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Afd. Kinderfysiotherapie
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
In this talk
• Prader Willi syndrome and motor performance
• PWS animal models
• Systematic literature search
• Results
• Discussion
Afd. Kinderfysiotherapie
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
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
Afd. Kinderfysiotherapie
Motor development is seriously delayed
A lot of reports
Infancy
Reports are scarce
Children and Adults
Motor performance↓
Muscle strength↓
Activity↓ Physical fitness↓
Systematic review on motor problems in PWS (no animal studies included)
Afd. Kinderfysiotherapie
25-37% decreased
Muscle mass
70% decreased muscle strength
Abnormal muscle tissue
Neurological abnormalities
A lot of evidence
Only pilot studies
Systematic review on causes of motor problems in PWS (no animal studies included)
Afd. Kinderfysiotherapie
Conclusions and questions
10
• 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?
Afd. Kinderfysiotherapie
PWS animal models
11
• Full genetic mouse models (PWS-IC, TgPWS)
• Micro deletion or knock-out mouse models (a.o.
Magel2, Necdin)
Afd. Kinderfysiotherapie
Neurological development: 6 articles
13
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
Afd. Kinderfysiotherapie
Neuromuscular functioning: 2 articles
Behavior
14
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↓
Afd. Kinderfysiotherapie
Neuromuscular functioning: 2 articles
31% cell death motoneurons
16
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
Afd. Kinderfysiotherapie
Motor activity: 1 article
17
Magel2-null mouse model
• Decreased growth
• Excessive weight gain
• Increased fat mass
• Abnormal metabolism
• Decreased motor activity
Conclusion
• Inactivity presumably caused by depression
Afd. Kinderfysiotherapie
Conclusion
18
Not suited
• Full genetic mouse models
• Magel2-null mouse model
Possibly suited
• Necdin knock-out mouse model