Genetic Findings as the Potential Basis of Personalized Pharmacotherapy in Phelan-McDermid Syndrome

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 < 50kb to > 9Mb, 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 8Mb. 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.

From Genes to Therapy in Autism Spectrum Disorder

“…Within groups of patients at risk for neurodevelopmental disorders based on shared carriership of a high impact genetic variant, refinement of individual risk is required to overcome the challenge of variable expressivity and pleiotropy invariably associated with genetic risk. Individualized treatments can in some instances be already pursued today, provided genetic results are analyzed also with this aim in mind [ 7 , 8 ], and clinicians have received sufficient training in their interpretation [ 58 ]. Further momentum will hopefully be provided by the translation of iPSC-based approaches into individualized pharmacological treatments [ 11 , 20 ].…”

“…These clinical insights are not only relevant with respect to various aspects related to reproductive counseling (e.g., probability of recurrence); in some cases, it can also directly inform therapeutic management of the individual patient. For example, Dyar et al, discuss how dosage of various psychotropic medications may require adjustment in those patients with Phelan–McDermid Syndrome with 22q13.3 deletions including the gene CYP2D6 [ 7 ]. Clinically actionable information derived from genetic testing is also center stage in the discussion of three individual patients with different genetic conditions, reported by Butler et al, These examples, drawn from clinical practice, illustrate how such knowledge can already inform clinicians about preventive monitoring, the need for additional medical examinations or for surveillance for specific conditions associated with the genetic variant as well as guide the choice of psychotropic medications [ 8 , 9 ].…”

Clinical and Genetic Aspects of Phelan–McDermid Syndrome: An Interdisciplinary Approach to Management

“…Interestingly, the treatment of behavioral abnormalities in PMS patients is complicated by pharmacogenomics issues, as the CYP2D6 enzyme, which metabolizes antidepressants and antipsychotics and is encoded by CYP2D6 gene, which maps to 22q13.2 and is lost in subjects with deletions larger than 8 Mb [ 50 ].…”

Phenotypic Variability in Phelan–McDermid Syndrome and Its Putative Link to Environmental Factors

“…For this reason, extensive research has been focused on the effect of variants in genes encoding CYP proteins on the pharmacokinetics of several compounds. Genes for CYP enzymes, such as CYP2C9 , CYP2C19 , CYP2D6 , CYP3A4 , and CYP3A5, have been classified as important pharmacogenes [ 36 ].…”