Mutation discovery could lead to treatment for rare neurological disorder

Mutation discovery could lead to treatment for rare neurological disorder
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A team of researchers have discovered a mutation in a protein that can cause a rare neurological disorder – leading to the identification of a possible treatment.

Biochemist Edwin Chapman and his team have figured out how mutations in one protein, called synaptotagmin-1 or syt1, can lead to a rare neurological disorder known as syt1-associated neurodevelopmental disorder, which has led them to identify a possible treatment.

The research ensued after Chapman was contacted by a mother whose two-year-old daughter had the disorder who was informed by doctors that that a mutation in the SYT1 gene could be the cause. Another patient with the condition was also introduced to Dr Chapman.

The report has been published in the journal Neuron.

Syt1-associated neurodevelopmental disorder

Syt1-associated neurodevelopmental disorder is extremely rare, with only 11 confirmed cases, and causes developmental delays, eye abnormalities, involuntary movements, and agitation that can cause them to hurt themselves.

Scientists have studied the process of communication between neurons thoroughly, but they know much less about how mutations in the syt1 protein can interfere with neuron-to-neuron communication.

Lab experiments with neurons in culture dishes showed that each patient’s mutation interfered with neurotransmitter release, but to different degrees. In all cases, however, the altered syt1 protein became less responsive to calcium, meaning it had a hard time detecting the signal to send out neurotransmitters, the researchers say.

Bradberry said: “That made us think that if there was some way we could enhance calcium signalling, we might be able to help compensate for the protein’s defects.”

Testing treatments

A familiar drug, known as 4-AP,  which is already approved to treat the disorder multiple sclerosis, was tested as a potential treatment, finding that neurons containing mutated syt1 proteins flashed only dimly under the microscope, but adding 4-AP boosted their fluorescence Because 4-AP prompts a greater-than-normal influx of calcium into neurons. Bradberry suspected it could help patients with SYT1 mutations.

Because the drug has already been approved by the U.S. Food and Drug Administration, doctors for the three patients should be able to quickly get permission to treat them with it, says Hugo Bellen, an HHMI Investigator at Baylor College of Medicine who was not involved with the study.

The new work helps explain how certain genetic errors can disrupt neurotransmitter release and lead to a neurological disorder, he says.

Treatment not a cure

Bradberry has cautiously shared the results of the team’s 4-AP experiments with the patients and their doctors, so they can decide if they want to try it, emphasising that a drug like 4-AP will not cure patients like the three in the study, because it cannot reverse changes that have already occurred in the developing brain. However, it might reduce symptoms.

“Behaviours seen in this condition, like self-injurious hitting, impact patients’ and caregivers’ lives, and it’s possible these could be addressed by whatever treatment we are able to offer,” Bradberry says.

Chapman agrees. “If it brings any relief at all, it will be incredibly satisfying for us.”

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