Phelan-McDermid Syndrome (PMS) is typically caused by deletion, or loss, of the terminal segment of the long arm of chromosome 22. The loss may result from a simple deletion, an unbalanced translocation, a ring chromosome, or other structural change. In the majority of cases, the SHANK3 gene is lost as a result of the deletion; other cases have been described with mutations within the SHANK3 gene.
The SHANK3 gene, which codes for the shank3 protein, is found in the brain, heart, kidney and other organs. Its most important role is in the brain. It supports the structure of excitatory synapses and is involved in processes crucial for learning and memory. It also has an important, if not fully understood, role in proper brain development. Defects of the SHANK3 gene are highly associated with autism. Individuals with Phelan-McDermid Syndrome often have autism or autism spectrum disorders.
There is a wide range of severity of symptoms observed in people with Phelan-McDermid Syndrome. Like other autism-related syndromes, PMS is associated with intellectual disabilities, sleep disorders and seizures. Most children with PMS have moderate to severe delays and often do not develop functional language. Infants with medium to large chromosomal deletions may have very low muscle tone, poor motor control, and problems with eating and sleeping. Other symptoms may include poor thermoregulation and dysplastic finger nails or toenails. Behavioral issues may stem from autism (e.g., repetitive behaviors), from poor communications skills, or unknown origin. For unknown reasons, toilet training is often difficult in this population. In spite of these issues, infants with PMS tend to be easily to amuse and adults often have a sweet disposition.
Thus far relatively few cases of PMS have been identified. Most identified cases are small children because testing is usually done early in life and reliable testing did not start until 1998. New genomic testing methods have not only made clinical testing more widely available, but have also led to significant new insights about the role of SHANK3 in PMS, autism, and schizophrenia, and the possible impact of other missing genes in cases of PMS.