Neuropediatrics 2021; 52(03): 201-207
DOI: 10.1055/s-0040-1718917
Original Article

Asparagine Synthetase Deficiency with Intracranial Hemorrhage Can Mimic Molybdenum Cofactor Deficiency

Ghada M. H. Abdel-Salam
1   Human Genetics and Genome Research Division, Clinical Genetics Department, National Research Centre, Cairo, Egypt
,
Mohamed S. Abdel-Hamid
2   Human Genetics and Genome Research Division, Medical Molecular Department, National Research Centre, Cairo, Egypt
› Author Affiliations

Abstract

Here we report a consanguineous Egyptian family with two siblings presented with congenital microcephaly, early-onset epileptic encephalopathy, feeding difficulties, and early lethality. The condition was initially diagnosed as molybdenum cofactor deficiency as the brain imaging for one of them showed brain edema and intracranial hemorrhage in addition to the hypoplastic corpus callosum, vermis hypoplasia, and small-sized pons. Subsequently, whole exome sequencing identified a novel homozygous missense variant in exon 4 of ASNS gene c.397_398GT > CA (p.Val133Gln) confirming the diagnosis of asparagine synthetase deficiency syndrome. No discernible alternative cause for the intracranial hemorrhage was found. Our patient is the second to show asparagine synthetase deficiency and intracranial hemorrhage, thus confirming the involvement of ASNS gene. As such, it is important to consider asparagine synthetase deficiency syndrome in patients with microcephaly, brain edema, and neonatal intracranial hemorrhage.

Data Availability Statement

The data supporting the findings of this study are available with the corresponding author upon request.




Publication History

Received: 25 February 2020

Accepted: 28 August 2020

Article published online:
03 December 2020

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Ruzzo EK, Capo-Chichi JM, Ben-Zeev B. et al. Deficiency of asparagine synthetase causes congenital microcephaly and a progressive form of encephalopathy. Neuron 2013; 80 (02) 429-441
  • 2 Alfadhel M, Alrifai MT, Trujillano D. et al. Asparagine synthetase deficiency: new inborn errors of metabolism. JIMD Rep 2015; 22: 11-16
  • 3 Ben-Salem S, Gleeson JG, Al-Shamsi AM. et al. Asparagine synthetase deficiency detected by whole exome sequencing causes congenital microcephaly, epileptic encephalopathy and psychomotor delay. Metab Brain Dis 2015; 30 (03) 687-694
  • 4 Palmer EE, Hayner J, Sachdev R. et al. Asparagine synthetase deficiency causes reduced proliferation of cells under conditions of limited asparagine. Mol Genet Metab 2015; 116 (03) 178-186
  • 5 Gataullina S, Lauer-Zillhardt J, Kaminska A. et al. Epileptic phenotype of two siblings with asparagine synthesis deficiency mimics neonatal pyridoxine-dependent epilepsy. Neuropediatrics 2016; 47 (06) 399-403
  • 6 Seidahmed MZ, Salih MA, Abdulbasit OB. et al. Hyperekplexia, microcephaly and simplified gyral pattern caused by novel ASNS mutations, case report. BMC Neurol 2016; 16: 105
  • 7 Gupta N, Tewari VV, Kumar M. et al. Asparagine synthetase deficiency-report of a novel mutation and review of literature. Metab Brain Dis 2017; 32 (06) 1889-1900
  • 8 Sun J, McGillivray AJ, Pinner J. et al. Diaphragmatic eventration in sisters with asparagine synthetase deficiency: a novel homozygous ASNS mutation and expanded phenotype. JIMD Rep 2017; 34: 1-9
  • 9 Sacharow SJ, Dudenhausen EE, Lomelino CL. et al. Characterization of a novel variant in siblings with asparagine synthetase deficiency. Mol Genet Metab 2018; 123 (03) 317-325
  • 10 Yamamoto T, Endo W, Ohnishi H. et al. The first report of Japanese patients with asparagine synthetase deficiency. Brain Dev 2017; 39 (03) 236-242
  • 11 Abhyankar A, Lamendola-Essel M, Brennan K. et al. Clinical whole exome sequencing from dried blood spot identifies novel genetic defect underlying asparagine synthetase deficiency. Clin Case Rep 2017; 6 (01) 200-205
  • 12 Galada C, Hebbar M, Lewis L. et al. Report of four novel variants in ASNS causing asparagine synthetase deficiency and review of literature. Congenit Anom (Kyoto) 2018; 58 (05) 181-182
  • 13 Schleinitz D, Seidel A, Stassart R. et al. Novel mutations in the asparagine synthetase gene (ASNS) associated with microcephaly. Front Genet 2018; 9: 245
  • 14 Faoucher M, Poulat AL, Chatron N. et al. Asparagine synthetase deficiency: a novel case with an unusual molecular mechanism. Mol Genet Metab Rep 2019; 21: 100509
  • 15 Radha Rama Devi A, Naushad SM. Molecular diagnosis of asparagine synthetase (ASNS) deficiency in two Indian families and literature review of 29 ASNS deficient cases. Gene 2019; 704: 97-102
  • 16 Sprute R, Ardicli D, Oguz KK. et al. Clinical outcomes of two patients with a novel pathogenic variant in ASNS: response to asparagine supplementation and review of the literature. Hum Genome Var 2019; 6: 24
  • 17 Chen B, Li W, Wang X, Chen K, Hong X. Cyst-Peritoneal shunt for the treatment of progressive intracerebral cyst associated with ASNS mutation: case report and literature review. World Neurosurg 2019; 127: 1-7
  • 18 de Koning TJ. Amino acid synthesis deficiencies. J Inherit Metab Dis 2017; 40 (04) 609-620
  • 19 Rota E, Vallisa D, Morelli N, Scagnelli P. Iatrogenic coagulopathy and the development of posterior reversible encephalopathy syndrome after L-asparaginase chemotherapy. J Clin Imaging Sci 2016; 6: 7
  • 20 Jaccard A, Gachard N, Marin B. GELA and GOELAMS Intergroup. et al; Efficacy of L-asparaginase with methotrexate and dexamethasone (AspaMetDex regimen) in patients with refractory or relapsing extranodal NK/T-cell lymphoma, a phase 2 study. Blood 2011; 117 (06) 1834-1839
  • 21 Alqasim AMZ, Al-Hadithi RH, Al-Khalidi AN. Coagulopathic side effect of L-asparaginase on fibrinogen level in childhood acute lymphoblastic leukemia during induction phase. Hematol Oncol Stem Cell Ther 2019; 12 (01) 67-69
  • 22 Vohora D, Saraogi P, Yazdani MA, Bhowmik M, Khanam R, Pillai KK. Recent advances in adjunctive therapy for epilepsy: focus on sodium channel blockers as third-generation antiepileptic drugs. Drugs Today (Barc) 2010; 46 (04) 265-277
  • 23 Alrifai MT, Alfadhel M. Worsening of seizures after asparagine supplementation in a child with asparagine synthetase deficiency. Pediatr Neurol 2016; 58: 98-100