Essa Alharby1, Eissa A Faqeih2, Mohammed Saleh2, Seham Alameer3, Makki Almuntashri4, Annalisa Pastore5, Manar A Samman6, Abdullah M Alnawfal6, Mais Hashem7, Dimah Zaytuni1, Ghadeer Alharbi1, Mohammed Almannai2, Ali Alasmari2, Adel A Mahmoud8, Ali H Alwadei8, Lamya Jad8, Ali AlOtaibi8, Fahad Al-Hakami3, Wafaa Eyaid9,10, Fowzan S Alkuraya7,11, Majid Alfadhel9,10, Roy W A Peake12, Naif A M Almontashiri13,14. 1. Center for Genetics and Inherited Diseases, Taibah University, Almadinah Almunwarah, Saudi Arabia. 2. Section of Medical Genetics, Children's Specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia. 3. King Abdulaziz Medical City/King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia. 4. Department of Radiology, King Abdulaziz Medical City, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia. 5. National Institute for Medical Research, The Ridgeway, Mill Hill, London, UK. 6. Molecular Pathology, Pathology and Clinical Laboratory Medicine Administration, King Fahad Medical City, Riyadh, Saudi Arabia. 7. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. 8. Pediatric Neurology Department, National Neuroscience Institute, King Fahad Medical City, Riyadh, Saudi Arabia. 9. Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard-Health Affairs (MNGHA), Riyadh, Saudi Arabia. 10. Division of Genetics, Department of Pediatrics, King Abdullah Specialized Children's Hospital (KASCH), King Abdulaziz Medical City, Ministry of National Guard-Health Affairs (MNGHA), Riyadh, Saudi Arabia. 11. College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. 12. Department of Laboratory Medicine, Boston Children's Hospital, Boston, MA, USA. 13. Center for Genetics and Inherited Diseases, Taibah University, Almadinah Almunwarah, Saudi Arabia. nmontashri@taibahu.edu.sa. 14. Faculty of Applied Medical Sciences, Taibah University, Almadinah Almunwarah, Saudi Arabia. nmontashri@taibahu.edu.sa.
Abstract
PURPOSE: Asparagine synthetase deficiency (ASNSD) is a rare neurometabolic disease. Patients may not demonstrate low asparagine levels, which highlights the advantage of molecular over biochemical testing in the initial work-up of ASNSD. We aimed to further delineate the ASNSD variant and phenotypic spectrum and determine the value of biochemical testing as a frontline investigation in ASNSD. METHODS: We retrospectively collected the clinical and molecular information on 13 families with ASNSD from the major metabolic clinics in Saudi Arabia. RESULTS: The major phenotypes included congenital microcephaly (100%), facial dysmorphism (100%), global developmental delay (100%), brain abnormalities (100%), spasticity (86%), and infantile-onset seizures (93%). Additional unreported phenotypes included umbilical hernia, osteopenia, eczema, lung hypoplasia, and hearing loss. Overall, seven homozygous variants accounted for ASNSD. The p.Tyr398Cys and p.Asn75Ile variants accounted for 54% of the cases. The clinical sensitivity and specificity of the proposed biochemical analysis of cerebrospinal fluid (CSF) for the detection of patients with ASNSD were 83% and 98%, respectively. CONCLUSION: Our study describes the largest reported ASNSD cohort with clinical, molecular, and biochemical characterization. Taking into consideration the suboptimal sensitivity of biochemical screening, the delineation of the phenotype variant spectrum is of diagnostic utility for accurate diagnosis, prognosis, counseling, and carrier screening.
PURPOSE: Asparagine synthetase deficiency (ASNSD) is a rare neurometabolic disease. Patients may not demonstrate low asparagine levels, which highlights the advantage of molecular over biochemical testing in the initial work-up of ASNSD. We aimed to further delineate the ASNSD variant and phenotypic spectrum and determine the value of biochemical testing as a frontline investigation in ASNSD. METHODS: We retrospectively collected the clinical and molecular information on 13 families with ASNSD from the major metabolic clinics in Saudi Arabia. RESULTS: The major phenotypes included congenital microcephaly (100%), facial dysmorphism (100%), global developmental delay (100%), brain abnormalities (100%), spasticity (86%), and infantile-onset seizures (93%). Additional unreported phenotypes included umbilical hernia, osteopenia, eczema, lung hypoplasia, and hearing loss. Overall, seven homozygous variants accounted for ASNSD. The p.Tyr398Cys and p.Asn75Ile variants accounted for 54% of the cases. The clinical sensitivity and specificity of the proposed biochemical analysis of cerebrospinal fluid (CSF) for the detection of patients with ASNSD were 83% and 98%, respectively. CONCLUSION: Our study describes the largest reported ASNSD cohort with clinical, molecular, and biochemical characterization. Taking into consideration the suboptimal sensitivity of biochemical screening, the delineation of the phenotype variant spectrum is of diagnostic utility for accurate diagnosis, prognosis, counseling, and carrier screening.