1. EVOLUTION OF TYPE 1
GAUCHER DISEASE PATIENTS
TREATED WITH
IMIGLUCERASE
Paula Grigorescu-Sido1) , Camelia Al-Khzouz 1) ,
Cristina Drugan 2), Simona Bucerzan 1) , Cristina Coldea 1)
1)Genetic Diseases Center –Emergency Children Hospital , First Pediatric Clinic Cluj
2) Biochemistry Department of University of Medicine and Pharmacy “Iuliu Hatieganu” Cluj

2. Gaucher Disease
- monogenic disease – AR
- glucocerebrosidase deficiency
- types: 1 nonneuronopathic (92%)*)
2 with neurological (1%)*)
3 involvement (7%)*)
*)
Gaucher Registry/2007

3. ●
Genetics
- 1q.21
- genomic region - 32 kilobases
- active gene 7,6 kb > 200 mutations -pointmutations !!
(11 exons) - insertions
- deletions
- pseudogene 5,6 kb - 2 pointmutations
- deletions
- AR - homozygote
- composed heterozygote

4. Glucosyl-ceramide (glucocerebroside)
creamed
glucosyl
Glucocerebrosidase - lysosomale enzyme
(acid β-glucosidase (acid-hydrolase – pH=5)
Glucose ceramide

5. Gaucher Cell

6. Multisystemic pattern
Monocytes
Bone Spleen
Marrow
Macrophages
Tissue
Macrophages
Liver Lung
Bone
Kupffer Cells
(Hepatocytes Spared) Alveolar
Osteoclasts Macrophages

7. Epidemiology:
- panethnical pattern: 1/40.0001)
1/50.0002)
1/200.0003)
1/100.0004)
- Ashkenazi jews: - 1/500 - 1/1.000 n.b. alive
- 25-30.000 patients all over the world
- 4.272 - Gaucher Registry 2005
- ≈ 3/4 - on enzyme
therapy
- Meha A Eur J Inte Med,2006,17:S2- 5
- Germain D.P. Hématologie 1999, 5: 480-493
3)
Grabowski G.A. Gaucher Disease: diagnosis, evaluation and treatment. Gardiner-Caldwell Syner-Med, New Jersey 1994
3)
Stirnemann J. et al. La maladie de Gaucher; Encyclopedie Orphanet, 2004

8. Clinical features in type 1 Gaucher disease
Organ enlargement - splenomegaly
- hepatomegaly
Hematological findings: - trombocytopenia
- anemia
- leucopenia
Osteopathy: - pain chronic
acute - “bone crisis”
- fractures
-bone deformities
Chronic respiratory failure.
Growth retardation and puberty delay1) (♀)

9. Enzyme replacement therapy
Preparations Obtaining Trade name Pharmaceutical
method company
Alglucerase’) Extracted from Ceredase Genzyme
studys:1970-1982)**) placenta
(FDA:1991)
(risk – prionic
disease ?)
Imiglucerase’) recombinant Cerezyme Genzyme
(FDA:1994) DNA technology vials
of 200 UI*)
400 UI
*)
changed inorder to expose manosic residures of lateral oligosaccharidic chains → binding to manoso-P receptors on the cell
membranes of macrophages → “targeted” enzyme therapy! R.O.Brady National Institutes of Health, Peter Pentchev –

10. In Romania
- specific diagnosis ..................................1997
- enzyme replacement therapy ………....2002 (sporadically)
....2004
Genetic Diseases Center –Emergency Children Clinical Hospital, First
Pediatric Clinic Cluj –
Biochemistry Department of University of Medicine and Pharmacy “Iuliu
Hatieganu”Cluj (Conf.Dr.Cristina Drugan)

11. Aim of the study
• Assessment of clinical outcome in Gaucher
patients with enzyme replacement therapy

12. Matherial:
- 32/50 type 1 Gaucher patients who received ERT
(22 females and 10 males)
age 28,4+/-12,1 ys

13. Treatment:
Cerezyme (imiglucerase)
- 30-60 U/kgc (45,4 + 13,6 U/kg/infusion)
- i.v. infusion
- every 2 weeks
- 0,25-6,5 years (3,1 ± 1,4 years)

14. ● Monitoring:
- Parametres:
- Hb
- thrombocyte countat at baseline and
- spleen volum - ultrasound assessment
- liver volum
- chitotriosidase
- radiograms
- osteodensitometry
- severity score (Zimran)
-
- body weight 6 ± 2 months treated
- heigth (children) 6-12 months untreated
*) xN (N=0,2% patients weight) 1) Weinreb N.Y. et al., Am J Med,
2002,113:112-119.
**)xN (N=2,5% patients weight)
2) Hollak C.E. et al. J.Clin.Invest., 1994,93:1288-1292.

15. RESULTS

16. Progression of hemoglobin in patients with anemia on
Cerezyme therapy
*)
(n=11/32: 34,3%; 3 –splenectomised patients )
Hb (g/dl)
X
15 9,5± 12,3± 13,5± 13± 12,8± 13± 12,8± 12,8 ± 12,8± 13,6±
10
5
11 11 11 11 9 8 8 8 6 4
0
0 0,5 1 1,5 2 2,5 3 3,5 4 4,5 years
1)
35% - Registrul Gaucher 2006
*)
~ Weinreb N.J. et al., Am. J. Med. 2002, 113

17. Progression of thrombocyte count in patients on
Cerezyme therapy
*)
(n=22/32: 68,6%; 1 p –splenectomised patient)
Tr/mmc
X
180000 168333
160944 163071
160000 151681 154444 151000
141318
140000
121318
120000
100000
76045
80000
60000
22 22 22 22 18 18 14 13 12
40000
20000
0
0 0,5 1 1,5 2 2,5 3 3,5 4 years
*)
~ Weinreb N.J. et al., Am. J. Med. 2002, 113

18. Regression of spleen volume on treatment (xN)
(n=21: 100%)
Spleen volume
(xN)
16
14,4
14
12 10,9
10
8
8
5,9
6 5
4,5
3,8 3,4
4 3
2
21 21 21 21 18 17 13 12 11
0
0 0,5 1 1,5 2 2,5 3 3,5 4 years
*)
Weinreb N.J. et al., Am. J. Med. 2002, 113 (50-60% în 2-5 ani)

19. Regression of liver volume on treatment (xN)
(n=28/32: 88%)
Liver volume
(xN)
1,6 1,5
1,4
1,2
1,2 1,1 1,1 1,06
1,03 1,02 1,01 1 1 1,02
1
0,8
0,6
0,4 28 28 28 28 26 25 23 22 18 5 3
0,2
0
0 0,5 1 1,5 2 2,5 3 3,5 4 4,5 5 years
Weinreb N.J. et al., Am. J. Med. 2002, 113 (30-40% în 2-5
*)
ani ↓)

20. • Bone disease :
1) Clinically: At onset At present
Chronic pain: 30 patients (96,8%) significantly improved
21 patients (66,6%)
Bone crises: 6 patients -2 patients
Fractures: 4 patients 1 patient (Male)
( after 6 years ERT)
+
1 patient ( Female)
(after 4 years ert)

21. Assessment of bone mineral density according to
lumbar column Z score (DXA)
(n=20 patients)
100%
65%
80%
60%
40% 35% 35%
30%
20% 6p 7p 7p
0%
Improvement Stationary Aggravation
- Cerezyme 30U/kg ... 6p
- climax .......................1p
- late start of the ERT

22. Chitotriosidase level on treatment
(n=31)
nmol/h/ml plasmă
X
45000
39548
40000
35000
30000
25000 22946
20000 16414
15000 8416 7184
9923
10000
4563 4517 3802
5000
31 31 31 31 28 26 22 21 17
0
0 0,5 1 1,5 2 2,5 3 3,5 4 years

23. Severity score (Zimran)
SS
20
14,8
15
12,4
10,1
10 9,4 8,9
8,1 8,08 8,1 7,9
5
32 32 32 32 29 27 23 22 17
0
0 0,5 1 1,5 2 2,5 3 3,5 4 years

24. Cerezyme treatment in assessed Gaucher patients:
- clinical improvement since the first year of ERT
- 4 female patients ...................... 5 healhty children
- no side effects
- quality of life improved notably

25. Imigluceraza (Cerezyme) –
- extraordinary chance for Gaucher patients
early specific diagnoses
early start of enzyme replacement therapy

26. Gaucher patients Day (2005)

27. Thanks :
- European Cerezyme Access Programme
- Genzyme Pharmaceutical Company