1. Whole body MRI technique in early treated non-neuronopathic patients with enzyme replacement therapy at least eight years Larissa Moos, Jörg Reinke, Miriam Brixius-Huth, Eugen Mengel and Gundula Staatz Department of Pediatric Radiology and Villa Metabolica Mainz Germany Department of Pediatric Radiology / Villa Metabolica

2. Introduction 3rd EWGGD in Lemnos: – Initiation of high dose ERT followed be individual adapted maintenance dosage inchildren ( signs of GD in preschool age) – n=10, age: 6-10 years, ERT follow up: – 6 years 10th EWGGD in Paris – Same cohort ( + 5 pts, 1 pts lost to follow up ) – 13 years later 2

3. Most of these Patients > 50 years What about red marrow and yellow marrow in young adults? Can we prevent bone disease ? 3 MOTIVATION

4. 4 AIM OF THE STUDY To show the outcome of early treated patients with treatment initiation before the age of 10 years after 8 – 20 years of ERT, when they become young adults.

5. Inclusion Criteria: a)Typ 1 GD is confirmed, clinical relevant manifestation b)Treatment initiation before the age of 10! c)Treated since a minimum of 8 years ∑ 14 patients Age of 17- 26 years Mainzer treatment protocol is used 5 Patients

6. Initial: Clinical manifestions before the age of 10 years! Advice: 60 IE/kg KG / 14 days Maintenence: Permanent therapy to prevent detoriation and complications Advice: 15-60 IE/kg KG/14 days Mainzer Protocol: Dosage depends on clinical symptoms and increase of chitotriosidase! Average: 38.5 IE/kg KG/14 days 6 TRETAMENT PROTOCOL FOR ERT

7. 7 Outcome Measures Bone-marrow Scores – Whole body MRI: Düsseldorfer Gaucher Score (DGS) Vetebra-Disc-ratio (VDR) Bone Marrow Burden Score (BMB) All-domain- Score: Sverity Score Index Type 1 (GD-S3)

8. 8 VDR, BMB, & DGS-Scores Source : vom Dahl S. et al. Cur Med Res Opin 2006;22:1045-1064

9. Includes only lower extremities Differentiates between A-&B Pattern Bone infiltration always bilateral A maximum of 8 points can obtained 9 DGS-SCORE Source: Poll et al. (2003)

10. Normal: hyperintense-signal intensity (T1-sequence)/ fine- structured Source: Institut für Kinderradiologie, Johannes-Gutenberg-Universität 10 GRADUATION OF BONE-MARROW INFILTRATION Low: mostly hyperintense-signal intensity with beginng of Gaucher-cell infiltration →hypointense (T1) /regular-structured Medium: more hypointense-signal intensity/ regular structured High: severe hypointense-signal intensity/ inhomogenous

11. Joint destruction Fracture Bone pain Short stature Osteopenia/ Osteoporosis Bone infarct Early beginning with ERT could prevent BONE COMPLICATIOS 11 Bone complications 0/14

12. 12 GD-S3 Scoring System Source: Weinreb N, et al. Gen Med 2010;12:44–51 9- 16 VAS 0/14 1/14 0/14

13. MedianQ25Q75Range Bone-marrow-Score: BMB-Sc.:768,263-11 DGS-Sc.:4A 3-5 A-B VDR-Sc.:1,331,051,591,19-2,01 All- Domain-Score: GD-S31,6 0-2,26 Score-classifications: BMB-Sc.: 0-4 (mild)/ 5-8 (moderate)/ 9-16 (severe) [Range: 0-16] DGS-Sc.: 1-6 (low)/ 7-8 (high) compared with type A & B-morphology [Range: 1-8] VDR-Sc.: 1.9 ±0.30 (normal)/ 1.29 ± 0.31 (untreated pat.)/ 1.7. ± 0.33 (long-treated pat.) 13 Results

14. Vertebra-Disc-Ratio Untreated PatientLong-treated Patient 14

15. Social aspects 8 pts with high school degree 1 pts still in high school 5 pts with jobs in offices or trades 4 pts had there own family: 7 healthy ERT- babies No hospitalisation 15

16. All Whole- Body-MRIs were well tolerated NO BONE COMPLICATIONS Typical manifestions of GD are reduced to a minimum! Only bone marrow infiltration was observed BMB-Score DGS-ScoreLOWER LEVEL GD-S3 Score VDR-ScoreEXCEPTION: located in the spectrum of non- treated pat. Postponed bone marrow conversion ?? Minimum effective dose ?? Consequence: Follow-up studies 16 Conclusion

17. Thanks Patients Larissa Moss Cooperation: Prof. G. Staatz, Pediatric Radiology Mainz Team of the Villa metabolica 17

18. Maas, M.; van Kuijk, C.; Stoker, J.; Hollak, C. E. M.; Akkerman, E. M.; Aerts, J. F. M. G.; den Heeten, G. J. (2003): Quantification of Bone Involvement in Gaucher Disease: MR Imaging Bone Marrow Burden Score as an Alternative to Dixon Quantitative Chemical Shift MR Imaging--Initial Experience. In: Radiology 229 (2), S. 554–561. Poll, Ludger W.; Cox, Marie-Louise; Godehardt, Erhard; Steinhof, Verena; Vom Dahl, Stephan (2011): Whole body MRI in type I Gaucher patients: Evaluation of skeletal involvement. In: Blood Cells, Molecules, and Diseases 46 (1), S. 53–59. Weinreb, Neal J.; Cappellini, Maria D.; Cox, Timothy M.; Giannini, Edward H.; Grabowski, Gregory A.; Hwu, Wuh- Liang et al. (2009): A validated disease severity scoring system for adults with type 1 Gaucher disease. In: Genet Med 12 (1), S. 44–51. Di Rocco, M.; Giona, F.; Carubbi, F.; Linari, S.; Minichilli, F.; Brady, R. O. et al. (2008): A new severity score index for phenotypic classification and evaluation of responses to treatment in type I Gaucher disease. In: Haematologica 93 (8), S. 1211–1218. http://radiopaedia.org/encyclopaedia/quizzes/all/8366 http://www.primary-surgery.org/ps/vol2/html/sect0322.html http://www.123rf.com/photo_11530363_human-knee-pain-running-man-skeleton-x-ray-visual-bone-health-fitness-exercise-chart- symbol.html http://seekingalpha.com/article/175098-growth-report-for-third-quarter-2009-part-i 18 References

19. 19 MAINZER TREATMENT PROTOCOL