Exploring the neurological features of individuals with germline PTEN variants: A multicenter study

Abstract

ObjectivePTEN, a known tumor suppressor gene, is a mediator of neurodevelopment. Individuals with germline pathogenic variants in the PTEN gene, molecularly defined as PTEN hamartoma tumor syndrome (PHTS), experience a variety of neurological and neuropsychiatric challenges during childhood, including autism spectrum disorder (ASD). However, the frequency and nature of seizures and the utilization of allied health services have not been described.MethodsYoung patients with PHTS and sibling controls were recruited across five centers in the United States and followed every 6–12 months for a mean of 2.1 years. In addition to the history obtained from caregivers, neurodevelopmental evaluations and structured dysmorphology examinations were conducted, and brain MRI findings, received therapies, and epilepsy characteristics were reported.ResultsOne hundred and seven patients with PHTS (median age 8.7 years; range 3–21 years) and 38 controls were enrolled. ASD and epilepsy were frequent among patients with PHTS (51% and 15%, respectively), with generalized epilepsy strongly associated with ASD. Patients with epilepsy often required two antiseizure medications. Neuroimaging revealed prominent perivascular spaces and decreased peritrigonal myelination in individuals with PHTS‐ASD. Allied therapy use was frequent and involved physical, occupational, speech, and social skills therapies, with 89% of all patients with PHTS, regardless of ASD diagnosis, utilizing at least one service.InterpretationThis prospective, longitudinal study highlights the wide neurological spectrum seen in young individuals with PHTS. ASD is common in PHTS, comorbid with epilepsy, and allied health services are used universally. Our findings inform care discussions with families about neurological outcomes in PHTS.

Analysis of DNA from brain tissue on stereo-EEG electrodes reveals mosaic epilepsy-related variants

“…Germline variants in CIC have been associated with an autosomal dominant intellectual disability disorder with seizures in some patients, 39 and germline variants in PTEN have been associated with a range of phenotypes including MCDs and epilepsy. 40,41 Thus, we believe these variants are at least disease-contributory, and these findings suggest that multiple mosaic variants may contribute to disease pathology in an individual patient. It is interesting to speculate if multiple mosaic variants with different distributions may contribute to epilepsy pathogenesis in patients with multifocal epilepsy, and future work is needed to investigate this hypothesis.…”