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Case Reports
. 2016 Jul 15:16:105.
doi: 10.1186/s12883-016-0633-0.

Hyperekplexia, microcephaly and simplified gyral pattern caused by novel ASNS mutations, case report

Mohammed Zain Seidahmed  1 , Mustafa A Salih  2 , Omer B Abdulbasit  3 , Abdulmohsen Samadi  3 , Khalid Al Hussien  3 , Abeer M Miqdad  3 , Maha S Biary  4 , Anas M Alazami  5 , Ibrahim A Alorainy  6 , Mohammad M Kabiraj  7 , Ranad Shaheen  5 , Fowzan S Alkuraya  5   8
Affiliations
Case Reports

Hyperekplexia, microcephaly and simplified gyral pattern caused by novel ASNS mutations, case report

Mohammed Zain Seidahmed et al. BMC Neurol. .

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.

Case presentation: 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)).

Conclusion: 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.

Keywords: ASNS gene; Arthrogryposis; Asparagine synthetase deficiency; Brain malformation; Case report; Hyperekplexia; Whole exome sequencing.

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Figures

Fig. 1
Fig. 1
Pedigrees of the two study families. The sequence chromatograms of the mutant alleles are shown below the respective pedigrees
Fig. 2
Fig. 2
a Photograph of patient 1 showing microcephaly, slopingforehead, micrognathia, and relatively large ears. b Photograph of patient 2 at age of four years. Note microcephaly, relatively large ears, sloping forehead, and severe contractures of all limbs (spastic quadriplegic posture)
Fig. 3
Fig. 3
Brain MR images at day 1 after birth of patient 1. a Sagittal T1-weighted image showing severe microcephaly, simplified gyral pattern, thin corpus callosum, small cerebellum, and small pons. b Axial T1-weighted image demonstrating small pons and cerebellum. c Axial T1-weighted image showing delayed myelination of the posterior limb of internal capsule, bilaterally. d Coronal FLAIR image demonstrating severely simplified gyral pattern and large extra-axial CSF spaces reflecting brain underdevelopment. e Proton MR Spectroscopy with long TE showing normal spectra for age
Fig. 4
Fig. 4
MRI brain at the age of 3 weeks. a Sagittal T1-weighted image showing severe microcephaly with overlapped lambdoid sutures, brain underdevelopment evident by simplified gyral pattern, small cerebellum, and small pons. b Axial FLAIR image revealing small pons and cerebellum. c Axial T1-weighted image demonstrating delayed myelination evident by absent myelination of the posterior limb of internal capsule, bilaterally. d Coronal T2-weighted image showing simplified gyral pattern (more in the frontal lobes) and large extra-axial CSF spaces due to brain underdevelopment
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