SYRCLE_Reus mini symposium sr animal studies 30082012

Afd. Kinderfysiotherapie

Pediatric Physical Therapy


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.


In this talk

• Prader Willi syndrome and motor performance

• PWS animal models

• Systematic literature search

• Results

• Discussion


The classical PWS patient

Small

Hyperphagia

Obesety

Chromosome 15


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


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


Typical motor development

(9-months-old)


Motor functioning in PWS infant

(9-months-old)


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)


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)


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?


PWS animal models

11

• Full genetic mouse models (PWS-IC, TgPWS)

• Micro deletion or knock-out mouse models (a.o.

Magel2, Necdin)


SR animal models: literature search

12


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


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↓



31% motoneuron cell death

15



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


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


Conclusion

18

Not suited

• Full genetic mouse models

• Magel2-null mouse model

Possibly suited

• Necdin knock-out mouse model


Questions?

19

SYRCLE_Reus mini symposium sr animal studies 30082012

Technology

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