A girl with developmental delay, ataxia, cranial nerve palsies, severe respiratory problems in infancy—Expanding NDST1 syndrome

Abstract

NDST1 encodes an enzyme involved in the first steps in the synthesis of heparan sulfate chains, proteoglycans that are regulators found on the cell surface and in the extracellular matrix. Eight individuals homozygous for one of four family-specific missense mutations in the sulfotransferase domain of the enzyme have been described. They have intellectual disability. Some additionally had hypotonia, ataxia. seizures, and/or short stature, but none had history of respiratory problems. No humans with homozygous null mutations are known. ndst1b (orthologous to NDST1) morpholino knockdown in zebrafish (Danio rerio) causes delayed development, craniofacial cartilage abnormalities, shortened body and pectoral fin length. Ndst1 homozygous null mice have craniofacial abnormalities and die within the first 10 h of life of respiratory failure. We report a girl upon whom deep phenotyping, extensive genetic and biochemical investigations, and exome sequencing were performed. She had cranial nerves dysfunction, gastroesophageal reflux, history of a seizure, ataxia, developmental delays, head sparing failure to thrive, and minor malformations including distinctive facial features and a bifid uvula. Compound heterozygous mutations in NDST1 were identified, in the heparan sulfate N deacetylatase domain of one allele and the sulfotransferase domain of the other allele. This report expands the phenotypic spectrum of Ndst1 deficiency in humans. © 2017 Wiley Periodicals, Inc.

Developmental delay, coarse facial features, and epilepsy in a patient with EXT2 gene variants

“…This condition has an onset in infancy or early childhood and is characterized by delayed psychomotor development, delayed or absent speech, intellectual disability and hypotonia. Patients in some cases have also been shown to display behavioral abnormalities such as agitation, aggression and sleep disturbances, seizures, and postnatal growth deficiency . The patient had aggressive behavior, intellectual disability, seizures, and sleep disturbance but no evidence of growth retardation.…”

“…Patients in some cases have also been shown to display behavioral abnormalities such as agitation, aggression and sleep disturbances, seizures, and postnatal growth deficiency. 3,15 The patient had aggressive behavior, intellectual disability, seizures, and sleep disturbance but no evidence of growth retardation. Notably, the mildly affected sister was also found to carry this variant.…”

“…EXT2 (MIM: 608210) and NDST1 (MIM: 600853) are two such genes critical to the polymerization and processing of heparan sulfate. EXT2 belongs to the exostosin family of glycosyltransferases involved in the chain elongation step of heparan sulfate biosynthesis, while NDST1 encodes the bifunctional enzyme GlcNAc N‐deacetylase/N‐sulfotransferase that modifies the glycosaminoglycan component of heparan sulfate and plays a role in establishing the extent and pattern of HS sulfation . EXT2 is implicated in the autosomal dominant disorder multiple Exostoses type 2 (MIM: 133701).…”

“…EXT2 belongs to the exostosin family of glycosyltransferases involved in the chain elongation step of heparan sulfate biosynthesis, 2 while NDST1 encodes the bifunctional enzyme GlcNAc N-deacetylase/N-sulfotransferase that modifies the glycosaminoglycan component of heparan sulfate and plays a role in establishing the extent and pattern of HS sulfation. 3 EXT2 is implicated in the autosomal dominant disorder multiple Exostoses type 2 (MIM: 133701). Biallelic EXT2 mutations, however, have also been reported in four siblings born to consanguineous parents, manifesting scoliosis, seizures, and macrocephaly (MIM: 616682) without exostosis, following an autosomal recessive pattern of inheritance.…”

Potential role for Ext1-dependent heparan sulfate in regulating P311 gene expression in A549 carcinoma cells

“…Missense mutations in NDST1 cause intellectual disability and other disorders such as postnatal growth deficiency (Reuter et al, 2014). NDST1 deficiency has also been associated with developmental delay, ataxia, cranial nerve palsies and respiratory problems in infancy (Armstrong et al, 2017). Mutations in the HS 6-O-sulfotransferase-1 (HS6ST1) have been associated with idiopathic hypogonadotropic hypogonadism which is characterized by infertility due to defective gonadotropin-releasing hormone, also as a result of impaired neuronal development and function (Tornberg et al, 2011).…”