DESCRIPTION
There is a wide range of symptoms in people with PMS. The severity of symptoms varies as well. People with PMS typically face challenges such as:
- Moderate to severe intellectual disability
- Poor communication or absent speech
- Complex medical issues
People with larger deletions of chromosome 22 tend to have more complex medical problems. They are less likely to reach milestones.
People with more minor genetic changes in SHANK3 are more likely to reach milestones. However, they may regress later. This group may also be more likely to be affected by mental illness.
CAUSES
Phelan-McDermid syndrome (PMS) has two causes. It can be caused by the deletion of a specific region of chromosome 22. This region is referred to as the distal long arm. It can also be caused by a pathogenic variant in the SHANK3 gene.
Most cases of PMS happen spontaneously, prior to conception. They are not inherited from the parents.
However, in some cases, a parent may have a “balanced translocation.” This means genetic material has been swapped between chromosomes. A balanced translocation does not typically affect the parent. This is because all genetic material is still present and functional in the parent who carries the balanced translocation.
A parent with a balanced translocation may produce a child with an “unbalanced” translocation. In this case, genetic material is lost or altered. This can lead to PMS if there is loss of the distal segment of chromosome 22.
Specific genetic tests can determine if either parent is at risk of having a child with genetic changes leading to PMS. Tests involve examining the chromosomes.
LABORATORY INVESTIGATIONS
The diagnosis of PMS is based on finding a genetic alteration of the 22q13 region of the chromosome. Multiple tests that can be used to get a diagnosis or reveal added risks in PMS are described below.
Talk to your doctor about which testing option or options are best for your family. To learn more about testing options for PMS, visit the How PMS Is Diagnosed page on the Phelan-McDermid Syndrome Foundation‘s website.
Test options include:
Chromosomal microarray analysis (CMA).
Cytogenetic testing.
“Cytogenetic” tests visualize chromosomes. They detect the number, structure, and rearrangements of chromosomes. This type of test is needed for people with 22q13 deletions for the following reasons:
- Karyotyping can detect Ring 22. Ring 22 occurs when there are deletions on each end of chromosome 22. The broken ends of the chromosome can fuse into a circle, or ring shape. Ring 22 carries a risk of tumors in the nervous system. It requires medical monitoring.
- Cytogenetics testing can detect the risk of PMS heritability. As mentioned above, a parent can have a “balanced translocation” in which genetic material is swapped between chromosomes. Because the correct amount of genetic material is present, the parent has no symptoms.
- However, a parent with a balanced translocation is at an increased risk of having a child with an “unbalanced” translocation in which some genetic material is lost and/or duplicated. This can result in a deletion of the 22q13 region.
- If a translocation in the child is suspected based on CMA results, both the child and the parent should have cytogenetic testing. This will show whether there is an increased risk of an unbalanced translocation in future pregnancies.
Two types of cytogenetic tests are commonly used in Phelan-McDermid syndrome. Both tests can detect the two concerns listed above. These tests are:
- Conventional karyotyping. This test visualizes common features of chromosomes by staining them. Chromosomes can then be arranged by size and shape. The two copies of each chromosome are assessed to see if there are abnormalities. This testing can identify ring chromosomes. It can also identify most balanced and unbalanced translocations.
- Fluorescence in situ hybridization (FISH). FISH is a molecular cytogenetic test. It uses fluorescent probes (dyed pieces of DNA) to visualize specific DNA sequences. It highlights specific groups of genes or parts of specific chromosomes. This technique can identify smaller chromosomal rearrangements than conventional karyotyping. It is a targeted technique to study a particular segment of a chromosome.
Whole exome sequencing (WES) and whole genome sequencing (WGS).
Sequencing tests can detect smaller errors in DNA. They can be needed if a deletion has not been detected but symptoms are consistent with:
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- PMS
- Intellectual disability
- Autism spectrum disorder
- These tests can detect errors in only one or a few letters of the genetic code. They can be useful for detecting errors in the SHANK3 gene. The SHANK3 gene is in the 22q13 region. It is highly linked with autism and PMS symptoms.
- Sometimes a small change in SHANK3 does not impact the function of the gene. Other times, a change is detrimental. This causes SHANK3 to make no protein or an abnormal protein that does not function properly. In that case, the change is called “pathogenic.”
- If a variant in SHANK3 is detected in the child, the parents should be tested. Tests will detect whether they have the same variant as the child. If a parent has the variant, it is unlikely to be problematic. This is because it is not causing symptoms in the parent. Detrimental variants in SHANK3 are thought to occur spontaneously.
- WES and WGS can yield much of the same information. WES sequences the parts of the genome that code for proteins. This is known as the “exome.” Proteins make up many of the structures and functions within cells.
- WGS is more expansive. It captures the entire sequence of the genome. Some parts of the genome that don’t directly lead to proteins still impact regulation of processes within cells.
In some cases, PMS can be detected in a fetus before birth (prenatally). This is done using special tests that sample the fluid surrounding the fetus or part of the placenta.
TREATMENT AND THERAPIES
No treatments have been shown to correct the cause of PMS. Treatment is aimed at managing symptoms and risks specific to each person.
Symptoms can vary between people with PMS. This is due to different genetics and other factors. Some symptoms may occur only in some people with PMS. They may only occur during specific stages of life, or they may be cyclical.
Families often see a team of specialists, including the following:
- A neurologist
- A primary care physician
- A gastroenterologist
- An endocrinologist
- A psychiatrist
- A speech and language therapist
- Occupational and physical therapists
- A nephrologist and/or urologist
Frequently, people with PMS undergo behavioral therapy. They may receive medication for:
- Seizures/epilepsy
- Psychiatric disorders
- Sleep disturbances
- GI symptoms
Clinical trials to test new treatments for PMS have increased in recent years. See the clinical trials section below to find current trials.
Resources
Phelan-McDermid Syndrome Foundation
It is the mission of the Phelan-McDermid Syndrome Foundation (PMSF) to improve the quality of life of people affected by PMS worldwide by providing family support, accelerating research, and raising awareness. They provide a family resource library, a parent’s guide, networking capabilities through regional reps, and much more.
Chromosome 22 Central (C22C) is a global collection of parents and people affected by chromosome 22 disorders who can connect, advocate, and grow together.
The website is a hub for people to find immediate connections with others through their various social media platforms, and to find basic information and links to other resources. Started in 1996 with just 17 families of children with what is now known as Emanuel syndrome, C22C has grown over the past 25 years into a community for anyone needing support or information about any of the disorders of chromosome 22, which includes Phelan-McDermid syndrome.
CureSHANK
CureSHANK is a research advocacy organization which advances life-changing therapies for Phelan-McDermid syndrome (PMS). They work toward this goal by funding targeted research and holding scientific meetings to connect diverse stakeholders. CureSHANK’s strategic priorities are projects that help to bridge the “translational research gap” between basic science and successful clinical trials. They identify and fund projects related to drug discovery and design, pre-clinical development, and (one day) early phase clinical trials.
