Presynaptic dysfunction in neurodevelopmental disorders

Neurodevelopmental disorders are a devastating group of conditions characterised by developmental impairments, which usually manifest in infants and children.

These disorders can result in a broad range of deficits, including learning delay and intellectual disability, problems with muscle control and movement, and behavioural and emotional issues. In severe cases the affected individuals may require lifetime care and/or have a reduced life expectancy.

Gene technology is now enabling the identification of many novel causes of neurodevelopmental disorder. This provides a new starting point for understanding the relationships between specific genetic mutations, brain function and development, cognition and mental health. There is growing evidence that the machinery that controls the release of neurotransmitters is compromised in a range of neurodevelopmental disorders, including intellectual disability, epilepsy, and autism spectrum disorders.

We have recently identified the first human mutation in synaptotagmin-1 (Syt1), in a child with a severe neurodevelopmental disorder. The child harbouring this mutation displayed profound intellectual disability, delayed motor development, and severe neurophysiological disturbance, but MRI revealed no structural brain abnormality. This mutation (I368T) occurs in a highly conserved residue in Syt1. We examined the effect of I368T Syt1 on presynaptic activity, and found that the presence of this mutant variant of Syt1 in neurons resulted in altered synaptic vesicle recycling dynamics.

We have now identified a further 5 mutations in Syt1, in individuals who have symptoms that largely overlap with our index case, but with differing degrees of severity.