title: Hyperekplexia, microcephaly and simplified gyral pattern caused by novel ASNS mutations, case report.
abstract: BACKGROUND
  Asparagine synthetase deficiency (OMIM# 615574) is a very rare newly described neurometabolic disorder characterized by congenital microcephaly and severe global developmental delay, associated with intractable seizures or hyperekplexia. Brain MRI typically shows cerebral atrophy with simplified gyral pattern and delayed myelination. Only 12 cases have been described to date. The disease is caused by homozygous or compound heterozygous mutations in the ASNS gene on chromosome 7q21.
  
  
  METHODS
  Family 1 is a multiplex consanguineous family with five affected members, while Family 2 is simplex. One affected from each family was available for detailed phenotyping. Both patients (Patients 1 and 2) presented at birth with microcephaly and severe hyperekplexia, and were found to have gross brain malformation characterized by simplified gyral pattern, and hypoplastic cerebellum and pons. EEG showed no epileptiform discharge in Patient 2 but multifocal discharges in patient 1. Patient 2 is currently four years old with severe neurodevelopmental delay, quadriplegia and cortical blindness. Whole exome sequencing (WES) revealed a novel homozygous mutation in ASNS (NM_001178076.1) in each patient (c.970C > T:p.(Arg324*) and c.944A > G:p.(Tyr315Cys)).
  
  
  CONCLUSIONS
  Our results expand the mutational spectrum of the recently described asparagine synthetase deficiency and show a remarkable clinical homogeneity among affected individuals, which should facilitate its recognition and molecular confirmation for pertinent and timely genetic counseling.
authors.affiliation: Neonatology Unit, Department of Pediatrics, Security Forces Hospital, Riyadh, 11481, Saudi Arabia. zainsidahmed@hotmail.com.
authors.forename: Mohammed Zain
authors.initials: MZ
authors.lastname: Seidahmed
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Mustafa A
authors.initials: MA
authors.lastname: Salih
authors.affiliation: Neonatology Unit, Department of Pediatrics, Security Forces Hospital, Riyadh, 11481, Saudi Arabia.
authors.forename: Omer B
authors.initials: OB
authors.lastname: Abdulbasit
authors.affiliation: Neonatology Unit, Department of Pediatrics, Security Forces Hospital, Riyadh, 11481, Saudi Arabia.
authors.forename: Abdulmohsen
authors.initials: A
authors.lastname: Samadi
authors.affiliation: Neonatology Unit, Department of Pediatrics, Security Forces Hospital, Riyadh, 11481, Saudi Arabia.
authors.forename: Khalid
authors.initials: K
authors.lastname: Al Hussien
authors.affiliation: Neonatology Unit, Department of Pediatrics, Security Forces Hospital, Riyadh, 11481, Saudi Arabia.
authors.forename: Abeer M
authors.initials: AM
authors.lastname: Miqdad
authors.affiliation: Pediatric Neurology, Department of Pediatrics, Security Forces Hospital, Riyadh, Saudi Arabia.
authors.forename: Maha S
authors.initials: MS
authors.lastname: Biary
authors.affiliation: Developmental Genetics Unit, Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Anas M
authors.initials: AM
authors.lastname: Alazami
authors.affiliation: Department of Radiology and Diagnostic Imaging, King Khalid University Hospital and College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Ibrahim A
authors.initials: IA
authors.lastname: Alorainy
authors.affiliation: Division of Clinical Neurophyisoloy, Department of Neuroscience, Prince Sultan Medical City, Riyadh, Saudi Arabia.
authors.forename: Mohammad M
authors.initials: MM
authors.lastname: Kabiraj
authors.affiliation: Developmental Genetics Unit, Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Ranad
authors.initials: R
authors.lastname: Shaheen
authors.affiliation: Developmental Genetics Unit, Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.|Department of Anatomy and Cell Biology, College of Medicine, Al Faisal University, Riyadh, Saudi Arabia.
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
mesh_terms: D001284:Atrophy; D001927:Brain Diseases / Q000235:genetics*; D002531:Cerebellum / Q000002:abnormalities; D002675:Child, Preschool; D002658:Developmental Disabilities / Q000235:genetics; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D008831:Microcephaly / Q000235:genetics*; D009154:Mutation; D009421:Nervous System Malformations / Q000235:genetics; D016750:Stiff-Person Syndrome / Q000235:genetics*
keywords: ASNS gene; Arthrogryposis; Asparagine synthetase deficiency; Brain malformation; Case report; Hyperekplexia; Whole exome sequencing