Characterizing regression in Phelan McDermid Syndrome (22q13 deletion syndrome)

Abstract

Purpose To describe the frequency and characteristics of developmental regression in a sample of 50 patients with Phelan McDermid Syndrome (PMS) and investigate the possibility of association between regression, epilepsy, and electroencephalogram (EEG) abnormalities and deletion size. Methods The Autism Diagnostic Interview-Revised (ADI-R) was used to evaluate regression in patients with a confirmed diagnosis of PMS. Information on seizure history and EEGs was obtained from medical record review. Deletion size was determined by array CGH. Results A history of regression at any age was present in 43% of all patients. Among those exhibiting regression, 67% had onset after the age of 30 months, affecting primarily motor and self-help skills. In 63% of all patients there was a history of seizures and a history of abnormal EEG was also present in 71%. No significant associations were found between regression and seizures or EEG abnormalities. Deletion size was significantly associated with EEG abnormalities, but not with regression or seizures. Conclusion This study found a high rate of regression in PMS. In contrast to regression in autism, that often occurs earlier in development and affects language and social skills, we found regression in PMS most frequently has an onset in mid-childhood, affecting motor and self-help skills. We also found high rates of seizures and abnormal EEGs in patients with PMS. However, a history of abnormal EEG and seizures was not associated with an increased risk of regression. Larger deletion sizes were found to be significantly associated with a history of abnormal EEG.

Psychiatric illness and regression in individuals with Phelan-McDermid syndrome

“…Regression has long been recognized in neurodevelopmental disorders such as ASD [37], but the triggers and mechanisms are not well understood, and the literature focuses largely on early childhood regression, especially as it relates to Rett syndrome [37][38][39][40]. Significant cognitive and behavioral regression has been documented in PMS [5,6,9,15,16,18,41]. Verhoeven et al [20] have recently published on the course of illness of 24 adolescents and adults with PMS referred for evaluation and treatment of "challenging behaviors and unstable mood."…”

Neuropsychiatric decompensation in adolescents and adults with Phelan-McDermid syndrome: a systematic review of the literature

“…However, the extent of clinical information available in the literature to date makes it difficult to fully assess the nature of skill loss and whether losses would meet typical criteria for regression. Questions about the phenomenology of loss of skills and regression in childhood reported in PMS [4, 17–20] as compared to changes that occur in adolescence or adulthood remain. Finally, it is important to consider whether progressive increased severity of symptoms, with a decline in adaptive functioning, may implicate a neurodegenerative process or early onset of dementia.…”

“…The PMS family and advocacy community is also reporting such changes in social media and at family conferences, generating a great deal of concern among caregivers. It should be noted that loss of skills has also been reported to occur in early childhood in some individuals with PMS, particularly in the domains of language and previously acquired motor skills [4, 17–20]. The relationship between this early regression and later-onset phenomena is currently unknown.…”

Co-occurrence of Metachromatic Leukodystrophy in Phelan-McDermid Syndrome

“…Our patient is the fourth case report of metachromatic leukodystrophy in an individual with Phelan-McDermid syndrome who was diagnosed after clinical neurologic deterioration. Given that patients with Phelan-McDermid syndrome have moderate to severe developmental delay and up to 43% experience developmental regression, 3 it is challenging for clinicians to attribute developmental decline to a different etiology and initiate diagnostic work up. The prevalence of these 2 conditions co-occurring is unknown but could be higher than reported.…”

“…2 Up to 43% of patients develop regression primarily in motor and self-help skills, with 67% occurring after 30 months of age. 3 The majority of patients with Phelan-McDermid syndrome have a de novo deletion of chromosome 22, of which 15% to 20% result from an unbalanced chromosome rearrangement or ring chromosome 22. 2 A small number of Phelan-McDermid syndrome patients have pathogenic variants in SHANK3 .…”