Diaphragmatic Eventration in Sisters with Asparagine Synthetase Deficiency: A Novel Homozygous ASNS Mutation and Expanded Phenotype

摘要

Background: Asparagine Synthetase Deficiency (ASNSD; OMIM #615574) is a newly described rare autosomal recessive neurometabolic disorder, characterised by congenital microcephaly, severe psychomotor delay, encephalopathy and progressive cerebral atrophy. To date, seven families and seven missense mutations in the ASNSD disease causing gene, ASNS, have been published. Methods: We report two further affected infant sisters from a consanguineous Indian family, who in addition to the previously described features had diaphragmatic eventration. Both girls died within the first 6 months of life. Whole exome sequencing (WES) was performed for both sisters to identify the pathogenic mutation. The clinical and biochemical parameters of our patient are compared to previous reports. Results: WES demonstrated a homozygous novel missense ASNS mutation, c.1019G > A, resulting in substitution of the highly conserved arginine residue by histidine (R340H). Conclusion: This report expands the phenotypic and mutation spectrum of ASNSD, which should be considered in neonates with congenital microcephaly, seizures and profound neurodevelopmental delay. The presence of diaphragmatic eventration suggests extracranial involvement of the central nervous system in a disorder that was previously thought to exclusively affect the brain. Like all previously reported patients, these cases were diagnosed with WES, highlighting the clinical utility of next generation sequencing in the diagnosis of rare, difficult to recognise disorders. >Electronic supplementary material: The online version of this chapter (doi:10.1007/8904_2016_3) contains supplementary material, which is available to authorized users.