1. NETWORK APPROACH OF THE
MANAGEMENT OF PRADER-WILLI AND
ANGELMAN SYNDROMES,
ROMANIAN EXPERIENCE
Maria Puiu1, Natalia Cucu2, Gabriela Anton3, Dorica Dan4,
Calin Popoiu5, Valerica Belengeanu1, Monica Stoian1,
Cristina Rusu6, Victor Pop7, Corin Badiu8
1. University of Medicine and Pharmacy “Victor Babes” Timisoara, Romania
2. Department of Epigenetics, Faculty of Biology Bucharest
3. National Institute of Virusology, Bucharest
4. Romanian Association Prader-Willi, Romanian Aliance of Rare Diseases
5. Clinical Hospital of Emergency for Children “L. Turcanu” Timisoara
6. University of Medicine and Pharmacy “T. Popa” Iasi
7. University of Medicine and Pharmacy “I. Hatieganu” Cluj- Napoca
8. National Institute of Endocrinology, Bucharest
2. The aim of the project is the
integration of a multidisciplinary
approach for Prader-Willi and
Angelman syndromes, distinct
genomic diseases, with a
neurodegenerative component.
6. The project has 8 partners:
• University of Medicine and Pharmacy “Victor
Babes” of Timisoara
• University of Bucharest
• Institute of Virusology “Stefan Nicolau” Bucharest
• Prader-Wlilli Association in Romania
• Clinical Hospital of Emergency for Children “L.
Turcanu” Timisoara
• University of Medicine and Pharmacy “T. Popa” Iasi
• University of Medicine and Pharmacy “I. Hatieganu”
Cluj- Napoca
• National Institute of Endocrinology “C. I. Parhon”
Bucharest
8. General objectives
• Implementation of new molecular methods
for genetic/epigenetic investigation and
establishment of national centres with high
expertise in approaching the two
syndromes, that will develop educational
reference and release centres.
9. • Evolving efficient partnership with patients
associations. The power of these
associations will propel the research, will
inform the patients and will respond to civil
society questions.
10. • Establishing international collaboration
and partnerships with researchers having
similar scientific preoccupations,
establishing partnerships with other
National and International Organizations
and affiliated research groups from each
country aiming financial support on
programs that intend to stimulate
collaboration between specialists,
researchers and nongovernmental
organizations.
11. • Developing a multidisciplinary partnership
to build a common platform of activities for
new innovative solutions in respect to rare
disease needs.
12. These new bridges of real and effective
collaboration will ascertain on the national
level the creation of a solid network
comprising institutions with high expertise in
this domain, well connected to other
national or international research networks.
13. Specific objectives
• Developing of a clinical interdisciplinary
investigation algorithm specified for PWS/
AS and clear evaluation after elaboration
of scores that will track down easily the
suspicious cases and will allow
genetic/epigenetic investigation, aiming a
rapid and correct diagnosis and an
efficient early treatment.
14. Cassidy and Driscoll, 2009
PWS
AS
65-75% 5-11% 3-7% 3%
70%
Rebecca Burdine and Erin Sheldon
20-30% 2-5%
< 1 % chromosomal translocation
15. PWS diagnostic criteria (Gunay-Aygun et al.
2001)
• children < age 3 years, 5 points are
required for diagnosis, 4 of which must be
major criteria.
• individuals age ≥ 3 years, 8 points are
required for diagnosis, at least 5 of which
must be major criteria.
16. Birth to two years
• Hypotonia with poor suck in the neonatal period
Two to six years
• Hypotonia with history of poor suck
• Global developmental delay
Six to 12 years
• History of hypotonia with poor suck (hypotonia often
persists)
• Global developmental delay
• Excessive eating with central obesity if uncontrolled
13 years to adulthood
• Cognitive impairment, usually mild mental retardation
• Excessive eating with central obesity if uncontrolled
• Hypothalamic hypogonadism and/or typical behavior
problems
Cassidy and Driscoll, 2009
17. Mutation Detection
Mutations
Test Method Frequency by Test
Detected
Method
Methylation
Methylation analysis 99%
abnormality
FISH/Quantitative
Deletion of PWCR 70%-75%
PCR
Uniparental disomy
UPD of PWCR 25%-29%
(UPD) studies
Imprinting center
Sequence analysis <1%
defect
Suzanne B Cassidy, 2008
18. Consensus criteria for the clinical
diagnosis of AS (Williams et al. 2006)
• Findings typically present in affected
individuals
• Findings in more than 80% of affected
individuals
• Findings in fewer than 80% of affected
individuals
19. Parent-
Mutation
Specific Locus, Gene,
Test Mutations Detection
DNA or
Methods Detected Frequency by
Methylation Chromosome
Test Method
Imprint
5-7 Mb
AS/PWS region FISH or CGH deletion of ~68%
15q11.2-q13
Abnormal Chromosome 15 UPD study UPD ~7%
Deletion 6-200 kb
AS IC ~3%
analysis deletions
Sequence Sequence
~11%
analysis variants
Normal UBE3A
Deletion/ Partial or
duplication whole-gene Rare
analysis deletions
Charles A Williams, 2008
21. • We gathered a multidisciplinary team which
includes: geneticists, paediatricians,
neurologists, endocrinologists, dietarians,
psychologists, pedagogues, social workers
and also educators, occupational
therapists, psychomotor therapists, physical
therapists, speech therapists.
22. • Access of a standardized base for
PSW/AS gathering clinical data,
genetic, epigenetic from all the country
aiming European integration and
describing an European model resulting
in a National Registry for Rare
Disease.
23. Hopefully this project and the
cooperation with the Ministry of
Health and other decisional forums,
will allow the approach of the rare
diseases in a network, with the
establishment of the reference
centers and the competence ones.
