2 Neuroscience2.11 Integrated neurobiology of syndromes and states

2.11.1 Autism

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Written by Resident Doctor Committee · Published

Heritability and family risk

Autism spectrum disorder involves differences in social communication and interaction, restricted and repetitive behaviour, and sensory responses.

  • Heritability is roughly 80 to 90%, among the highest of any psychiatric condition.

  • Sibling recurrence risk is about 10 to 20%, against a population prevalence of about 1 to 2%.

Risk genes

Many genes contribute, and their pathways converge on synapse development. Variants have incomplete penetrance and can also lead to intellectual disability, epilepsy or no diagnosis at all.

Gene

Protein

Site

Function

NRXN1

Neurexin

Presynaptic

Binds neuroligin across the synapse

NLGN3

Neuroligin

Postsynaptic

Binds neurexin and supports synapse development

SHANK3

Scaffold protein

Postsynaptic density of glutamatergic synapses

Holds the postsynaptic machinery together

  • Neurexin and neuroligin form a trans-synaptic adhesion complex, and the genes encoding both halves are autism risk genes.

  • SHANK3 mutation or deletion is linked to autism, and deletion of 22q13 causes Phelan-McDermid syndrome.

  • Autistic features also occur in fragile X syndrome, tuberous sclerosis and Rett syndrome.

Neuroligin sits on the postsynaptic membrane and binds presynaptic neurexin across the cleft, the trans synaptic bridge that NLGN3 mutations disrupt in familial autism. Cbr52, CC BY-SA 4.0, via Wikimedia Commons

Brain structure

  • Cerebellar vermis hypoplasia is the most consistently replicated structural brain finding in autism spectrum disorder.

  • The cerebellar hypoplasia is attributed to loss of Purkinje cells, whose degenerating myelinated axons reduce cerebellar volume.

  • The corpus callosum is reduced even though overall brain volume tends to be increased.

  • Some children show accelerated early brain growth that later converges with typical growth or reverses.

Imaging in practice

  • No structural MRI finding is diagnostic, because the abnormalities are nonspecific; diagnosis rests on developmental history and clinical assessment.

  • Imaging is used to look for associated conditions such as tuberous sclerosis complex.

Treatment-relevant findings

  • Raised whole-blood serotonin is replicated in a subgroup, but selective serotonin reuptake inhibitors do not treat the core features of autism.

  • A large trial of intranasal oxytocin found no benefit for core social features.

Revision material for the MRCPsych examinations. Not clinical guidance, and not for use in patient care.