A few months ago I wrote a blog about Dravet syndrome (http://bit.ly/1IOKxum ). In this condition a genetic defect impairs the normal development of the brain thus giving rise to cortical malformations and seizures during infancy. Seizures are propitiated by both fever and flashing lights. Deterioration of learned abilities follows the onset of seizures. Dravet syndrome is highly penetrant for autism, meaning that a significant proportion of individuals exhibiting this mutation manifest the behavioral characteristics of autism spectrum disorders (ASD).
Focal malformations of the brain are the most common developmental defects causing refractory epilepsy. The genesis for brain malformations occurs during the first 2 trimester of gestation when an inciting agent disturbs the migration of neurons towards the cerebral cortex. The malformed tissue bears abnormal circuits which makes the same epileptogenic and difficult to treat. Surgical resection is suggested in cases of focal lesions but this option may not be adequate when multiple lesions are present. In autistic patients the presence of focal cortical dysplasias were described in 2013 (Casanova et al., 2103). These malformations help explain the presence of seizures, cognitive difficulties and sensory abnormalities often seen in ASD individuals while underscoring its neurodevelopmental nature.
The syndrome of cortical dysplasia-focal epilepsy syndrome (CDFES) mirrors many of the salient characteristics observed in Dravet as well as other syndromes whose neuropathology involve brain malformations. As in Dravet, the mutation is highly penetrant for autism and regression is observed sometime during infancy after seizure onset . The condition, caused by a mutation in the CNTNAP2 gene on chromosome 7q35-q36, was first described in 9 Amish children. In these patients mild motor delays were evident but growth trajectories, verbal comprehension, and language development were normal. Sometime between 2 and 7 years of age intractable seizures became evident. These seizures, severe and intractable, were closely associated with a regression in learning and social behaviors. Children became hyperactive and exhibited impulsive aggression. Neuroimaging studies reveal the presence of brain malformations. Surgical resection of these malformations do not prevent seizure recurrence and the overall outcome is extremely poor, i.e., patients fully dependent on others for their daily living requirements.
As in Dravet syndrome, neuropathological examination of brain tissue has shown abnormalities in the migration of neurons to the cerebral cortex. Comorbidities are common in both Dravet syndrome and CDFES. In effect, CNTNAP2 mutations have been associated with Gilles de la Tourette syndrome, intellectual disability, obsessive compulsive disorder, schizophrenia and attention deficit hyperactivity disorder.
Other medical conditions bear similarities in that febrile seizures propitiate a regression into autistic behaviors (see my previous blog on fever and autism: http://bit.ly/1HvchPj ). As an example, a mutation in the NRXN1 gene on chromosome 2p16 gives rise to the Pitt-Hopkins syndrome. Patients with this mutation exhibit severe mental retardation, gross motor abnormalities (e.g., difficulties in walking), and seizures. The seizures lead to both a regression of acquired skills and the behavioral manifestation of autistic traits. Similarly, loss of function mutations in the CACNA1A gene causes an epileptic encephalopathy that is followed by cognitive impairment, mild cerebellar symptoms and autism. Other reported examples showing an association between fever, seizures and autism are known but still in need of genetic characterization (Dixon-Salazar et al., 2004).
The association between continuous epileptiform discharges and mental stagnation followed by regression is well known (van Rijckevorsel, 2006). Measures of seizure severity (e.g. seizure type, age of seizure onset, seizure duration) seem to be predictive of mental deterioration. At least in the laboratory, research with animal models hold promise for new therapeutic interventions. Seizures cause the breakdown of the skeletal proteins that help support some of the outgrowths from neurons. An experimental drug, FK506 or tacrolimus (commonly used as an immunosuppressant), given prior to inducing seizures, was capable of preventing that breakdown.
Casanova MF, El-Baz AS, Kamat SS, et al., Focal cortical dysplasias in autism spectru disorders. Acta Neuropathological Commun 1:67, 2013. Doi:10.1186/2051-5960-1-67.
Dixon-Salazar TJ, Keeler LC, Trauner DA, Gleeson JG. Autism in several members of a family with generalized epilepsy with febrile seizure plus. J Child Neurol 19(8):597-603, 2004.
Van Rikckevorsel K. Cognitive problems related to epilepsy syndromes, especially malignant epilepsies. Seizure, 15(4):227-234, 2006.