This blog provides a brief summary of the FPWR 2017 conference presentation about the ways in which Schaaf-Yang syndrome and PWS are related. The talk was presented by Drs. Christian Schaaf, Ryan Potts and Rachel Wevrick. You can watch the full presentation by clicking on the embedded video below.
In case you don't have time to watch the full video, we've captured some of the key points in the notes below.
Approximately 108 individuals around the world have been diagnosed with Schaaf-Yang syndrome, a genetic disorder caused by a disruption of the MAGEL2 gene on chromosome 15. The syndrome is named for Drs. Christian Schaaf and Yaping Yang, two colleagues at Baylor College of Medicine who identified the first patient and characterized the features of the disorder.
Dr. Ryan Potts has a lab at St. Jude Children’s Research Hospital where he works on elucidating the functions of MAGE proteins, with an emphasis on the cellular functions of MAGEL2.
Dr. Rachel Wevrick co-discovered many of the genes inactivated in Prader-Willi syndrome, including MAGEL2. She has been an active part of our PWS community and is a member of the FPWR Scientific Advisory Board and a board member of FPWR-Canada.
Dr. Schaaf: Schaaf-Yang Overview
How Did It All Begin?
In 2012, Dr. Schaaf identified the child considered patient number one with Schaaf-Yang syndrome, a 13-year-old boy named Donnie. He had diagnosis of autism, and physicians thought he looked like a child with PWS because he was born with low muscle tone and had feeding difficulties – but the test was negative. Dr. Schaaf discovered that Donnie had a mutation in the MAGEL2 gene.
Clinical Features of Schaaf-Yang Syndrome
Starts with pregnancy: Mothers report decreased fetal movement and problems with a higher accumulation of fluid around the baby than other pregnancies. At birth, babies are born with low muscle tone and feeding difficulties. Most newborns receive PWS testing, which comes back negative.
Developmental delay is a common feature: Children reach developmental milestones at a later age than would be expected. Children do get better over time and continue to progress, and they don’t typically stop progressing or regress.
Cognition and behavior: Intellectual disability, a term used after age five and is based on measurement of IQ and functioning level, is present in more than 90 percent of children. Autism spectrum disorder is part of SYS, and about 75 percent of children have it.
Cognitive difficulties vary greatly between patients: Ten children ages 5 to 18 were brought in for in-depth assessment, including endocrine studies and X-ray studies. There was a wide range of how they performed in cognitive tests and IQ tests.
The hands and faces of SYS: Hands in SYS are quite distinct; children are born with contractures, they cannot fully extend their fingers, and they have tapering fingers that bend in funny ways. Their facial features have some commonalities, such as frontal bossing, small, sunken in noses, and in older children, prominent, bushy eyebrows. There is a great deal of variability, and doctors aren’t comfortable making a diagnosis based on looks alone.
Additional common features of SYS:
- Sleep apnea
- Eye abnormalities
- Difficulties with temperature regulation
Endocrine system of SYS:
- Growth hormone deficiency
- Difficulty handling glucose
- Diabetes in teenage years
- Abnormalities in satiety and food intake
Scoliosis and osteoporosis are frequently seen. Scoliosis tends to progress over time and needs to be closely monitored. Bone mineral density tends to be low.
Tests recommended for every SYS patient
- Sleep study
- Referral to endocrinologist: Thyroid hormones & Glucose tolerance test
- Clinical exam for scoliosis
- DEXA scan for bone density (children 5 and older)
Genetics of Schaaf-Yang Syndrome
We each have two copies of chromosome 15, which contains a region of DNA called the Prader-Willi Syndrome region
- We have one copy from each parent
- In these cases, the copy from the mother is “silenced,” meaning it isn’t active
- The piece of chromosome 15 is missing from the father
- Or there are two copies from the mother and nothing from the father
- Chromosomes are there, but in Magel 2 gene, there’s a mutation
- Magel 2 is within PWS Region on Chromosome 15
Why is the PWS test negative in kids with SYS?
- The regular Prader-Willi test only looks at the presence of dad’s information in the relevant part of chromosome 15
- Test doesn’t go to the level of the genetic code to find the mutation
How is SYS diagnosed?
- Single gene sequencing of MAGEL2 gene
- Whole exome sequencing: whole genetic code
- Lab test to prove that the MAGEL2 mutation is on the paternal copy of the gene
Dr. Potts: Molecular Aspects of MAGEL2
- MAGEL2 protein highlights
- Overview of molecular function
- Cellular function in intracellular transport
- Therapeutic intervention strategies
Dr. Wevrick: Mouse Models of MAGEL2 deficiency
Approaches to understanding MAGEL2 deficiency through mouse models
- Gene discovery and protein function
- Animal models