期婴儿癫痫性脑病的基础，但鉴于其在糖基化中的重要作用，它也被认为是一种先天性糖基化障碍 (CDG)，即 ALG13-CDG。之前报道的 24 例 ALG13-CDG 病例具有从头变异，但令人惊讶的是，与大多数形式的 CDG 不同，ALG13-CDG 没有表现出预期的糖基化缺陷，通常通过改变的转铁蛋白糖基化检测到。两个复发性新变体 p.A81T 和 p.N107S 的结构同源性建模表明两者都可能影响 ALG13 的功能。使用相应的 ALG13 缺陷酵母菌株，我们表明，用任一高度保守的热点变体表达酵母 ALG13 可以挽救观察到的生长缺陷，但不能挽救其糖基化异常。ALG13。这使已知病例的数量增加了一倍多。一个关键发现是，绝大多数人都患有 West 综合征，这是其他 CDG 类型的共同特征。其中，最初的癫痫痉挛对促肾上腺皮质激素或泼尼松龙的反应最好，而氯巴占和非氨酯显示出继续治疗癫痫的希望。生酮饮食似乎在这些人的治疗中发挥着重要作用。

更新日期：2020-07-18

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