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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.

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Presentation on theme: "ERT IN JUVENILE AND ADULT GLYCOGENOSIS TYPE 2 Bruno Bembi – Giovanni Ciana – Andrea Dardis Unità di Malattie Metaboliche-Laboratorio di Malattie Rare Istituto."— Presentation transcript:

1 ERT IN JUVENILE AND ADULT GLYCOGENOSIS TYPE 2 Bruno Bembi – Giovanni Ciana – Andrea Dardis Unità di Malattie Metaboliche-Laboratorio di Malattie Rare Istituto per lInfanzia Burlo Garofolo Trieste - Italy

2 Glycogenosis type II, Pompe disease or acid maltase deficiency Autosomal recessive lysosomal storage Autosomal recessive lysosomal storage disease disease Deficit of a-glucosidase or acid maltase Deficit of a-glucosidase or acid maltase Glycogen accumulation within the lysosomes Glycogen accumulation within the lysosomes leads to enlargement of cardiac and leads to enlargement of cardiac and skeletal muscle skeletal muscle

3 Glycogenosis type II Phenotypic continuum Rapidly progressive muscle weaknessRapidly progressive muscle weakness Cardiomegaly and cardiomyopathyCardiomegaly and cardiomyopathy Moderate hepatomegalyModerate hepatomegaly MacroglossiaMacroglossia Feeding difcultiesFeeding difculties Frequent respiratory infectionsFrequent respiratory infections Respiratory distressRespiratory distress Delayed motor milestonesDelayed motor milestones Markedly elevated CKMarkedly elevated CK Rapidly progressive disease courseRapidly progressive disease course no GAA activityno GAA activity Progressive muscular weaknessProgressive muscular weakness No cardiac involvementNo cardiac involvement Swallowing difcultySwallowing difculty Frequent respiratory infectionsFrequent respiratory infections Respiratory distressRespiratory distress Exercise intoleranceExercise intolerance Elevated CKElevated CK Moderate hepatomegalyModerate hepatomegaly Residual GAA activityResidual GAA activity Infantile onset Late onset

4 Molecular diagnosis Genomic DNA amplification Screening frequent mutations Screening frequent mutations DHPLC DHPLC Direct sequencing Direct sequencing RT-PCR analysis

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

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

7 Pt# (sex) (sex)Age(years) First symptoms noted Mobility status % enzyme activity Respiratoryfollow-up onsetDiagnosis At diagnosis Follow-up 1(F)1314 Elevated CK, AST, ALT Lower limb weakness, Fatigue unrestricted With help 18(M) Reduction of pulmonary function 2 (F) (F)22 Elevated CK, AST, ALT unrestricted unrestricte d NANormal 3(F)3031 Elevated CK, Fatigue Generalized weakness unrestricted With walker or wheelchair 4.3(L) Respiratory distress 4(M)1827 Elevated CK, AST, ALT Generalized weakness unrestricted With help 10 (M) (M) non invasive ventilation 5(F)3052 Difficulty in walking up steps Fatigueunrestricted With help absent Supplemental oxygen 6(M)2246 Generalized weakness Fatigueunrestricted With help 0.1 (L) (L) Reduction of pulmonary function 7(M)3838 Generalized weakness Fatigueunrestricted With difficulty 8(L) Reduction of pulmonary function 8 (M) (M)12 Elevated CK, AST, ALT Muscular weakness Impaired ambulation With wheelchair 3.7 (M) (M) non invasive ventilation 9(M)110 Elevated CK, AST, ALT unrestricted unrestricte d 0.02 (M) (M)Normal Late onset c T>G/ c.2237G>A genotype: clinical aspects

8 Enzyme Replacement Therapy

9 Myozyme dosage: 20 mg/kg/every two weeks Treatment period: 12 to 24 months Juvenile forms: 7 (4 male, 3 female, age yrs) Adult forms: 6 (3 male, 3 female; age 27-54)

10 Clinical symptoms JuvenilesAdults Tracheotomy1/72/6 Assisted ventilation2/74/6 Severe hypotonia2/75/6 Wheelchair1/72/6 Reduced/impaired motility4/76/6 Lordosis-scoliosis3/75/6 Muscle pain3/72/6 Headache2/76/6 Residual enzyme activity: %

11 Efficacy evaluation: clinical parameters JuvenilesAdults T0T > 12T0T > 12 tracheotomy1-2- Ventilatory support 2144 Reduced time PCO 2 > 40 mmHg 5264 Respiratory parameters

12 Efficacy evaluation: clinical parameters JuvenilesAdults T 12 –24 Muscular stenghtImproved: 7/7Improved: 6/6 FatigueReduced: 4/4Reduced: 5/6 MobilityImproved: 4/4Improved: 6/6 Muscle pain0/31/6 Headache0/21/6 No need of life-saving procedures

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14 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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18 Efficacia terapia: Wilks' Lambda F test p= Durata malattia: Wilks' Lambda F test p= RELAZIONE TRA INCREMENTO DEL 6 MINUTES WALKING TEST E DURATA DELLA MALATTIA A T0

19 RELAZIONE TRA INCREMENTO DEL 6mwt E SUO COMPLETAMENTO A T0 Efficacia terapia: p= Influenza del completamento a T0: p= (Wilks' Lambda F test)

20 presenteassente p (two sided exact binomial test ) Cefalea N%N% T T Dolore muscolare T T EFFICACIA DELLA ERT SULLA SINTOMATOLOGIA DOLOROSA (29 pazienti: 7 in età pediatrica, 22 adulti)

21 N pazienti Incremento medio95%CIrangep PCO2 T0 - T T6 – T T0 - T VC T0 – T T6 - T TO - T FEV 1 T0 – T T6 – T T0 – T VARIAZIONI MEDIE DEI PARAMETRI RESPIRATORI, A 6 E 12 MESI

22 OPEN PROBLEMS IN PRE-ADOLESCENT SEVERE JUVENILE PATIENTS

23 IMAGING

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25 FBL: born May 2006 May 2007

26 FBL: born Jan 2005 March 2007 July 2007

27 Coordinamento Regionale Malattie Rare, AOU- Udine Unità di Malattie Metaboliche IRCCS Burlo Garofolo Giovanni Ciana Andrea Dardis Roberta Cariati Riccardo Addobbati, Marco Nevyjel Silvia Dominissini Stefania Zampieri Maria Gabriela Pittis Unità di Pneumologia, Ospedale di Cattinara - Trieste Marco Confalonieri Maja Demsar Metka Kodric Rossana DellaPorta Project supported Agenzia Ialiana del Farmaco and Genzyme Co. All patients and familiesAll patients and families AIGAIG


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