Asparagine Synthetase Deficiency
Asparagine synthetase deficiency is a rare genetic disorder that causes severe neurological problems, including progressive brain atrophy, microcephaly, and developmental delay, starting shortly after birth.
Overview & Symptoms
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 the loss (atrophy) of brain tissue. Affected individuals experience severe developmental delay affecting both mental and motor skills (psychomotor delay). They cannot sit, crawl, or walk, and are unable to communicate verbally or nonverbally. Children who do achieve developmental milestones often lose these skills over time (developmental regression).
Other common symptoms of asparagine synthetase deficiency include:
- Exaggerated reflexes (hyperreflexia)
- Weak muscle tone (hypotonia) that worsens through childhood, leading to muscle stiffness, uncontrolled movements, and ultimately, paralysis of the arms and legs (spastic quadriplegia)
- Recurrent seizures (epilepsy), which can include loss of consciousness, muscle rigidity, and convulsions (tonic-clonic); involuntary muscle twitches (myoclonic); or abnormal muscle contraction (tonic)
- An exaggerated startle reaction (hyperekplexia) to unexpected stimuli
- Blindness due to impairment of the occipital cortex, the area of the brain responsible for processing vision (cortical blindness)
People with asparagine synthetase deficiency typically do not survive past childhood.
Frequency
Asparagine synthetase deficiency is thought to be a rare condition. More than 20 affected individuals have been described in the medical literature.
Causes & Genetic Factors
Asparagine synthetase deficiency is caused by mutations in the ASNS gene. 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 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 lead to a decrease or loss of functional enzyme. While asparagine from the diet likely makes up for the enzyme's inability to produce the amino acid in most cells, asparagine cannot cross the protective blood-brain barrier. As a result, brain cells in people with this condition have a shortage (deficiency) of this amino acid, which is necessary for normal brain development.
Inheritance
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.
Other Names for This Condition
- ASNS deficiency
- ASNSD
- Congenital microcephaly-severe encephalopathy-progressive cerebral atrophy syndrome
- Disorder of asparagine metabolism