ASNS deficiency is an autosomal recessive severe neurologic disorder characterized by microcephaly, severely delayed psychomotor development, progressive encephalopathy, cortical atrophy, and seizure or hyperekplexic activity. The disorder shows onset in utero or at birth and may result in ... ASNS deficiency is an autosomal recessive severe neurologic disorder characterized by microcephaly, severely delayed psychomotor development, progressive encephalopathy, cortical atrophy, and seizure or hyperekplexic activity. The disorder shows onset in utero or at birth and may result in early death (summary by Ruzzo et al., 2013).
Ruzzo et al. (2013) reported 9 patients from 4 unrelated families with a similar phenotype characterized by congenital and progressive microcephaly (up to -7 SD), lack of or severely delayed psychomotor development, appendicular hypertonia and hyperreflexia, and decreased ... Ruzzo et al. (2013) reported 9 patients from 4 unrelated families with a similar phenotype characterized by congenital and progressive microcephaly (up to -7 SD), lack of or severely delayed psychomotor development, appendicular hypertonia and hyperreflexia, and decreased cerebral volume. Two families were Iranian Jewish, 1 was Bangladeshi, and 1 was French Canadian. Patients in 3 of the families developed early-onset seizures, including tonic, myoclonic, generalized tonic-clonic, and partial complex seizures associated with multiple independent spike foci or suppression burst patterns on EEG. Three sibs had hypsarrhythmia. Three sibs in the fourth family did not have overt seizures, but showed hyperekplexia and jitteriness with disorganized background activity on EEG. Brain imaging showed decreased cerebral volume with enlarged lateral ventricles. Some patients had cerebellar hypoplasia, pontine hypoplasia, thin corpus callosum, simplified gyral pattern, cortical dysgenesis, and/or delayed myelination. Other more variable features included dysmorphism, such as micrognathia, receding forehead, and large ears, axial hypotonia, and cortical blindness. Most had feeding difficulties and respiratory insufficiency, and 6 patients died in infancy.
In 9 patients from 4 unrelated families with ASNS deficiency, Ruzzo et al. (2013) identified 3 different homozygous or compound heterozygous missense mutations in the ASNS gene (108370.0001-108370.0003). The mutations were found by whole-exome sequencing and segregated with ... In 9 patients from 4 unrelated families with ASNS deficiency, Ruzzo et al. (2013) identified 3 different homozygous or compound heterozygous missense mutations in the ASNS gene (108370.0001-108370.0003). The mutations were found by whole-exome sequencing and segregated with the disorder in all families. Functional studies were not performed, but cellular studies showed that 2 of the mutant proteins were expressed at lower levels compared to wildtype, and the third mutant protein was expressed at higher levels than wildtype. Two patients had decreased levels of asparagine, whereas a third had increased levels of glutamine and aspartic acid. Ruzzo et al. (2013) postulated a loss-of-function effect. Ruzzo et al. (2013) suggested that the brain is responsible for local de novo synthesis of asparagine, which may explain why the phenotype was neurologically restricted. Brain accumulation of aspartate and glutamate may result in increased excitability, seizure activity, and neuronal damage.