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

Abstract

Asparagine-linked glycosylation 13 homolog (ALG13) encodes a nonredundant, highly conserved, X-linked uridine diphosphate (UDP)-Nacetylglucosaminyltransferase 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

Congenital Disorders of Glycosylation from a Neurological Perspective

“…Most patients with this mutation, as stated above, were girls showing initially ESp, successively developing myoclonic-tonic spasms, focal seizures, generalized seizures. In 2020, Ng et al provided information on 29 unreported ALG13-CDG patients, among them, 34 females and 2 males harbor c.320A >G (p.Asn107Ser) variant [ 49 ]. Most patients presented with ESp responding to ACTH (87%) or prednisolone therapy (38%) and later benzodiazepines (clonazepam CZP, NZP, CLB) with most commonly used CLB (7–88%) and felbamate (FLB) [ 49 ].…”

“…In 2020, Ng et al provided information on 29 unreported ALG13-CDG patients, among them, 34 females and 2 males harbor c.320A >G (p.Asn107Ser) variant [ 49 ]. Most patients presented with ESp responding to ACTH (87%) or prednisolone therapy (38%) and later benzodiazepines (clonazepam CZP, NZP, CLB) with most commonly used CLB (7–88%) and felbamate (FLB) [ 49 ]. Also ketogenic diet gave a sustained antiepileptic effect in 27% of patients.…”

“…In 87% of patients, hypsarrhythmia was the initial abnormality seen on EEG. Based on literature data Ng et al concluded that epileptic phenotype in ALG-13 is very homogenous with the mean age of ESp appearance around 6.5 months [ 49 ]. Patients’ observation allowed for the suggestion of the first line treatment of ESp in CDG, which is ACTH or prednisolone.…”

“…ALG13-CDG clinical spectrum apart from epilepsy covers developmental delay (100%), intellectual disability (92%), hypotonia (85%), coagulation abnormalities and endocrine dysfunction [ 49 ].…”

The First Metabolome Analysis in Children with Epilepsy and ALG13-CDG Resulting from c.320A>G Variant

“…ALG13-CDG presents as an early infantile epileptic encephalopathy. According to the most recent data, the c.320A>G (p.Asn107Ser) variant is the most frequent female predominant mutation [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. The clinical courses are, however, very variable among affected individuals, which justifies and explains the need to look for new markers or risk factors related to the phenotype.…”