West syndrome caused by ST3Gal‐III deficiency

Abstract

Summary West syndrome consists of infantile spasms, hypsarrhythmia, and developmental arrest. Most patients remain mentally retarded and many develop Lennox‐Gastaut syndrome. Using homozygosity mapping followed by exome sequencing we identified an ST3GAL3 mutation in three infants with West syndrome. ST3GAL3 encodes a sialyltransferase involved in the biosynthesis of sialyl‐Lewis epitopes on cell surface–expressed glycoproteins. The mutation affected an essential sialyl‐motif and abolished enzymatic activity. Abnormalities in proteins involved in forebrain γ‐aminobutyric acid (GABA)ergic synaptic growth and function were recently proposed to account for infantile spasms. Dysfunctional ST3GAL3 may thus result in perturbation of the posttranslational sialylation of proteins in these pathways.

Epilepsy genetics: The ongoing revolution

“…Biallelic mutations in ST3GAL3, encoding a sialyltransferase involved in the biosynthesis of sialyl-Lewis epitopes on cell surface-expressed glycoproteins and previously associated with ID, were found in four family members with IEES [98,99]. Compound heterozygous mutations in DOCK7, encoding a Rac guanine nucleotide exchange factor, have been identified in patients with intractable early-onset IEES, severe psychomotor involvement, cortical blindness, and dysmorphic features.…”

“…Mutations in WWOX, encoding WW domain-containing oxidoreductase, have been associated with cerebellar ataxia, ID, and epilepsy [141,142]. Other genes causing encephalopathy with epilepsy include ST3GAL3, SLC35A2, PNPO, PLCB1, SLC25A22 (see Sections 6.1, 6.2 and 6.4), and PIGA [67,79,82,98,127,[143][144][145]. Mutations in TNK2, encoding a brain-expressed tyrosine kinase, has been found in three siblings with severe infantile-onset epilepsy [146].…”

Novel Genes of Early-Onset Epileptic Encephalopathies: From Genotype to Phenotypes

“…The mutations were identified in two boys presenting with mental retardation and epilepsy with onset after the second year of life. 42 One of them had complex partial seizures and showed a hypoplastic frontal lobe on MRI, whereas the other had status epilepticus during sleep and showed a right frontal polymicrogyria. 41…”

“…42 Clinical presentations and genotypeephenotype relationships Edvardson et al described a c. 958G>C mutation in the ST3Gal III gene discovered in four members of a consanguineous Palestinian family through a linkage analysis following whole exome sequencing and a confirmatory Sanger sequencing. All affected patients presented with West syndrome.…”

“…All affected patients presented with West syndrome. 42 Even if mutations in the ST3Gal III gene have been associated with intellectual disability, a precise mechanism for its role in epileptogenesis has not been established yet. 42 Ww domain-containing oxidoreductase (WWOX; OMIM number 605131)…”