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

BOBBY G. NG; ERIK A. EKLUND; SERGEY A. SHIRYAEV; YIN Y. DONG; MARY ALICE ABBOTT; CARLA ASTEGGIANO; MICHAEL J. BAMSHAD......; HUDSON H. FREEZE

JOURNAL OF INHERITED METABOLIC DISEASE

SPRINGER

Lugar: Berlin; Año: 2020

0141-8955

Human ALG13 encodes a non-redundant, highly conserved, X-linked UDP-N-Acetylglucosaminyltransferase required for the synthesis of lipid linked oligosaccharide precursor and proper N-linked glycosylation. De novo variants in ALG13 were shown to cause 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, ALG13-CDG. Twenty-four previously reported 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 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 unreported individuals specifically with de novo variants in ALG13. This more than doubles the number of known cases. Among these individuals, the initial epileptic spams were best treated with ACTH or prednisolone, while clobazam and felbamate showed promise for continued epilepsy treatment. Also, ketogenic diet seems to have an important role in the treatment arsenal of these individuals.