ert in juvenile and adult glycogenosis type 2 bruno bembi – giovanni ciana – andrea dardis...
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ERT IN JUVENILE AND ADULT
GLYCOGENOSIS TYPE 2
Bruno Bembi – Giovanni Ciana – Andrea Dardis
Unità di Malattie Metaboliche-Laboratorio di Malattie Rare
Istituto per l’Infanzia “Burlo Garofolo”Trieste - Italy
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Glycogenosis type II, Pompe diseaseGlycogenosis type II, Pompe diseaseor acid maltase deficiencyor acid maltase deficiency
• Autosomal recessive lysosomal Autosomal recessive lysosomal storagestorage diseasedisease
• Deficit of a-glucosidase or acid Deficit of a-glucosidase or acid maltasemaltase
• Glycogen accumulation within the Glycogen accumulation within the lysosomeslysosomes leads to enlargement of cardiac andleads to enlargement of cardiac and skeletal muscleskeletal muscle
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Glycogenosis type IIGlycogenosis type IIPhenotypic continuumPhenotypic continuum
•Rapidly progressive muscle Rapidly progressive muscle
weakness weakness •Cardiomegaly and Cardiomegaly and
cardiomyopathy cardiomyopathy •Moderate hepatomegaly Moderate hepatomegaly •Macroglossia Macroglossia •Feeding difficulties Feeding difficulties •Frequent respiratory infectionsFrequent respiratory infections•Respiratory distressRespiratory distress•Delayed motor milestonesDelayed motor milestones•Markedly elevated CKMarkedly elevated CK•Rapidly progressive disease Rapidly progressive disease
coursecourse•no GAA activityno GAA activity
•Progressive muscular Progressive muscular
weakness weakness •No cardiac involvementNo cardiac involvement•Swallowing difficultySwallowing difficulty•Frequent respiratory Frequent respiratory
infectionsinfections•Respiratory distressRespiratory distress•Exercise intoleranceExercise intolerance•Elevated CKElevated CK•Moderate hepatomegalyModerate hepatomegaly•Residual GAA activityResidual GAA activity
Infantile onsetInfantile onset Late onsetLate onset
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Molecular diagnosisMolecular diagnosis
Genomic DNA amplificationGenomic DNA amplification
•Screening frequent Screening frequent mutationsmutations• DHPLCDHPLC• Direct sequencingDirect sequencing
RT-PCR analysisRT-PCR analysis
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Allele frequency in the Italian Allele frequency in the Italian infantile GSDII populationinfantile GSDII population
c.525delT(11.8%)
c.1064T>C(7.9%)
c.1655T>C(10.5%)
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c.-32-13T>G (42.3%)
c.2237G>A (10.3%)
Allele frequency in the Italian Allele frequency in the Italian late onset GSDII populationlate onset GSDII population
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Pt#Pt#
(sex)(sex)
AgeAge(years)(years)
First symptoms First symptoms notednoted
Mobility statusMobility status % % enzyme enzyme activityactivity
Respiratory Respiratory follow-upfollow-up
onsonsetet
DiagnoDiagnosissis
At At diagnosisdiagnosis
Follow-upFollow-up
11(F)(F)
1313 1414 Elevated CK, AST, Elevated CK, AST, ALTALT
Lower limb Lower limb weakness, Fatigueweakness, Fatigue
unrestricteunrestrictedd
With helpWith help 18 18 (M)(M)
Reduction of Reduction of pulmonary pulmonary functionfunction
22 (F)(F)
22 22 Elevated CK, AST, Elevated CK, AST, ALTALT
unrestricteunrestrictedd
unrestrictunrestricteded
NANA NormalNormal
33(F)(F)
3030 3131 Elevated CK, FatigueElevated CK, FatigueGeneralized Generalized weaknessweakness
unrestricteunrestrictedd
With With walker or walker or wheelchaiwheelchai
rr
4.3 4.3 (L)(L)
Respiratory Respiratory distressdistress
4 4 (M)(M)
1818 2727 Elevated CK, AST, Elevated CK, AST, ALTALT
Generalized Generalized weaknessweakness
unrestricteunrestrictedd
With helpWith help 1010 (M)(M)
non invasive non invasive ventilationventilation
55(F)(F)
3030 5252 Difficulty in walking Difficulty in walking up stepsup stepsFatigueFatigue
unrestricteunrestrictedd
With helpWith help absentabsent SupplementaSupplemental oxygenl oxygen
6 6 (M)(M)
2222 4646 Generalized Generalized weaknessweaknessFatigueFatigue
unrestricteunrestrictedd
With helpWith help 0.10.1 (L)(L)
Reduction of Reduction of pulmonary pulmonary functionfunction
77(M)(M)
3838 3838 Generalized Generalized weaknessweaknessFatigueFatigue
unrestricteunrestrictedd
With With difficultydifficulty
8 8 (L)(L)
Reduction of Reduction of pulmonary pulmonary functionfunction
88 (M)(M)
11 22 Elevated CK, AST, Elevated CK, AST, ALTALT
Muscular weaknessMuscular weakness
Impaired Impaired ambulatioambulatio
nn
With With wheelchaiwheelchai
rr
3.73.7 (M)(M)
non invasive non invasive ventilationventilation
99(M)(M)
11 1010 Elevated CK, AST, Elevated CK, AST, ALTALT
unrestricteunrestrictedd
unrestrictunrestricteded
0.020.02 (M)(M)
NormalNormal
Late onset c.-32-13T>G/ c.2237G>A genotype: Late onset c.-32-13T>G/ c.2237G>A genotype: clinical aspects clinical aspects
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Enzyme Replacement Therapy
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Myozyme dosage:20 mg/kg/every two weeks
Treatment period:12 to 24 months
•Juvenile forms: 7 (4 male, 3 female, age 12- 18 yrs)
•Adult forms: 6 (3 male, 3 female; age 27-54)
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Clinical symptoms
Juveniles
Adults
Tracheotomy 1/7 2/6
Assisted ventilation 2/7 4/6
Severe hypotonia 2/7 5/6
Wheelchair 1/7 2/6
Reduced/impaired motility
4/7 6/6
Lordosis-scoliosis 3/7 5/6
Muscle pain 3/7 2/6
Headache 2/7 6/6Residual enzyme activity: 2.8-10%
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Efficacy evaluation: clinical parameters
Juveniles
Adults
T0 T > 12 T0 T > 12
tracheotomy
1 - 2 -
Ventilatory support
2 1 4 4Reduced
time
PCO2 > 40 mmHg
5 2 6 4
Respiratory parameters
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Efficacy evaluation: clinical parameters
Juveniles Adults
T 12 –24 T 12 –24
Muscular stenght
Improved: 7/7 Improved: 6/6
Fatigue Reduced: 4/4 Reduced: 5/6
Mobility Improved: 4/4 Improved: 6/6
Muscle pain 0/3 1/6
Headache 0/2 1/6
No need of life-saving procedures
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6 Minute Wolking Test
0
100
200
300
400
500
600
700
800
900
t 0 t 3 t 6 t 9 t 12 t18
flb
apb
depf
dond
pm
pal
gn
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Efficacy evaluation: laboratory and instrumental parameters
• CK, LDH, AST, ALT modifications
• Plasmatic creatinine
• Urinary oligosaccharides
• Muscular biopsy: histochemical and EM variations
• Imaging: muscular MNR
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CPK
0
200
400
600
800
1000
1200
1400
t 0 t 3 t 6 t 9 t 12 t 18
flb
apb
depf
dond
pm
pal
gn
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LDH
400
500
600
700
800
900
1000
1100
1200
1300
1400
t 0 t 3 t 6 t 9 t 12 t18
flb
apb
depf
dond
pm
pal
gn
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ALT
0
50
100
150
200
250
300
350
t 0 t 3 t 6 t 9 t 12 t 18
flb
apb
depf
dond
pm
pal
gn
AST
0
50
100
150
200
250
300
t 0 t 3 t 6 t 9 t 12 t18
flb
apb
depf
dond
pm
pal
gn
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Efficacia terapia: Wilks' Lambda F test p= 0.0021
Durata malattia: Wilks' Lambda F test p= 0.7605
RELAZIONE TRA INCREMENTO DEL 6 MINUTES WALKING TEST E DURATA DELLA MALATTIA A T0
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RELAZIONE TRA INCREMENTO DEL 6mwt E SUO COMPLETAMENTO A T0
Efficacia terapia: p=0.0016
Influenza del completamento a T0: p= 0.4769
(Wilks' Lambda F test)
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presente assente
p (two sided exact
binomial test )
Cefalea N % N %
T0 8 27.6 21 72.40.0122
T12 2 6.9 27 93.1
Dolore muscolare
T0 11 37.9 18 62.10.0020
T12 3 10.3 26 89.7
EFFICACIA DELLA ERT SULLA SINTOMATOLOGIA DOLOROSA (29 pazienti: 7 in età pediatrica, 22 adulti)
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N pazienti
Incremento medio 95%CI range p
PCO2
T0 - T6 22 -2.5 -5.4 - 0.4 -19.6 - 7.0 0.2863
T6 – T12 23 -3.2 -5.5 -0.9 -15.6 - 9.0 0.0043
T0 - T12 25 -5.1 -8.7 -1.5 -28.5 - 3.9 0.0347
VC
T0 – T6 28 0.4 -3.5 - 4.4 -36.0 - 28 0.1516
T6 - T12 28 0.7 -1.3 - 2.8 -11.0 - 13 0.8318
TO - T12 29 1.1 -3.2 - 5.3 -38.5 - 27 0.7011
FEV 1
T0 – T6 20 0.23 0.07 - 0.37 -0.27 - 1.22 0.0044
T6 – T12 20 0.05 -0.05 - 0.15 -0.48 - 0.44 0.3593
T0 – T12 27 0.16 0.05 - 0.27 -0.33 - 0.72 0.0755
VARIAZIONI MEDIE DEI PARAMETRI RESPIRATORI, A 6 E 12 MESI
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OPEN PROBLEMS IN PRE-ADOLESCENT SEVERE JUVENILE PATIENTS
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IMAGING
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IMAGING
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FBL: born 04.1993
May 2006May 2007
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FBL: born 04.1993
Jan 2005 March 2007 July 2007
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Coordinamento Regionale Malattie Rare, AOU-UdineUnità di Malattie MetabolicheIRCCS Burlo Garofolo
Giovanni CianaAndrea DardisRoberta CariatiRiccardo Addobbati,Marco NevyjelSilvia DominissiniStefania Zampieri
Maria Gabriela Pittis
Unità di Pneumologia, Ospedale di Cattinara - Trieste
Marco ConfalonieriMaja DemsarMetka KodricRossana DellaPorta
Project supported Agenzia Ialiana del Farmaco and Genzyme Co.
•All patients and familiesAll patients and families
•AIGAIG