PPP2R5D-Related Syndrome

PPP2R5D-related syndrome happens when there are changes to the PPP2R5D gene. These changes can keep the gene from working as it should.

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 PPP2R5D-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 PPP2R5D-related syndrome, the sibling’s risk of having a child who has PPP2R5D-related syndrome depends on the sibling’s genes and their parents’ genes.

• If neither parent has the same genetic variant causing PPP2R5D-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit PPP2R5D-related syndrome.

As of 2024, at least 138 people with PPP2R5D-related syndrome have been identified in a medical clinic and the Simons Searchlight registry.

People who have PPP2R5D-related syndrome may look different. Appearance can vary and can include some but not all of these features:

• Larger than average head size
• Widely spaced eyes
• Large, noticeable forehead
• Low ear lobes
• Eye issues
• Bone and joint issues

Scientists and doctors have only just begun to study PPP2R5D-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 PPP2R5D-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

Speech and Learning

About one-half of people with PPP2R5D-related syndrome had developmental delay or intellectual disability. People with PPP2R5D-related syndrome also had a language disorder. Research suggests that people with variants p.Asp251Ala, p.Asp251Tyr, p.Asp251His, p.Asp251Val, and p.Glu200Lys had better expressive language skills, personal care, and social skills compared with people with variants p.Glu198Lys and p.Trp207Arg.

• 44 out of 104 people had developmental delay or intellectual disability (42 percent)
• 58 out of 88 people had a language disorder (66 percent)

Behavior

Autism diagnosis occurred in about 1 out of 3 people with PPP2R5D-related syndrome. Increased aggression was reported more often for people with variants p.Glu198Lys and p.Glu200Lys than for people with variants in 251. People with variant p.Glu200Lys reported more oppositional behavior as they got older. People with PPP2R5D-related syndrome had increased attention difficulties and hyperactivity as they got older, except for people with variants in 251.

• 25 out of 84 people had autism or features of autism (30 percent)

Brain

Almost one-half of people with PPP2R5D-related syndrome had seizures. Seizure types included tonic–clonic (grand mal) seizures and myoclonic seizures. The average age of seizure onset was 2.3 years, but some people developed seizures as early as birth or as late as almost 18 years old. Many people had larger than average head size, also called macrocephaly, and lower than average muscle tone.

• 42 out of 98 people had seizures (43 percent)
• 12 out of 33 people had tonic–clonic seizures (36 percent) 
• 10 out of 33 people had myoclonic seizures (30 percent)
• 67 out of 99 people had macrocephaly (68 percent)
• 77 out of 98 people had lower than average muscle tone (79 percent)

Feeding and digestion

People with PPP2R5D-related syndrome had diarrhea or gastroesophageal reflux disease (GERD).

• 17 out of 72 people had diarrhea (24 percent)
• 20 out of 72 people had GERD (28 percent)

Vision

Some people had vision issues, including strabismus (crossed eyes) and astigmatism (an imperfection of the eye that causes blurred distance and near vision).

• 20 out of 72 people had strabismus (28 percent)
• 12 out of 72 people had astigmatism (17 percent)

Other findings

There have been seven people with PPP2R5D-related syndrome that developed early onset parkinsonism. Ages of diagnosis were within the range of 25 to 42 years old.

About 2 out of 3 children with a pathogenic PPP2R5D variant had excessive drooling.