Abstract
Phelan-McDermid syndrome (PMS) is a genetic disorder often characterized by autism or autistic-like behavior. Most cases are associated with haploinsufficiency of the SHANK3 gene resulting from deletion of the gene at 22q13.3 or from a pathogenic variant in the gene. Treatment of PMS often targets SHANK3, yet deletion size varies from <50 kb to >9 Mb, potentially encompassing dozens of genes and disrupting regulatory elements altering gene expression, inferring the potential for multiple therapeutic targets. Repurposed drugs have been used in clinical trials investigating therapies for PMS: insulin-like growth factor 1 (IGF-1) for its effect on social and aberrant behaviors, intranasal insulin for improvements in cognitive and social ability, and lithium for reversing regression and stabilizing behavior. The pharmacogenomics of PMS is complicated by the CYP2D6 enzyme which metabolizes antidepressants and antipsychotics often used for treatment. The gene coding for CYP2D6 maps to 22q13.2 and is lost in individuals with deletions larger than 8 Mb. Because PMS has diverse neurological and medical symptoms, many concurrent medications may be prescribed, increasing the risk for adverse drug reactions. At present, there is no single best treatment for PMS. Approaches to therapy are necessarily complex and must target variable behavioral and physical symptoms of PMS.
Highlights
Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder frequently associated with autism spectrum disorder (ASD), seizures, and variable dysmorphic features
The bulk of research into PMS phenotypes is primarily focused on neurobehavioral aberrations attributed to the loss of SHANK3
Patients with interstitial deletions in chromosome 22 that do not include SHANK3 still present with neurological symptoms typical of PMS. This suggests the presence of other genes on chromosome 22 that contribute to the stereotypical PMS phenotype, likely candidates being SULT4A1 and BRD1
Summary
Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder frequently associated with autism spectrum disorder (ASD), seizures, and variable dysmorphic features. It is typically caused by deletions of 22q13.3. Young children typically present with delayed motor milestones, hypotonia, dysplastic toenails, and absent to severely delayed speech As they get older, they may develop large fleshy hands, long eyelashes, and decreased perspiration that results in a tendency to overheat. Pathogenic variants in the synaptic scaffolding protein gene SHANK3 are strongly implicated in autism and Phelan–McDermid 22q13 deletion syndrome and have been associated with abnormal glutamate receptor function and spine morphology. It appears to be one of the more common chromosome deletion syndromes and well over 3000 individuals have been reported worldwide. These deletions contain a variable number of genes that may potentially impact both the phenotype and response to therapies
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