Epilepsy drives autism in neurodevelopmental disorders

Van Eeghen et al. have assessed two genetic disorders that disrupt the mTOR pathway, tuberous sclerosis complex (TSC), and neurofibromatosis 1 (NF1), and compared them with a cohort of childhood-onset epilepsy, and those with idiopathic autism and their typically developing siblings.¹ They found that the autistic features in TSC, NF1, and childhood-onset epilepsy are significantly correlated with IQ and epilepsy variables, such that those with a lower IQ and seizures have a greater level of autistic features as measured by the Social Responsiveness Scale. Autistic features or the severity of autism spectrum disorders (ASD) correlated better with the cognitive level and the experience of seizures than the etiological diagnosis of a child’s condition. These findings suggest that the presence of intellectual disability and seizures have factors in common with the development of ASD, and indeed they do.

Currently there are estimated to be between 350 and 400 gene mutations associated with autism or ASD.² More than half of these genes are involved with changes in synaptic plasticity, which can impact brain connectivity, one of the principle problems in ASD. Many of the genes associated with autism also influence the balance of inhibitory (γ-Aminobutyric acid [GABA]) or stimulatory (glutamate) pathways in the brain. Mutations that interfere with the neuronal network of the brain by creating problems associated with migration, synaptic plasticity, or systems important for maintaining neuronal function such as transport and degradation of proteins and production of energy from mitochondria are also associated with intellectual disability and ASD. However, the unique effect of seizures can also add to the baseline dysfunction of a neuron that is more vulnerable because of a genetic disorder. For instance, early death in cell culture compared with controls has been demonstrated in neurons that carry the premutation of the FMR1 gene.³ However, most individuals with the premutation do not have developmental problems, although approximately 10% do, especially if seizures occur in childhood. Chonchaiya et al.⁴ have shown that male children with the premutation who have seizures are more likely to have ASD and intellectual disability, basically the same situation reported by van Eeghen et al. The same is true for children with the full mutation of FMR1: seizures are associated with a higher risk of ASD.⁵ So what do seizures do to the central nervous system that may add insult to injury in the genetically vulnerable populations?

There are numerous studies demonstrating a variety of neurochemical changes that occur with seizures which impact the neuronal network structure and alter gene expression.^6,7 Seizures are associated with enhanced production of brain-derived neurotrophic factor, which regulates GABAA receptor expression leading to further GABA/glutamate imbalances in some neurodevelopmental disorders. Expression of microRNAs changes with seizures. These changes can influence the expression of many genes involved in autism such as CNTNAP2,GABRB3, FMR1, MeCP2, RELN, TSC1, and TSC2.⁶ Matrix metalloproteinase 9 (MMP9) is upregulated with seizures and this protein is probably involved with seizure-induced dendritic spine pruning. Seizures also increase aberrant synaptogenesis and mossy fiber sprouting; these activities also involve MMP9.⁷ Most recently the Benke laboratory has demonstrated that seizures cause the fragile X mental retardation protein (FMRP) to retract from dendritic spines.⁸ All of these neurochemical changes that occur with seizures are likely to increase autistic features. For many genetically vulnerable populations, this can push them over the threshold for an autism diagnosis as is seen not only in TSC and NF1 but also in the fragile X premutation,⁴ fragile X syndrome,⁵ and probably other neurodevelopmental disorders.

The clinical ramifications of this knowledge are that early and aggressive treatment of seizures is essential to avoid the long-term consequences of recurrent seizures. In addition, targeted treatments such as minocycline, which can lower the elevated MMP9 levels in fragile X syndrome⁹ leading to clinical improvements in patients,¹⁰ may also be helpful in other disorders such as autism or Angelman syndrome, particularly if seizures are common or MMP9 is elevated. Additional targeted treatments for fragile X syndrome such as mGluR5 antagonists¹¹ or GABA agonists such as arbaclofen¹² may also be helpful in autism or other neurodevelopmental disorders. These targeted treatments reverse the effects of lowered FMRP that occurs in many more disorders than just fragile X syndrome, either focally at the dendrite during seizures or more globally in the brain as seen in postmortem studies in bipolar disorder, depression, schizophrenia, and autism.¹³