WHAT IS A SHANKOPATHY?
Shankopathies are SHANK protein deficiency-induced synaptic diseases. The SHANK protein family includes three members: SHANK1, SHANK2, and SHANK3. Shankopathies are associated with autism, intellectual disability, schizophrenia, and other neuropsychiatric disorders, including Phelan-McDermid Syndrome (PMS).
CAUSES OF SHANKOPATHIES
Shankopathies are caused by copy number variations (CNVs) and pathogenic variants (mutations) of the SHANK genes.
Deletions and pathogenic variants of SHANK3 cause Phelan-McDermid syndrome, characterized by varying degrees of developmental delay, intellectual disability, delayed or absent speech, and autism spectrum disorder or symptoms of autism. Individuals with PMS may also have other comorbid conditions, such as epilepsy, hypotonia, gastrointestinal problems, and psychiatric illness in adolescence or adulthood. Factors that modulate the severity of symptoms are unknown.
SHANK3 overexpression is caused by duplications of the SHANK3 gene. The symptoms of SHANK3 overexpression include hyperkinetic disorders and seizures. The roles played by SHANK1 and SHANK2 genes in human disease phenotypes are being explored.
Other genes that regulate the expression of the SHANK genes may contribute to the faulty expression of SHANK proteins, even if a CNV or mutation of a SHANK gene is not present. Although, at present, there is no diagnostic test for measuring the level of expression of the SHANK genes in the brain, the study of regulatory genes is critical for the identification of small molecules that could normalize the expression of SHANK proteins.
DIAGNOSIS & TREATMENTS
Deletions of mutations of SHANK3 occur in slightly under 1% of individuals with autism. The estimated prevalence is 1/15,000. The diagnosis of Phelan-McDermid Syndrome is made through genetic testing. (Please visit pmsf.org to learn more about how Phelan-McDermid Syndrome is diagnosed.)
There are currently no treatments for any Shankopathies. Patients are monitored for symptom management. Practice parameters for assessment and monitoring of patients with Phelan-McDermid Syndrome can be found here.