A number sign (#) is used with this entry because of evidence that asparagine synthetase deficiency (ASNSD) is caused by homozygous or compound heterozygous mutation in the ASNS gene (108370) on chromosome 7q21.

ASNS deficiency (ASNSD) 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 may show onset in utero or at birth and may result in early death (summary by Ruzzo et al., 2013); it may also present with early normal development followed by infantile-onset seizures and neurodevelopmental delays (Sacharow et al., 2018).

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.

Sun et al. (2017) reported 2 sisters from a consanguineous Indian family with ASNSD. In addition to typical features of the disorder, including congenital microcephaly with a progressive course, severe psychomotor delay, appendicular hypertonia, hyperreflexia, and progressive brain atrophy, both girls had diaphragmatic eventration. Neither patient had epilepsy, but one had hyperekplexia and the other had an abnormal EEG. One of the sisters was described as having unusual jittery movements. One girl died at 6 months of age and the other at 11 days. Sun et al. (2017) proposed that the presence of diaphragmatic eventration suggested extracranial involvement of the central nervous system.

Abhyankar et al. (2018) reported an infant who presented at birth with clonic tremors, microcephaly, cerebellar hypoplasia, blindness, and seizures. Metabolic testing was reportedly normal. MRI revealed increased extraaxial space, foreshortened frontal lobe, a simplified gyral pattern, small basal ganglia and thalami, reduced volume of white matter, thin corpus callosum, mild brainstem hypoplasia, and moderate cerebellar hypoplasia. The infant had hypertonia, developmental delay, moderate sleep apnea, gastrointestinal reflux, and epilepsy and died at 15 months of age.

Gupta et al. (2017) reported a 2.5-year-old girl, born of nonconsanguineous Indian parents, with a pregnancy complicated by fetal hypokinesia on prenatal ultrasound. Excessive irritability was noted at birth, with onset of generalized tonic and multifocal clonic seizures at 3 months of age. The patient had significant failure to thrive, severe microcephaly (head circumference more than -6 SD). She had a left convergent squint, cortical blindness, and optic nerve hypoplasia. She also had spastic quadriparesis with hyperreflexia leading to contractures involving bilateral ankle joints. MRI showed generalized cerebral atrophy, vermian hypoplasia, and a small pons. EEG showed multifocal epilepsy. Asparagine level was 9 micromol/L (normal range 38-65 micromol/L).

Sacharow et al. (2018) reported a brother and sister, born to consanguineous parents, with ASNS. Both sibs had normal prenatal course, normal height, weight, and head circumference at birth, and normal early development. Seizures and neurodevelopmental delays began in both sibs at 6 months of age. In the brother, growth plateaued at age 25 months. At age 7 years his head circumference and weight were less than the first percentile, and his height was at the first to third percentile. He experienced episodes of regression throughout his course with partial recovery. He had oropharyngeal dysphagia, was gastric tube dependent, and had severe global developmental delays with hyperactivity and self-harming behaviors. He also had cortical visual impairment. Plasma asparagine was normal, and asparagine in cerebral spinal fluid was borderline-low. His younger sister did not experience episodic regression. At age 3 years, her development was tested to be at a 1-year-old level. At age 4, her head circumference was less than the third percentile, but height and weight were normal. She had mild limb and axial hypotonia, brisk deep tendon reflexes, and an unsteady gait. Plasma asparagine was normal.

The transmission pattern of ASNS deficiency in the families reported by Ruzzo et al. (2013) was consistent with autosomal recessive inheritance.

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.

In 2 sisters with ASNSD from a consanguineous Indian family, Sun et al. (2017) identified a homozygous missense mutation in the ASNS gene (R340H; 108370.0004). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family.

By whole-exome sequencing of an archived newborn blood spot, Abhyankar et al. (2018) identified compound heterozygous mutations in the ASNS gene (G366D, 108370.0005; V243A, 108370.0006). The infant, who had died at 15 months of age without a specific diagnosis, had typical findings consistent with asparagine synthetase deficiency.

In a girl with ASNSD from a nonconsanguineous Indian family, Gupta et al. (2017) identified a homozygous missense mutation in the ASNS gene (A380S; 108370.0007). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family.

Sacharow et al. (2018) identified a homozygous mutation in the ASNS gene (R49Q; 108370.0008) in 2 sibs, born to consanguineous Emirati parents, with ASNSD. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family.

Ruzzo et al. (2013) found that homozygous mice with a hypomorphic Asns mutation (about 20% residual enzyme activity) had structural brain abnormalities, including reduced cortical thickness and enlarged ventricles. Mutant mice also showed deficits in learning and memory, but did not show motor abnormalities or seizure activity.