Clinical characteristics: Asparagine synthetase deficiency (ASD) mainly presents as a triad of congenital microcephaly, severe developmental delay, and axial hypotonia followed by spastic quadriplegia. Low cerebrospinal fluid (CSF) asparagine level can help the clinician in differentiating this disorder from others. In most cases age of onset of apnea, excessive irritability, and seizures is soon after birth. Affected individuals typically do not acquire any developmental milestones. Spastic quadriplegia can lead to severe contractures of the limbs and neurogenic scoliosis. Feeding difficulties (gastroesophageal reflux disease, frequent vomiting, swallowing dysfunction, and gastroesophageal incoordination) are a significant problem in most affected individuals. A majority have cortical blindness. MRI findings are nonspecific but may include generalized atrophy and simplified gyral pattern.
Diagnosis: The diagnosis of ASD is established in a proband by identification of biallelic pathogenic variants in ASNS on molecular genetic testing.
Management: Treatment of manifestations: Antispastic medication (baclofen, tizanidine, and/or Botox® injection) for spasticity; clonazepam for hyperekplexia; mechanical ventilation may be required for apnea; nasogastric or gastrostomy tube to support nutrition; standard treatment for seizures, hearing loss, gastroesophageal reflux disease, constipation, and kyphosis/scoliosis; supportive developmental therapies.
Prevention of secondary complications: Regular immunization to prevent life-threatening infections.
At each visit: evaluation of developmental progress and growth; assessment for progression of spasticity, contractures, and scoliosis/kyphosis.
Every six months: assessment of nutritional status through serum total protein, albumin, and prealbumin levels.
Annually: ophthalmologic evaluation.
As needed: EEG if there are concerns for new-onset seizure activity or progression of seizures; audiologic evaluation if there are concerns for hearing loss.
Genetic counseling: Asparagine synthetase deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for a pregnancy at increased risk are possible if the ASNS pathogenic variants in the family are known.
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