Predominant and novel de novo variants in 29 individuals with ALG13 deficiency: Clinical description, biomarker status, biochemical analysis, and treatment suggestions

• Autores: Ng, Bobby G.; Eklund, Erik A.; Shiryaev, Sergey A.; Dong, Yin Y.; Abbott, Mary Alice; Asteggiano, Carla Gabriela; Bamshad, Michael J.; Barr, Eileen; Bernstein, Jonathan A.; Chelakkadan, Shabeed; Christodoulou, John; Chung, Wendy K.; Ciliberto, Michael A.; Cousin, Janice; Gardiner, Fiona; Ghosh, Suman; Graf, William D.; Grunewald, Stephanie; Hammond, Katherine; Hauser, Natalie S.; Hoganson, George E.; Houck, Kimberly M.; Kohler, Jennefer N.; Morava, Eva; Larson, Austin A.; Liu, Pengfei; Madathil, Sujana; McCormack, Colleen; Meeks, Naomi J.L.; Papazoglu, Gabriela Magali
• Año de publicación: 2020
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: CONGENITAL DISORDERS OF GLYCOSYLATION; EPILEPSY; N-LINKED GLYCOSYLATION; WHOLE EXOME SEQUENCING
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

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.
Fil: Ng, Bobby G.. Sanford Burnham Prebys Medical Discovery Institute; Estados Unidos
Fil: Eklund, Erik A.. Sanford Burnham Prebys Medical Discovery Institute; Estados Unidos. Lund University; Suecia
Fil: Shiryaev, Sergey A.. Sanford Burnham Prebys Medical Discovery Institute; Estados Unidos
Fil: Dong, Yin Y.. University of Oxford; Reino Unido
Fil: Abbott, Mary Alice. University of Massachusetts Medical School; Estados Unidos
Fil: Asteggiano, Carla Gabriela. Universidad Católica de Córdoba; Argentina. Universidad Nacional de Córdoba. Facultad de Medicina. Centro de Estudios de las Metabolopatías Congénitas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina
Fil: Bamshad, Michael J.. University of Washington; Estados Unidos
Fil: Barr, Eileen. University of Emory; Estados Unidos
Fil: Bernstein, Jonathan A.. University of Stanford; Estados Unidos
Fil: Chelakkadan, Shabeed. Monash Children's Hospital; Australia
Fil: Christodoulou, John. Sydney Medical School; Australia. University of Melbourne; Australia
Fil: Chung, Wendy K.. Columbia University; Estados Unidos
Fil: Ciliberto, Michael A.. University of Iowa; Estados Unidos
Fil: Cousin, Janice. National Human Genome Research Institute ; Estados Unidos
Fil: Gardiner, Fiona. University of Melbourne; Australia
Fil: Ghosh, Suman. University of Florida; Estados Unidos
Fil: Graf, William D.. University of Connecticut; Estados Unidos
Fil: Grunewald, Stephanie. University College London; Estados Unidos
Fil: Hammond, Katherine. University of Alabama at Birmingahm; Estados Unidos
Fil: Hauser, Natalie S.. Inova, Fairfax Hospital Falls Church; Estados Unidos
Fil: Hoganson, George E.. University Of Illinois At Chicago; Estados Unidos
Fil: Houck, Kimberly M.. Baylor College of Medicine; Estados Unidos
Fil: Kohler, Jennefer N.. University of Stanford; Estados Unidos
Fil: Morava, Eva. Mayo Clinic; Estados Unidos
Fil: Larson, Austin A.. University Of Colorado Anschutz Medical Campus.; Estados Unidos
Fil: Liu, Pengfei. Baylor Genetics; Estados Unidos. Baylor College Of Medicine; Estados Unidos
Fil: Madathil, Sujana. University of Iowa; Estados Unidos
Fil: McCormack, Colleen. University of Stanford; Estados Unidos
Fil: Meeks, Naomi J.L.. University Of Colorado Anschutz Medical Campus.; Estados Unidos
Fil: Papazoglu, Gabriela Magali. Universidad Nacional de Córdoba. Facultad de Medicina. Centro de Estudios de las Metabolopatías Congénitas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina