In this 85‑minute video, Dr. Christian Schaaf, medical director and department chair at the Institute of Human Genetics at the University of Heidelberg and visiting professor at the Baylor College of Medicine, explains our understanding of Schaaf-Yang syndrome to date and the direction of current studies
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
0:01 Matt L. introduction
0:50 Dr. Christian Schaaf introduction
2:41 How It All Started
- First patient was 13-year-old Donny at Texas Children’s Hospital in 2013
- In infancy his physicians had identified clinical symptoms of Prader-Willi syndrome
- Donny tested negative for PWS, but doctors were unable to determine the cause of his symptoms
4:12 MAGEL2 Gene
- Later genetic on Donny testing identified a mutation in the MAGEL2 gene
4:45 Clinical Characteristics of PWS and SYS
- Overlap between clinical signs of PWS and SYS
- Low muscle tone
- Feeding difficulties
- Developmental delays
- Hypogonadism
- Differences
- More hyperphagia and obesity in PWS
- More autism spectrum disorders and hand contractures in SYS
- Additional cases identified; initial discoveries first published 2013
6:55 More Than 300 Cases with Truncating MAGEL2 Mutations Known Today
- Schaaf team in touch with more than 300 families
- Identified region of MAGEL2 where many mutations tend to cluster
- c.1996dupC mutation most common
- c.1996delC mutation creates most severe symptoms
8:41 Familial Cases Illustrate Inheritance Pattern of an Imprinted Disorder
- MAGEL2 mutation can be passed on in families
- Maternal versus paternal inheritance patterns
- Men who carry the MAGEL2 mutation have 50/50 chance of passing it on to their children
12:18 Clinical Features of SYS
- Individual differences; no child displays all the clinical features
13:01 Infancy and Childhood
- Symptoms appear shortly after birth
- Low muscle tone often first noticed
- Feeding difficulties often occur soon after birth
- Contractures another early sign of SYS
- Developmental delays appear later
15:05 Additional Common Features of SYS
- Intellectual challenges
- Sleep apnea and other sleep disorders
- Respiratory problems affect most children with SYS
- Dysphagia affects 97%
22:00 Hands of SYS
- Contractures can improve over time and with therapy
22:50 Scoliosis
- Can worsen over time
- Bone mineral density is decreased in children with SYS
- Bone deficiencies lead to developmental delays
- Fracture risk is higher in SYS; vitamin D intake can help
24:40 How Do the Clinical Features Develop Over Time?
- Muscular issues, developmental issues, and acute medical needs tend to improve
- Behavioral issues and issues of personal independence become more of a concern as children get older
28:02 Morbidity and Mortality in SYS
- Some children with SYS die in early infancy
- Sleep apnea a major cause of death
- Respiratory problems cause many deaths in young children with SYS
- First five years of life are most challenging for survival
33:50 Adults with SYS
- Marbach et al. publication describes how clinical symptoms change over time as children with SYS reach adulthood
- Weight control is a common concern
- Metabolic syndrome risks
- Benefits of growth hormone therapy
37:43 Caregiver-Based Perception of Disease Burden in SYS
- Finding of Dotsch et al. patient voices study
- Cognitive and behavioral issues that caregivers raise as concerns
- Conditions for which caregivers most want to see effective treatments
39:51 What Can We Learn From PWS Research and Translate to SYS?
40:15 Individuals with SYS Have Growth Hormone Deficiency
- Growth hormone therapy benefits for both PWS and SYS
- Benefits found in growth, strength, stamina, BMI
- Caregivers report high satisfaction
- There are some contraindications to growth hormone therapy
47:19 In SYS, We Find an Upregulation of mTOR Pathway
- In one study, skin cells were reprogrammed to become stem cells and eventually neurons
- Differences were noted in SYS neurons
- Molecular alterations in SYS neurons can be successfully treated with rapamycin
48:54 Mouse Models
- Several mouse models available for study
- One MAGEL2 knockout mouse reflects major clinical symptoms of SYS and is commonly used in research
- Rapamycin was found to improve treadmill performance in these mice in the long term, but had no effect on other deficiencies
- Researchers were disappointed to find that rapamycin probably would not be an effective treatment for SYS in humans
52:33 Type of Mutation—Truncating vs Missense
- Missense mutations occur when translation errors cause the wrong amino acid to be encoded in a protein
- Missense variants in MAGEL2 make SYS more difficult to diagnose
- Most children with SYS have truncating mutations to MAGEL2, that is, missing portions
- Nonsense mutations and frameshift mutations result in faulty proteins
- Under study: Do missense mutations cause SYS?
57:56 Ongoing Research in Schaaf Lab
- Completing MAGEL2 knockout mouse study with rapamycin
- Studying truncating mutations with a MAGEL2 rat model developed with support from FPWR
- Induced pluripotent stem cell studies
- MAGEL2 missense variants project
- Other MAGEL2 function explorations
1:01:16 Acknowledgements
1:02:38 Ferdinand Althammer
- Grant received to support study of effects of oxytocin on neurological function in MAGEL2 rat model
1:11:58 Q & A
