I RISULTATI A LUNGO TERMINE DELLA ERT NELLE FORME GIOVANILI E ADULTE DELLA GLICOGENOSI 2 - Bruno Bembi

1. I RISULTATI A LUNGO TERMINE
DELLA ERT NELLE FORME GIOVANILI
E ADULTE DELLA GLICOGENOSI 2
Bruno Bembi
Centro di Coordinamento Regionale
per le Malattie Rare
AOUD S. Maria della Misericordia di Udine
25 novembre 2014

2. Glicogenosis II,
malattia di Pompe o deficit di maltasi acida
• Malattia da accumulo lisosomiale
• ereditarietà autosomico recessiva
• Deficit dell’a-glucosidasi lisosomiale
• accumulo di glicogeno nei lisosomi dei
muscoli scheletrici, lisci e del miocardio

3. Glicogenosi II
continuum fenotipico
Esordio infantile Forme tardive
•Debolezza muscolare progressiva
•Cardiomegalia and cardiomiopatia
•Epatomegalia moderata
•Macroglossia
•Difficoltà d’alimentazione
•Infezioni respiratorie frequenti
•Distress respiratorio
•Ritardo tappe motorie
•CK elevate (marcatamente)
•Decorso progressivo, rapido, fatale
•no attività residua della GAA
•Debolezza muscolare progressiva
•No cariomiopatia
•Epatomegalia moderata
•Difficltà deglutizione
•Infezioni respiratorie frequenti
•Distress respiratorio
•Faticabilità muscolare
•CK elevate
•attività residua della GAA

4. Diagnosi di Laboratorio
Basta sulla dimostrazione del deficit di GAA
(linfociti, fibroblasti, amniociti)
Possibile misurare l’attività enzimatica su
goccia di sangue su carta da filtro (screening?)
Altri parametri di laboratorio: CK, LDH,
AST, ALT, oligosacharides su urine e plasma
Conferma diagnostica: analisi molecolare

5. Allele frequency in the Italian
infantile GSDII population
c.525delT
(11.8%)
c.1064T>C
(7.9%)
c.1655T>C
(10.5%)

6. Allele frequency in the Italian
late onset GSDII population
c.-32-13T>G
(42.3%)
c.2237G>A
(10.3%)

7. Approcci Terapeutici
• Terapie di Supporto
• Dieta + fisioterapia
• Terapia Enzimatica Sostitutiva

8. Terapia Enzimatica Sostitutiva

9. Long-term observational, non-randomized study of enzyme
replacement therapy in late-onset glycogenosis type II
Bembi B1, Pisa FE, Confalonieri M, Ciana G, Fiumara A, Parini R, Rigoldi M,
Moglia A, Costa A, Carlucci A, Danesino C, Pittis MG, Dardis A, Ravaglia S.
J Inherit Metab Dis. 2010 Dec;33(6):727-3
Studio multicentrico (5 centers) con il supporto dell’Agenzia
Italiana del Farmaco (AIFA)
Patienti:
Giovanili: 7 (5 maschi, 2 femmine; età 8-18 yrs)
•Adulti*: 22 (11 maschi, 11 femmine; età 29-83)
* 6 pazienti adultsi esclusi dallo studio per: 2 HCV, 1 HIV, 1
leyucopenia idiopatica, 1 cancro sel seno, 1 età avanzata)
Myozyme : 20 mg/kg/every two weeks
Durata: 36 months

10. Dati Demografici e caratteristiche cliniche alla baseline
Giovanili
7 (30.4%)
Adulti
16 (69.6%)
Età (min–max) 8 - 18 29 – 62
Età (mean + SD) 13.9 ± 3.7 52.6 ± 2.8
Femmine (n,%) 2 28.6 7 43.7
Maschi (n,%) 5 71.4 9 56.3
Età primi sintomi (media+SD) 2.5 ± 1.3 25.7 12.8
Età diagnosi (mdia+SD) 2.8 ± 1.4 33.4 ± 14.6
Età TES (media+SD) 12.0 ± 3.3 47.1 ± 10.7
BMI (media+SD) 18.0 ± 6.4 22.3 ± 4.9
Tracheostomia (n,%) 1 14.3 3 18.7
Support Ventilatorio mascherina
2 14.3 11 68.7
(n,%)
6MWT completato (n,%)
2 28.6 8 50.0
6MWT non completato (n,%) 5 71.4 8 50.0

11. Protocol di studio
• Visite di Follow-up : ogni 3 mesi per i primi 24
months, poi ogni 6
• Functione Muscolare : Scala di Walton, 6MWT
• Functione Respiratoria: supporto ventilatorio,
CV, FEV1, pCO2 arteriosa
• Sintomi Clinici (cefalea, dolore muscolare)
• Parametri biochimici: enzimi muscolari

12. WOLTON SCALE
according to Slonime et al. (Muscle Nerve 35: 70-77, 2007)
Grade
0 All activities normal
1 Walks normal; unable to run freely
2 Defect in posture/gait;
2.5 Sometimes use of bannister to climb stairs
3 Stairs only with bannister
3.5 Sometimes unable to climb stairs with bannister
4 Walks without assistance; unable to climb stairs
5 Walks without assistance; unable to rise from a chair
6 Walks only with calipers or other aids
7 Wheelchair bound

13. WS score T0 T6 T12 T18 T24 P
T0-T12
p
T0-T24
0 - 2
8
34.8
9
39.1
10
43.5
11
47.8
12
52.2
0.0033 0.0002
2.5. - 5
9
30.4
7
30.4
8
34.8
7
30.4
7
30.4
6 – 7 8
34.8
7
30.4
5
21.7
5
21.7
4
17.4

14. 6MWT T0 T6 T12 T24 T36
P
T0-T12
P
T0-T24
Overall
median (m)
n° pts
197.0
23
360.2
23
381.3
23
331.0
21
328.0
21
<0.0001 <0.0001
Juveniles
Median (m)
n° pts
572.9
7
626.0
7
589.0
7
720.0
5
630.0
5
<0.0001 0.0002
Adults
Median (m)
n° pts
116.6
16
203.0
16
213.1
16
200.0
16
206-0
16
<0.0001 0.0002

15. T0 T6 T12 T24 T36
P
T0-T12
P
T0-T24
Pts with
ventilatory
support
13 11 11 11 11
Hours/day 14 12 8 8 8
pCO2 *
(mmHg)
44.0 40.0 40.4 44-0 40-8 0.1127 0.0189
* median

16. Risposta del dolore alla TES
(29 pazienti: 7 ppediatrici, 22 adulti)
SI NO P
cefalea % %
T0 8 27.6 21 72.4
0.0122
T12 2 6.9 27 93.1
Dolore
muscolare
T0 11 37.9 18 62.1
0.0020
T12 3 10.3 26 89.7

17. T 0 T 36
DEXA
BMD
Osteoporosi 1 (Z score: -4) 1
Normali 8 (Z score: -0.2 – 0.1) 8
Scoliosi Severa 1
Moderata 2
Lieve 4
Normali 2
Iperlordosi Severa 1
Moderata 4
Deambulazione alterata 3
Bembi et al. Unpublished data.

18. Enzyme replacement therapy in juvenile glycogenosis
type II: a longitudinal study
Laura Deroma, Mattia Guerra, Annalisa Sechi, Giovanni Ciana,
Giorgia Cisilino, Andrea Dardis, Bruno Bembi
European Journal of Pediatrics
June 2014, Volume 173, Issue 6, pp 805-813

19. Characteristics of the study patients at therapy start (1/2)
CK: creatine kinase

20. Characteristics of the study patients at therapy start (2/2)
a: Invasive ventilation

22. Muscle enzymes levels from baseline (therapy start) to the end of follow-up. CK creatine phosphokinase,
LDH lactate dehydrogenase, AST aspartate phosphatase, ALT alanine aminotransferase

23. Six-minute walk test (6MWT) Z score from
baseline (therapy start) to the end of follow-up
Forced vital capacity (FVC) from baseline
(therapy start) to the end of follow-up. FVC
values are expressed as percentage pradicted
for height, age and gender using standard
reference values

24. New motor outcome function measures in evaluation of late-onset
Pompe disease before and after enzyme replacement therapy.
Angelini C1, Semplicini C, Ravaglia S, Moggio M, Comi GP, Musumeci O, Pegoraro E, Tonin
P, Filosto M, Servidei S, Morandi L, Crescimanno G, Marrosu G, Siciliano G, Mongini T,
Toscano A; Italian Group on GSDII.
Muscle Nerve. 2012 Jun;45(6):831-4
RESULTS:
At baseline, the GSGC (Gait, Stairs, Gower, Chair) score correlated with both WGM (P <
0.001, n = 33) and 6MWT (P < 0.001, n = 26). After 1 year of ERT, we observed a significant
change in gait, stairs and chair performance on the GSGC scale. The 6MWT significantly
increased from 319 to 371 meters in 32 patients, and the WGM score was reduced.
CONCLUSIONS:
GSGC is a group of functional tests that requires only a few minutes to perform, therefore, this
score might be a good indicator to be used in future studies

25. Observational clinical study in juvenile-adult glycogenosis type
2 patients undergoing enzyme replacement therapy for up to 4
years.
Angelini C1, Semplicini C, Ravaglia S, Bembi B, Servidei S, Pegoraro E, Moggio M,
Filosto M, Sette E, Crescimanno G, Tonin P, Parini R, Morandi L, Marrosu G, Greco G,
Musumeci O, Di Iorio G, Siciliano G, Donati MA, Carubbi F, Ermani M, Mongini T,
Toscano A; Italian GSDII Group
J Neurol. 2012 May;259(5):952-8
Causistry: 33 males and 41 females (M:F = 0.8:1
mean age first symptoms 28.3 yrs (2-55); mean age study entry 43 yrs (7-72 )
7 wheelchair bound, 27 ventilation support
Clinical assessment included: 6MWT, FVC, Walton and Gardner-Medwin score, the
number of hours of ventilation, BMI, echocardiography and CK.
After treatment:
• increase 6MWT in 48/58 (83%), mean increase of 63 m After treatment in
• improved or unchanged FVC in 45/69 (65%).
• reduced ventilatory support from 15.6 to 12.
• 6 patients stopped mechanical ventilation and two others started it.

26. FBL: born 04.1993
Jan 2005 March 2007 July 2007

27. FBL: born 04.1993
May 2006 May 2007

28. Giovanni Ciana
Laura Deroma
Annalisa Sechi
Rosi Da Riol
Daniela Macor
Katja Bianchi
Giulia Liva
Serena Valent
Andrea Dardis
Stefania Zampieri
Silvia Cattarossi
Irene Zanin
Erika Malini
Milena Romanello
Annalisa Pianta
Marco Confalonieri
Federica Edith Pisa
Regional Coordinator Centre for Rare Disorders,
University Hospital of Udine
Pulmonary Unit, University Hospital of Trieste
Inst. of Hygiene and Epidemiology, University
Hospital of Udine