In this one hour and 22-minute video, Dr. Christian Schaaf, Department Chair of Human Genetics at Heidelberg University, discusses current research into Schaaf-Yang syndrome (SYS).
Click below to watch the video. If you're short on time, scroll down for timestamps to find the portions you're most interested in.
Presentation Summary With Timestamps
0:50 Dr. Christian Schaaf presents
What We can learn from SYS Research?
0:00 Introduction
- Christian Schaaf is a clinical geneticist, formerly at Texas Children’s Hospital and Baylor College of Medicine.
- He and his family moved back to Germany, where he is from.
- He is the Department Chair of Human Genetics at Heidelberg University.
5:14 How it Started
- In 2012, a patient came to his clinic from Arizona. He was 13 years old, and had autism spectrum disorder.
- The patient’s mother said she wanted to find out if he had Prader-Willi syndrome.
- It did not appear to be PWS, but mother explained that he was born with severe hypotonia, had a club foot, had an undescended testicle, and needed to be tube fed.
- Doctors in the NICU had ordered a test for PWS, and it came back negative, but for 13 years, she always felt it looked like PWS.
- The lab did a sequencing and found a point of mutation in the MAGEL2, which is one of the genes that plays a role in PWS.
- Since that patient was identified, they have identified 3 more with the same mutation.
- The geneticists submitted a paper to the journal Nature Genetics, which began the journey of identifying more than 300 families with children with Schaaf-Yang syndrome.
7:30 MAGEL2 Gene
- MAGEL2 is a gene within the PWS domain.
- It is an area on chromosome number 15, and when you lose a chunk of material in this domain, or if you get two copies of chromosome 15 from Mom, and none from dad, then you have Prader-Willi syndrome.
- It is maternally imprinted, paternally expressed.
- When you have a typographical error, a point mutation, in the MAGEL2 gene, this can lead to a particular type of mutation called Schaaf-Yang syndrome.
- Not all patients with SYS have a truncating mutation, which means it’s a mutation that leads to a stop somewhere in the gene.
- When the gene is translated into a protein, it leads to a stop and the protein is truncated: a truncating mutation.
- It’s important to understand that there is something special about this region on chromosome 15. Even though we have two copies of chromosome 15, one from mom and one from dad, only the dad’s is used.
- Even though you may have perfect instructions from mom, if you have a mutation in dad’s copy, you develop SYS. If you have a mutation in mom’s copy that you got from your mom, you are actually healthy.
- What they realized when they identified those first individuals with MAGEL2 mutations, was that there was a lot of overlap with PWS. It’s not just molecularly related, but also clinically related.
12:03 Clinical Characteristics of PWS and SYS
- A graph shows an overlap where PWS has the characteristics of hyperphagia and obesity. SYS has autism (ASD) and contractures. And both have hypotonia, feeding difficulties, DD/ID, and hypogonadism.
- When kids with SYS are born, they look like babies with PWS. They have hypotonia, they are floppy, they have feeding difficulties, and many of them need to be tube fed, or get a g-button.
- As they get older, they experience delays in developmental milestones.
- Many have intellectual disabilities.
- Another overlap between PWS and SYS is easier to recognize in boys, hypogonadism, or underdevelopment of the gonads.
- Males often have small penises and undescended testicles
- A lot of the features that are considered very typical for PWS—hyperphagia and severe obesity— are not seen in SYS.
- However, SYS has a higher prevalence of autism spectrum disorder; four out of five kids with SYS get an autism diagnosis.
- Another striking and visible difference in SYS is contractures, in small finger joints, but also affecting elbows, knees, and other joints.
14:20 MAGEL2 mutations known today
- The researchers have been in touch with 300 families and have cataloged all the mutations, and have done extensive studies to better understand the clinical manifestations.
- What stands out is a hot spot where most of the mutations happen. Approximately half the children have the exact same C1996 mutation, the addition of one letter C in a stretch of letters right in the middle of the gene.
- Important to remember that they have to be on the paternal copy to develop the features of SYS.
15:21 Familial Cases
- One family in Europe has 16 family members with SYS, and that is because unaffected individuals can pass the mutation on. As long as the mutation runs in the maternal line, nobody will be affected.
- This has implications for family planning and the chance of having additional children with SYS.
- Once you have an affected child, the dad should get tested to see whether he carries the same MAGEL2 mutation; if he does, every subsequent pregnancy will have a 50 percent chance of the child inheriting the mutation.
- If the father does not carry the mutation, the chances are lower than 2%.
17:29 Clinical Features of SYS
17:37 Infancy and Childhood
- Low muscle tone and feeding difficulties
- Contractures
- Undescended testicles for many boys
- Developmental delays, intellectual disability, and autism spectrum disorder
21:23 Additional Common Features
- Sleep apnea (obstructive, central, combined): 71%; some children have died during early childhood when they stopped breathing.
- Respiratory problems: history of intubation (58%) and history of tracheostomy (18%)
- Feeding problems: 97%
- Dysphagia-altered swallowing (97%)
- History of tube feeding (75%)
- Scoliosis and osteoporosis. These conditions can get worse over the course of the lifespan.
- Hyperphagia and obesity are not as severe in SYS as in PWS.
27:09 Adults with SYS
- Clinical manifestations shift throughout life span.
- Adults with SYS become more stable, respiratory issues and sleep apnea become less of an issue.
- Developmental delay and intellectual disability remain stable.
- Lack of satiety, overeating, and obesity can become an issue as people get older.
- Unlike PWS, eating problems become an issue later in life.
- Some people with SYS do have food-seeking behaviors, so it is something to keep an eye on.
- Some patients with SYS experience daytime sleepiness.
- Some people with SYS have constipation due to altered gastric motility. They may need medications, enemas, or manual decompactions.
34:47 SYS Patient Voices Survey
- A 2021 FPWR survey collected data from 81 parents and primary caregivers from 90 different countries.
- Data divided into 4 age groups: 0-4, 4-10, 11-18, and adults.
- Goal was to identify medical needs and treatment priorities.
- Caveat: this is data reported by caregivers, and may differ from the medical data.
- Respondents were presented with 19 different symptoms and asked to state whether their child had experienced any of those symptoms.
- Developmental delay or intellectual disability was the most important issue. Over 90% of patients under the age of 4 showed developmental delay or disability, a similar percentage to communication problems.
- Sometimes the impact was even perceived to be higher than the diagnosis, especially with communication difficulties.
- Autism spectrum disorder seems to increase in its prevalence in the oldest cohort. Many caregivers rated the impact of autism to be very important, well before the symptom was diagnosed. Like many many mental health challenges, it is always a source of concern for many parents.
- Parents of the youngest cohort are concerned about contractures, but the perceived impact decreases with age.
- Physical therapy was very effective for most patients with contracture.
- In terms of eating, it was a big issue for many parents, even before onset, and has an onset later in life.
- Most parents worried about eating, sleeping, and breathing problems.
- Parents and caregivers also worry about growth hormone deficiency, but there is a specific treatment, and many children with SYS are on growth hormones.
- Many respondents rated the ability of a person with SYS to reach long-term goals as “not likely,” which is something researchers need to keep in mind as we seek more treatments for a better quality of life.
- This survey helps researchers understand the issues that are important to parents and caregivers to pursue medical improvement.
- The importance of addressing the stress of being caregivers for special needs children.
1:00 Individuals with SYS have Growth Hormone Deficiency
- One important feature shared by SYS and PWS is growth hormone deficiency.
- This is a way that SYS research can benefit from decades of PWS study.
- Growth hormone treatment has become one of the mainstays of PWS treatment, and we know that hormones have many effects on the body, including shifting in body composition and mass, increasing lean muscle mass, adding strength, and exercise tolerance, endurance, and stamina.
- Growth hormone treatment also improves glucose profile and may increase physical and cognitive function.
- Kids on growth hormone treatment make great strides with developmental milestones.
- Chart shows a statistically significant difference between kids who were not treated and kids who were on growth hormone.
- Height increases.
- BMI improves
- Strength and stamina improve.
1:05 What We Can Learn from SYS Research
- Parents donated skin biopsies that were reprogrammed to become stem cells, which taught researchers about molecular changes.
- Fibroblasts>induced pluripotent stem cells>induced neurons
- The PhD students in Dr. Schaaf’s lab are looking at the shape of those neurons, and found that they are different in SYS compared to healthy controls.
- The amount of intersections and connections that they form was decreased, but when those cells were treated with Rapamycin, they went back to normal.
- So, the important question is whether this would also work in a living organism.
- The lab has been treating mouse models of SYS both prenatally and postnatally with Rapamycin, and found that when you give it prenatally or very early in life, it can actually slow development and cause developmental delay.
- They also found that MAGEL2 knockout mice (SYS)on a treadmill get exhausted earlier and travel less. Rapamycin helped restore that stamina, but it did not rescue grip strength.
- Rapamycin is used in tuberous sclerosis, which is also a neurological genetic disorder that causes seizures.
1:11 New Lines of Research in Schaaf Lab
- Oxytocin signaling. Oxytocin plays a role in social bonding, and has been discussed in autism spectrum disorder. One member of the team has submitted a grant to the German research foundation, which would allow them to do SYS and PWS research for 5 years.
- One lab has been investigating the effects of oxytocin in PWS, and have given it intranasally.
- Critical period for oxytocin treatment seems to be 0-5 years, 5-11 years, and the beginning of 11+ years.
- Neuronal cell culture
- Neurite outgrowth
- Normalization of synaptic proteins
- Stimulation of genes involved in forming synapses
- MAGEL2KO Mice
- Suckling, grooming
- Social recognition
- Learning abilities, spatial memory
- In part restoration of normal OT system
- Human patients
- Normalization of suckling in infants
- Increased trust and decreased disruptive behaviors
- Improved social skills
- Emotional control
1:13 Summary
- PWS and SYS are both molecularly and phenotypically related.
- The SYS phenotype may be more similar to PWS than was initially thought.
- Human growth hormone (rGH) has proven beneficial in both syndromes.
- There are ongoing investigations into the mTOR pathway and Rapamycin
- A new line of investigation is looking into oxytocin in PWS and SYS.
1:16:00 Q&A
