The spectrum of epilepsy and electroencephalographic abnormalities due to SHANK3 loss-of-function mutations

Abstract

Objective: The coincidence of autism with epilepsy is 27% in those individuals with intellectual disability.¹ Individuals with loss-of-function mutations in SHANK3 have intellectual disability, autism, and variably, epilepsy.^2-5 The spectrum of seizure semiologies and electroencephalography (EEG) abnormalities has never been investigated in detail. With the recent report that SHANK3 mutations are present in approximately 2% of individuals with moderate to severe intellectual disabilities and 1% of individuals with autism, determining the spectrum of seizure semiologies and electrographic abnormalities will be critical for medical practitioners to appropriately counsel the families of patients with SHANK3 mutations.

Methods: A retrospective chart review was performed of all individuals treated at the Blue Bird Circle Clinic for Child Neurology who have been identified as having either a chromosome 22q13 microdeletion encompassing SHANK3 or a loss-of-function mutation in SHANK3 identified through whole-exome sequencing. For each subject, the presence or absence of seizures, seizure semiology, frequency, age of onset, and efficacy of therapy were determined. Electroencephalography studies were reviewed by a board certified neurophysiologist. Neuroimaging was reviewed by both a board certified pediatric neuroradiologist and child neurologist.

Results: There is a wide spectrum of seizure semiologies, frequencies, and severity in individuals with SHANK3 mutations. There are no specific EEG abnormalities found in our cohort, and EEG abnormalities were present in individuals diagnosed with epilepsy and those without history of a clinical seizure.

Significance: All individuals with a mutation in SHANK3 should be evaluated for epilepsy due to the high prevalence of seizures in this population. The most common semiology is atypical absence seizure, which can be challenging to identify due to comorbid intellectual disability in individuals with SHANK3 mutations; however, no consistent seizure semiology, neuroimaging findings, or EEG findings were present in the majority of individuals with SHANK3 mutations.

Keywords: SHANK3; Autism; Electroencephalography; Epilepsy; Phelan-McDermid syndrome.

Figure 1

Electroencephalograms in individuals with loss of function mutations in SHANK3 (A) Subject 22 with generalized slowing of the occipital dominant rhythm (B) Subject 4 with frontal dominant generalized burst of 1.5 Hz spike and slow wave activity (C) Subject 2 with generalized burst of 1.5–2.5 Hz spike and slow wave activity.

Figure 2

Brain Magnetic Resonance Imaging (MRI) in individuals with loss of function mutations in SHANK3 (A) Sagittal T1 weighted image of subject 9 demonstrating thinning of the corpus callosum (B) Sagittal T1 weighted image of subject 17 with mild cerebral volume loss (C) Axial T1 weighted image of subject 21 with left sylvian fissure arachnoid cyst (D) Axial T2 weighted image of subject 4 with mild T2 hyperintensity of the posterior centrum semiovale.