Predominant and novel de novo variants in 29 individuals with ALG13 deficiency: Clinical description, biomarker status, biochemical analysis, and treatment suggestions.
Predominant and novel de novo variants in 29 individuals with ALG13 deficiency: Clinical description, biomarker status, biochemical analysis, and treatment suggestions.
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DOI：
10.1002/jimd.12290
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发表时间：
2020-11
影响因子：
4.2
通讯作者：
Freeze HH
中科院分区：
文献类型：
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作者：
Ng BG;Eklund EA;Shiryaev SA;Dong YY;Abbott MA;Asteggiano C;Bamshad MJ;Barr E;Bernstein JA;Chelakkadan S;Christodoulou J;Chung WK;Ciliberto MA;Cousin J;Gardiner F;Ghosh S;Graf WD;Grunewald S;Hammond K;Hauser NS;Hoganson GE;Houck KM;Kohler JN;Morava E;Larson AA;Liu P;Madathil S;McCormack C;Meeks NJL;Miller R;Monaghan KG;Nickerson DA;Palculict TB;Papazoglu GM;Pletcher BA;Scheffer IE;Schenone AB;Schnur RE;Si Y;Rowe LJ;Serrano Russi AH;Russo RS;Thabet F;Tuite A;Villanueva MM;Wang RY;Webster RI;Wilson D;Zalan A;Undiagnosed Diseases Network, University of Washington Center for Mendelian Genomics (UW-CMG);Wolfe LA;Rosenfeld JA;Rhodes L;Freeze HH
天冬酰胺连接的糖基化13同源物（ALG 13）编码非冗余的、高度保守的、X-连接的尿苷二磷酸（UDP）-N-乙酰葡糖胺基转移酶，其是合成脂质连接的寡糖前体和适当的N-连接的糖基化所需的。ALG 13的新生变异体是一种称为EIEE 36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），ALG 13-CDG。24个先前报道的ALG 13-CDG病例具有从头变体，但令人惊讶的是，与大多数形式的CDG不同，ALG 13-CDG没有显示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。两种复发性从头变异体p.A81T和p.N107S的结构同源性建模表明两者都可能影响ALG 13的功能。使用相应的ALG 13缺陷型酵母菌株，我们表明，表达酵母ALG 13与任何一个高度保守的热点变体拯救观察到的生长缺陷，但不是其糖基化异常。我们目前的分子和临床数据29个以前未报告的个体与ALG 13的新生变异。这使已知病例的数量增加了一倍多。一个关键的发现是，绝大多数人都患有韦斯特综合征，这是与其他CDG类型共有的特征。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持续癫痫治疗的希望。生酮饮食似乎在这些个体的治疗中起着重要作用。
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.
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影响因子：
4.8
作者：
Bickel, T;Lehle, L;Jakob, CA
通讯作者：
Jakob, CA
DOI：
10.1007/8904_2017_53
发表时间：
2018-01-01
期刊：
JIMD REPORTS, VOL 40
影响因子：
--
作者：
Galama, Wienke H.;Verhaagen-van den Akker, Sandra L. J.;Verrips, Aad
通讯作者：
Verrips, Aad
影响因子：
4.8
作者：
Averbeck, Nicole;Keppler-Ross, Sabine;Dean, Neta
通讯作者：
Dean, Neta
影响因子：
3.5
作者：
Dimassi, S.;Labalme, A.;Lesca, G.
通讯作者：
Lesca, G.
影响因子：
64.8
作者：
通讯作者：
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