Abstract
Phelan-McDermid syndrome (PMS) is caused by haploinsufficiency of the SHANK3 gene on chromosome 22q13.33 and is characterized by intellectual disability, hypotonia, severe speech impairments, and autism spectrum disorder. Emerging evidence indicates that there are changes over time in the phenotype observed in individuals with PMS, including severe neuropsychiatric symptoms and loss of skills occurring in adolescence and adulthood. To gain further insight into these phenomena and to better understand the long-term course of the disorder, we conducted a systematic literature review and identified 56 PMS cases showing signs of behavioral and neurologic decompensation in adolescence or adulthood (30 females, 25 males, 1 gender unknown). Clinical presentations included features of bipolar disorder, catatonia, psychosis, and loss of skills, occurring at a mean age of 20 years. There were no apparent sex differences in the rates of these disorders except for catatonia, which appeared to be more frequent in females (13 females, 3 males). Reports of individuals with point mutations in SHANK3 exhibiting neuropsychiatric decompensation and loss of skills demonstrate that loss of one copy of SHANK3 is sufficient to cause these manifestations. In the majority of cases, no apparent cause could be identified; in others, symptoms appeared after acute events, such as infections, prolonged or particularly intense seizures, or changes in the individual’s environment. Several individuals had a progressive neurological deterioration, including one with juvenile onset metachromatic leukodystrophy, a severe demyelinating disorder caused by recessive mutations in the ARSA gene in 22q13.33. These reports provide insights into treatment options that have proven helpful in some cases, and are reviewed herein. Our survey highlights how little is currently known about neuropsychiatric presentations and loss of skills in PMS and underscores the importance of studying the natural history in individuals with PMS, including both cross-sectional and long-term longitudinal analyses. Clearer delineation of these neuropsychiatric symptoms will contribute to their recognition and prompt management and will also help uncover the underlying biological mechanisms, potentially leading to improved interventions.
Highlights
Phelan-McDermid syndrome (PMS, MIM 606232) is a genetic disorder characterized by hypotonia, intellectual disability (ID), severe speech impairments, and autism spectrum disorder (ASD) [1]
Earlier papers focus on subjects with ring chromosome 22, diagnosed with karyotype, before the introduction of fluorescent in situ hybridization (FISH) and later chromosomal microarrays allowed the diagnosis of terminal deletions
Severe neuropsychiatric decompensation has been reported in 14 individuals with SHANK3 point mutations [2, 4, 7, 28, 38–40]. These results indicate that SHANK3 haploinsufficiency alone is sufficient to increase risk. These findings suggest that patients with SHANK3 mutations are overrepresented among individuals with PMS with neuropsychiatric decompensation or loss of skills
Summary
Phelan-McDermid syndrome (PMS, MIM 606232) is a genetic disorder characterized by hypotonia, intellectual disability (ID), severe speech impairments, and autism spectrum disorder (ASD) [1]. The core neurodevelopmental features of PMS are caused by haploinsufficiency of the SHANK3 gene, resulting from either 22q13.33 deletions encompassing SHANK3 or point mutations of SHANK3 [2–4]. Deletions can be either simple or result from complex rearrangements such as unbalanced translocations or ring chromosome 22. The prevalence of PMS is unknown, chromosome microarray and targeted resequencing of SHANK3 in ASD and ID suggest that up to 0.5–1% of subjects may show haploinsufficiency at this locus [5–8]. SHANK3 encodes a scaffolding protein that functions at excitatory postsynaptic densities to organize signaling pathways as well as the synaptic cytoskeleton [9]. In this way, the SHANK3 protein plays a critical role in glutamate transmission, synaptic spine dynamics, and, in learning and memory processes
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