Psychiatric illness and regression in individuals with Phelan-McDermid syndrome

Abstract

Background: Phelan-McDermid syndrome (PMS) is a genetic condition characterized by intellectual disability, speech and language deficits, hypotonia, autism spectrum disorder, and epilepsy. PMS is caused by 22q13.33 deletions or mutations affecting SHANK3, which codes for a critical scaffolding protein in excitatory synapses. SHANK3 variants are also known to be associated with an increased risk for regression, as well as for psychiatric disorders, including bipolar disorder and catatonia. This study aimed to further describe these phenomena in PMS and to explore any relationship between psychiatric illness and regression after early childhood. Methods: Thirty-eight people with PMS were recruited to this study through the Phelan-McDermid Syndrome Foundation based on caregiver report of distinct development of psychiatric symptoms. Caregivers completed a clinician-administered semi-structured interview focused on eliciting psychiatric symptomatology. Data from the PMS International Registry were used to confirm genetic diagnoses of participants and to provide a larger sample for comparison. Results: The mean age of the 38 participants was 24.7 years (range = 13 to 50; SD = 10.06). Females (31 of 38 cases; 82%) and sequence variants (15 of 38 cases; 39%) were over-represented in this sample, compared to base rates in the PMS International Registry. Onset of psychiatric symptoms occurred at a mean age of 15.4 years (range = 7 to 32), with presentations marked by prominent disturbances of mood. Enduring substantial loss of functional skills after onset of psychiatric changes was seen in 25 cases (66%). Symptomst indicative of catatonia occurred in 20 cases (53%). Triggers included infections, changes in hormonal status, and stressful life events. Conclusions: This study confirms that individuals with PMS are at risk of developing severe neuropsychiatric illness in adolescence or early adulthood, including bipolar disorder, catatonia, and lasting regression of skills. These findings should increase the awareness of these phenotypes and lead to earlier diagnosis and the implementation of appropriate interventions. Our findings also highlight the importance of genetic testing in the work-up of individuals with intellectual disability and acute psychiatric illness or regression. Future research is needed to clarify the prevalence and nature of psychiatric disorders and regression among larger unbiased samples of individuals with PMS.

Genotype–phenotype correlation in Phelan‐McDermid syndrome: A comprehensive review of chromosome 22q13 deleted genes

“…Regression of previously acquired motor, cognitive, and communication skills, usually beginning in adolescence or early adulthood, is another puzzling phenomenon which occurs in 28%–43% of PMS patients (Reierson et al, 2017). Another severe co‐morbidity observed in as many as 53% of PMS patients is represented by catatonia, characterized by motor and autonomic dysregulation (Kohlenberg et al, 2020). The onset of these clinical conditions is often triggered by infections, hormonal changes or stressful life events (Kohlenberg et al, 2020).…”

“…Another severe co‐morbidity observed in as many as 53% of PMS patients is represented by catatonia, characterized by motor and autonomic dysregulation (Kohlenberg et al, 2020). The onset of these clinical conditions is often triggered by infections, hormonal changes or stressful life events (Kohlenberg et al, 2020). All psychiatric comorbidities, as well as behavioral regression, have been observed also in patients with only SHANK3 haploinsufficiency, but other genes may contribute.…”

DNA methylation epi-signature is associated with two molecularly and phenotypically distinct clinical subtypes of Phelan-McDermid syndrome

“…This gene has been implicated in susceptibility to schizophrenia and bipolar disorders due to its effect on transcriptional regulation of numerous genes and brain development [ 33 , 35 – 37 ]. Although psychiatric presentation of PHMDS is not well characterized, there are a few cases reported with schizophrenia and other psychiatric features [ 38 , 39 ].…”

6.1 a Study From Turkey: Identification of Copy Number Variants in Children and Adolescents With Autism Spectrum Disorder

“…In our patient, developmental delay (DD) accompanied autism, but there was no epileptic disorder detected so far. PMS has also been suggested as a risk factor for bipolar disorder and its associated cognitive and behavioural regression (Kohlenberg et al 2020;Verhoeven et al 2020). We detected that this deletion may cause to the ASD and DD seen in patient 7.…”