GABA transaminase deficiency: Year of the Zebra 2026

GABA transaminase deficiency is a rare inherited disorder that affects how the brain breaks down a neurotransmitter called gamma-aminobutyric acid, or GABA for short. It usually begins in infancy and primarily affects brain signaling and development.

Neurotransmitters are chemical messengers that allow neurons to communicate. When one neuron sends a message, it releases neurotransmitters into the tiny gap between the neurons, called the synaptic cleft. In this synaptic cleft are receptors known as postsynaptic receptors, where the neurotransmitters will bind to and generate a response in the receiving neuron.

Some neurotransmitters make receiving neurons more likely to generate an action potential, or electrical impulse, while others make the neuron less likely to fire. Neurons accumulate many incoming signals and fire only when the overall signal reaches a threshold.

GABA is the brain's main inhibitory neurotransmitter. In other words, it acts like a brake on neuronal activity. So, when GABA binds to postsynaptic receptors on a neighboring neuron, it makes the neuron less likely to generate an action potential. This inhibitory signaling helps to prevent excessive activity and allows neural circuits to communicate properly.

Of course, GABA's job doesn't end once it binds to its receptors. After GABA has delivered its message, it must be cleared from the synapse so the circuit can reset. Transport proteins carry GABA into neurons and nearby support cells called astrocytes. From there, GABA can be reused or broken down. An enzyme called GABA transaminase begins that breakdown process.

In GABA transaminase deficiency, mutations in the ABAT gene decrease the activity of this enzyme, so GABA cannot be broken down efficiently, and thus GABA starts to accumulate in the brain. This disrupts the normal balance of neurotransmitter signaling. These mutations are inherited in an autosomal recessive pattern, meaning a child must inherit two non-working copies of the ABAT gene, one from each parent, to develop the disorder. A person with one altered copy is called a carrier and usually has no symptoms because the other copy provides enough enzyme activity.

Because GABA plays such an important role in regulating brain signaling and development, its buildup leads to a range of neurological symptoms that appear very early in life. Early signs can include excessive sleepiness, poor feeding, and weak muscle tone. Some infants also have an unusually high-pitched cry or grow rapidly in length even while weight gain is slow.