Clinical, genetic, and cognitive correlates of seizure occurrences in Phelan-McDermid syndrome

Abstract

Background: Phelan-McDermid syndrome (PMS) is a genetic neurodevelopmental disorder caused by SHANK3 haploinsufficiency and is associated with an increased risk for seizures. Previous literature indicates that around one third of individuals with PMS also have epilepsy or seizures, with a wide range of types and ages of onset. Investigating the impact of seizures on intellectual and adaptive functioning for PMS is a primary concern for caregivers and is important to understanding the natural history of this syndrome.

Methods: We report on results from 98 individuals enrolled in a prospective, longitudinal study. We detailed seizure frequency, type, and age of onset, and we analyzed seizure occurrence with best estimate IQ, adaptive functioning, clinical features, and genotype. We conducted multiple linear regression analyses to assess the relationship between the presence of seizures and the Vineland Adaptive Behavior Scale, Second Edition (VABS-II) Adaptive Behavior Composite score and the best estimate full-scale IQ. We also performed Chi-square tests to explore associations between seizure prevalence and genetic groupings. Finally, we performed Chi-square tests and t-tests to explore the relationship between seizures and demographic features, features that manifest in infancy, and medical features.

Results: Seizures were present in 41% of the cohort, and age of onset was widely variable. The presence of seizures was associated with significantly lower adaptive and intellectual functioning. Genotype-phenotype analyses were discrepant, with no differences in seizure prevalence across genetic classes, but with more genes included in deletions of participants with 22q13 deletions and seizures compared to those with 22q13 deletions and no seizures. No clinical associations were found between the presence of seizures and sex, history of pre- or neonatal complications, early infancy, or medical features. In this cohort, generalized seizures were associated with developmental regression, which is a top concern for PMS caregivers.

Conclusions: These results begin to eludicate correlates of seizures in individuals with PMS and highlight the importance of early seizure management. Importantly, presence of seizures was associated with adaptive and cognitive functioning. A larger cohort might be able to identify additional associations with medical features. Genetic findings suggest an increased capability to realize genotype-phenotype relationships when deletion size is taken into account.

Keywords: 22q13; Epilepsy; Phelan-McDermid syndrome; SHANK3; Seizures.

Fig. 1

Seizure onset. Legend: Histogram of the age of seizure onset (years). The Y axis is the proportion of individuals. Bin width is 1 year

Fig. 2

Effect of seizures on Vineland Adaptive Behavior Composite. Legend: Multiple linear regression including presence of seizures at baseline with VABS-II Adaptive Behavior Composite. Blue scatterpoints and line represent individuals without seizures (left), without generalized seizures (middle), or without focal seizures (right). Red scatterpoints and line represent individuals with any seizures (left), generalized seizures (middle), or focal seizures (right). The X axis is age in years. Downward slope indicates that skills are not increasing at a rate comparable with the general population not that skills are declining

Fig. 3

Association between occurrence of seizures and best estimate full scale IQ. Legend: Multiple linear regression of seizure occurrence at baseline and the best estimate full scale IQ. Blue scatterpoints and line represent individuals without any seizures (left), generalized seizures (middle), or focal seizures (right). Red scatterpoints and line represent individuals with seizures (left), generalized seizures (middle), or focal seizures (right). The X axis is age in years. Downward slope indicates that skills are not increasing at a rate comparable with the general population not that skills are declining

Fig. 4

Number of genes included in deletions of participants with and without seizures. Legend: Boxplots representing the number of genes deleted in participants’ deletions for those with chromosomal deletions and without seizures (blue) or with seizures (red). The minimum and maximum values are represented with tails, the box represents the interquartile range, the bold line represents the median, and the dashed line represents the mean genes deleted per group. Asterisks represent significance level, ** p <  = 0.01, *** p <  = 0.001, ns p > 0.05