Asparagine synthetase deficiency is a condition that causes neurological problems in affected individuals starting soon after birth. Most people with this condition have an unusually small head size (microcephaly) that worsens over time due to loss (atrophy) of brain tissue. They also have severe developmental delay that affects both mental and motor skills (psychomotor delay). Affected individuals cannot sit, crawl, or walk and are unable to communicate verbally or nonverbally. The few affected children who achieve developmental milestones often lose these skills over time (developmental regression).
Most individuals with asparagine synthetase deficiency have exaggerated reflexes (hyperreflexia) and weak muscle tone (hypotonia). The muscle problems worsen through childhood and lead to muscle stiffness, uncontrolled movements, and ultimately, paralysis of the arms and legs (spastic quadriplegia). Many affected individuals also have recurrent seizures (epilepsy). Not all affected people experience the same type of seizure. The most common types involve a loss of consciousness, muscle rigidity, and convulsions (tonic-clonic); involuntary muscle twitches (myoclonic); or abnormal muscle contraction (tonic). People with asparagine synthetase deficiency may have an exaggerated startle reaction (hyperekplexia) to unexpected stimuli. Some affected individuals have blindness due to impairment of the area of the brain responsible for processing vision, called the occipital cortex (cortical blindness).
People with asparagine synthetase deficiency typically do not survive past childhood.
Asparagine synthetase deficiency is thought to be a rare condition. More than 20 affected individuals have been described in the medical literature.
Asparagine synthetase deficiency is caused by mutations in a gene called ASNS. This gene provides instructions for making an enzyme called asparagine synthetase. This enzyme is found in cells throughout the body, where it converts the protein building block (amino acid) aspartic acid to the amino acid asparagine.
In addition to being a component of proteins, asparagine helps to break down toxic ammonia within cells, is important for protein modification, and is needed for making a molecule that transmits signals in the brain (a neurotransmitter). Mutations in the ASNS gene that cause asparagine synthetase deficiency lead to a decrease or loss of functional enzyme. Asparagine from the diet likely makes up for the enzyme's inability to produce the amino acid in most cells. However, asparagine cannot cross the protective barrier that allows only certain substances to pass between blood vessels and the brain (the blood-brain barrier). As a result, brain cells in people with asparagine synthetase deficiency have a shortage (deficiency) of this amino acid. The exact effect of asparagine synthetase deficiency on brain cells is unknown, but because of the severe features of this condition, it is clear that asparagine is necessary for normal brain development.
This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.