GENE GUIDE

PPP3CA-Related Syndrome

This guide is not meant to take the place of medical advice. Please consult with your doctor about your genetic results and health care choices. This Gene Guide was last updated on 2024. As new information comes to light with new research we will update this page. You may find it helpful to share this guide with friends and family members or doctors and teachers of the person who has PPP3CA-Related Syndrome.
a doctor sees a patient

PPP3CA-related syndrome is also called developmental and epileptic encephalopathy 91. For this webpage, we will be using the name PPP3CA-related syndrome to encompass the wide range of variants observed in the people identified.

PPP3CA-related syndrome happens when there are changes in the PPP3CA gene. These changes can keep the gene from working as it should.

Key Role

The PPP3CA gene plays an important role in brain cell communication. 

Symptoms

Because the PPP3CA gene is important for brain activity, many people who have PPP3CA-related syndrome have: 

  • Kidney and urinary issues 
  • Poor feeding 
  • Low muscle tone 
  • Developmental delay 
  • Intellectual disability 
  • Features of autism 
  • Seizures 
  • Brain changes seen on magnetic resonance imaging (MRI) 
  • Difficulty speaking 
  • Unsteady walking 
  • Bone defects

PPP3CA-related syndrome is a genetic condition, which means that it is caused by variants in genes. Our genes contain the instructions, or code, that tell our cells how to grow, develop, and work. Every child gets two copies of the PPP3CA gene: one copy from their mother’s egg, and one copy from their father’s sperm. In most cases, parents pass on exact copies of the gene to their child. But the process of creating the egg or sperm is not perfect. A change in the genetic code can lead to physical issues, developmental issues, or both. 

Sometimes a spontaneous variant happens in the sperm, egg or after fertilization. When a brand new genetic variant happens in the genetic code is called a ‘de novo’ genetic variant. The child is usually the first in the family to have the genetic variant.

De novo variants can take place in any gene. We all have some de novo variants, most of which don’t affect our health. But because PPP3CA plays a key role in development, de novo variants in this gene can have a meaningful effect. 

Research shows that PPP3CA-related syndrome is often the result of a de novo variant in PPP3CA. Many parents who have had their genes tested do not have the PPP3CA genetic variant found in their child who has the syndrome. In some cases, PPP3CA-related syndrome happens because the genetic variant was passed down from a parent.

Autosomal dominant conditions

PPP3CA-related syndrome is an autosomal dominant genetic condition. This means that when a person has the one damaging variant in PPP3CA they will likely have symptoms of PPP3CA-related syndrome. For someone with an autosomal dominant genetic syndrome, every time they have a child there is a 50 percent chance they pass on the same genetic variant and a 50 percent chance they do not pass on the same genetic variant.

Autosomal Dominant Genetic Syndrome

GENE / gene
GENE / gene
Genetic variant that happens in sperm or egg, or after fertilization
GENE / gene
Child with de novo genetic variant
gene / gene
Non-carrier child
gene / gene
Non-carrier child

Why does my child have a change in the PPP3CA gene?

No parent causes their child’s PPP3CA-related syndrome. We know this because no parent has any control over the gene changes that they do or do not pass on to their children. Please keep in mind that nothing a parent does before or during the pregnancy causes this to happen. The gene change takes place on its own and cannot be predicted or stopped.

Each family is different. A geneticist or genetic counselor can give you advice on the chance that this will happen again in your family.

The risk of having another child who has PPP3CA-related syndrome depends on the genes of both biological parents. 

  • If neither biological parent has the same genetic variant found in their child, the chance of having another child who has the syndrome is on average 1 percent. This 1 percent chance is higher than the chance of the general population. The increase in risk is due to the very unlikely chance that more of the mother’s egg cells or the father’s sperm cells carry the same genetic variant. 
  • If one biological parent has the same genetic variant found in their child, the chance of having another child who has the syndrome is 50 percent. 

For a symptom-free brother or sister of someone who has PPP3CA-related syndrome, the sibling’s risk of having a child who has PPP3CA-related syndrome depends on the sibling’s genes and their parents’ genes. 

  • If neither parent has the same genetic variant causing PPP3CA-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit PPP3CA-related syndrome. 

As of 2024, over 42 people with PPP3CA-related syndrome have been identified in a medical clinic. 

People who have PPP3CA-related syndrome may look different. Appearance can vary and can include some but not all of these features: 

  • Lower than average weight 
  • Lower than average height 
  • Wide-set eyes

Scientists and doctors have only just begun to study PPP3CA-related syndrome. At this point, there are no medicines designed to treat the syndrome. A genetic diagnosis can help people decide on the best way to track the condition and manage therapies. Doctors can refer people to specialists for:

  • Physical exams and brain studies
  • Genetics consults
  • Development and behavior studies
  • Other issues, as needed

A developmental pediatrician, neurologist, or psychologist can follow progress over time and can help:

  • Suggest the right therapies. This can include physical, occupational, speech, or behavioral therapy.
  • Guide individualized education plans (IEPs).

Specialists advise that therapies for PPP3CA-related syndrome should begin as early as possible, ideally before a child begins school.

If seizures happen, consult a neurologist. There are many types of seizures, and not all types are easy to spot. To learn more, you can refer to resources such as the Epilepsy Foundation’s website: epilepsy.com/…t-is-epilepsy/seizure-types

This section includes a summary of information from major published articles. It highlights how many people have different symptoms. To learn more about the articles, see the Sources and references section of this guide.

Speech and learning 

People with PPP3CA-related syndrome had developmental delay or intellectual disability, and some had speech issues. 

  • 11 out of 13 people had developmental delay or intellectual disability (85 percent)
  • 3 out of 10 people had speech disorder (30 percent)
85%
11 out of 13 people had developmental delay or intellectual disability.
30%
3 out of 10 people had speech disorder.

Behavior 

People with PPP3CA-related syndrome had behavioral issues, including autism. 

  • 2 out of 10 people had autism (20 percent) 

Brain 

All people with PPP3CA-related syndrome had seizures, most often focal motor seizures, but also epileptic spasms, generalized spike waves, generalized clonic seizures, generalized myoclonic seizures, generalized tonic seizures, and/or generalized tonic–clonic seizures. Seizures started from the first few weeks of life up to 4 years. Some people had a developmental regression. One person had brain changes seen on magnetic resonance imaging (MRI). 

  • 14 out of 14 people had seizures (100 percent)
  • 4 out of 14 people had regression (29 percent)
Human head showing brain outline
100%
14 out of 14 people had seizures.
29%
4 out of 14 people had regression.

Mobility 

Lower than average muscle tone (hypotonia) was common in people with PPP3CA-related syndrome. Mobility issues included spasticity, toe walking, or eventually needing a wheelchair.  

  • 12 out of 14 people had lower than average muscle tone (86 percent)

Where can I find support and resources?

PPP3CA Hope Foundation

The PPP3CA Hope Foundation’s ambition is to find a treatment for PPP3CA gene mutations and change the lives of children around the world.

Simons Searchlight

Simons Searchlight is an online international research program, building an ever growing natural history database, biorepository, and resource network of over 175 rare genetic neurodevelopmental disorders. By joining their community and sharing your experiences, you contribute to a growing database used by scientists worldwide to advance the understanding of your genetic condition. Through online surveys and optional blood sample collection, they gather valuable information to improve lives and drive scientific progress. Families like yours are the key to making meaningful progress. To register for Simons Searchlight, go to the Simons Searchlight website at www.simonssearchlight.org and click “Join Us.”

Sources and References

The content in this guide comes from published study about PPP3CA-related syndrome.

  • Favaro, J., Iodice, A., Nosadini, M., Asta, F., Toldo, I., Ancona, C., Cavaliere, E., Pelizza, M. F., Casara, G., … & Sartori, S. (2024). PPP3CA gene-related developmental and epileptic encephalopathy: Expanding the electro-clinical phenotype. Seizure, 121, 253-261. https://pubmed.ncbi.nlm.nih.gov/39305655/

Stay connected with Simons Searchlight

Join our newsletter to receive updates