Recessive mutations in SLC35A3 cause early onset epileptic encephalopathy with skeletal defects

Abstract

We describe the clinical and whole genome sequencing (WGS) study of a non-consanguineous Italian family in which two siblings, a boy and a girl, manifesting a severe epileptic encephalopathy (EE) with skeletal abnormalities, carried novel SLC35A3 compound heterozygous mutations. Both siblings exhibited infantile spasms, associated with focal, and tonic vibratory seizures from early infancy. EEG recordings showed a suppression-burst (SB) pattern and multifocal paroxysmal activity in both. In addition both had quadriplegia, acquired microcephaly, and severe intellectual disability. General examination showed distal arthrogryposis predominant in the hands in both siblings and severe left dorso-lumbar convex scoliosis in one. WGS of the siblings-parents quartet identified novel compound heterozygous mutations in SLC35A3 in both children. SLC35A3 encodes the major Golgi uridine diphosphate N-acetylglucosamine transporter. With this study, we add SLC35A3 to the gene list of epilepsies. Neurological symptoms and skeletal abnormalities might result from impaired glycosylation of proteins involved in normal development and function of the central nervous system and skeletal apparatus.

DPAGT1 Deficiency with Encephalopathy (DPAGT1-CDG): Clinical and Genetic Description of 11 New Patients

“…Epilepsy is a common finding in patients with glycosylation deficiencies, with a wide spectrum of severity and semiology (Freeze et al 2015). Severe epilepsy, often beginning as Ohtahara syndrome (early infantile epileptic encephalopathy) or West syndrome (hypsarrhythmia, clinical spasms, and developmental arrest) and sometimes developing into multifocal hard-to-treat epilepsy, has been reported for many CDG types, including ALG1-CDG (Fiumara et al 2016;Barba et al 2016), ALG3-CDG (Fiumara et al 2016;Barba et al 2016), ALG6-CDG (Fiumara et al 2016), ALG13-CDG (Hamici et al 2017), ALG14-CDG (Schorling et al 2017), DPM2-CDG (Fiumara et al 2016), DOLK-CDG (Helander et al 2013), RFT1-CDG (Barba et al 2016), SLC35A2-CDG (Ng et al 2013), and SLC35A3-CDG (Marini et al 2017). In the published cohort of DPAGT1-CDG patients including this report, 4/24 patients have had the diagnosis West syndrome, and 9 more have a definitive diagnosis of epilepsy, whereas only 3 were negated to have epilepsy.…”

Biosynthesis of GlcNAc-rich N- and O-glycans in the Golgi apparatus does not require the nucleotide sugar transporter SLC35A3

“…Initially, NSTs were demonstrated to be specific for the translocation of a single nucleotide sugar (8), but later multisubstrate transporters were reported (9)(10)(11). Mutations in genes encoding mammalian NSTs are associated with severe defects in development and physiology, demonstrating their requirement for proper functioning of multicellular organisms (e.g., [12][13][14][15][16].…”

Serum bikunin isoforms in congenital disorders of glycosylation and linkeropathies

“…34 Moreover, this alteration in the pattern of serum Bkn light forms suggests overall CS defects in line with the skeletal abnormalities observed in our patient (showing major long bones growth retardation) as well as in other cases described elsewhere. 35,36 Inherited defects in the enzymes involved in the stepwise synthesis of the common GAG tetrasaccharide linker, that is, xylosyltransferases (XYLT1 or XYLT2), galactosyltransferases (B4GALT7 and B3GALT6), and glucuronyltransferase (B3GAT3), correspond to linkeropathies. 37 In this work, we corroborated previously described high levels of abnormal Bkn light forms in B4GALT7, B3GALT6, and B3GAT3 deficiencies (Figure 2).…”