1. Pediatric Physical Therapy
Afd. Kinderfysiotherapie

2. Can animal models provide insight into
neuromuscular functioning in
Prader Wili syndrome?
Dr. Carlijn Hooijmans
Dr. Janielle van Alfen-van der Velden
Prof. dr. Merel Ritskes-Hoitinga
Prof. dr. Ria Nijhuis-van der Sanden
Linda Reus, MSc.
Afd. Kinderfysiotherapie

3. In this talk
• Prader Willi syndrome and motor performance
• PWS animal models
• Systematic literature search
• Results
• Discussion
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4. The classical PWS patient
Small
Hyperphagia
Obesety
Chromosome 15
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5. The most prominent characteristics of PWS
• Infant hypotonia
• Abnormal body composition: Fat mass ↑
Muscle mass ↓
• Metabolism ↓
• Muscle strength ↓
• Hypogonadism
• Obesity
• Short stature
• Motor problems
• Cognitive and behavioral defects
• Mild dysphormic facial features
Afd. Kinderfysiotherapie

6. Motor problems in PWS infants
• Hypotonia,
• Failure to thrive
• Feeding problems
• Fat mass↑, Muscle mass ↓ Muscle force↓
• Inactivity
• Comprehension of motor skills↓
Independent sitting: 11-13 months
Independent walking: 30-34 months
First spoken words: 21-23 months
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7. Typical motor development
(9-months-old)
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8. Motor functioning in PWS infant
(9-months-old)
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9. Systematic review on motor problems in PWS
(no animal studies included)
A lot of reports Reports are scarce
Infancy Children and Adults
Motor Muscle
Motor development is performance↓ strength↓
seriously delayed
Physical
Activity↓
fitness↓
Afd. Kinderfysiotherapie

10. Systematic review on causes of motor problems in PWS
(no animal studies included)
Only pilot studies
70% decreased
A lot of evidence muscle strength
25-37% decreased
Muscle mass Abnormal muscle
tissue
Neurological
abnormalities
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11. Conclusions and questions
• Body composition: fat mass↑, muscle mass↓
Does not solely explain motor problems in PWS
• Can animal models provide more insight into
neuromuscular functioning in PWS?
• Is there an animal model suited to study effects of
training or medication on the neuromuscular system?
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12. PWS animal models
• Full genetic mouse models (PWS-IC, TgPWS)
• Micro deletion or knock-out mouse models (a.o.
Magel2, Necdin)
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13. SR animal models: literature search
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14. Neurological development: 6 articles
Necdin knock-out mouse models
•Necdin is one of the 5 genes related to PWS
•Necdin was the first gene studied in PWS models
•Its neuro-developmental function is extensively
studied
• Cell growth
• Cell migration
• Cell differentiation
• Cell death/survival
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15. Neuromuscular functioning: 2 articles
Behavior
Necdin knock-out mouse models
• Breathing disorders
• Behavioral abnormalities
• Sensory defects
• Abnormal hypothalamic nuclei
Adult mice
• Normal: weight, activity, exploration, muscle strength
• Abnormal: slip↑, balance↓, running↓
Infant mice (10-days-old)
• Abnormal motor activity, muscle strength↓
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16. Neuromuscular functioning: 2 articles
31% motoneuron cell death
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17. Neuromuscular functioning: 2 articles
31% cell death motoneurons
During embryonic development
•Increased natural occurring cell death motoneurons
•31% loss of lumbar motoneurons
11-day-old mouse
• 27% loss of lumbar motoneurons
Conclusion:
•The lack of Necdin is involved in motor deficiency in
PWS patients
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18. Motor activity: 1 article
Magel2-null mouse model
• Decreased growth
• Excessive weight gain
• Increased fat mass
• Abnormal metabolism
• Decreased motor activity
Conclusion
•Inactivity presumably caused by depression
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19. Conclusion
Not suited
• Full genetic mouse models
• Magel2-null mouse model
Possibly suited
• Necdin knock-out mouse model
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20. Questions?
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