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  • Gaucher disease in Romania – Baseline

    characteristics, specific diagnosis, treatment

    and outcome

    Cecilia Lazea1,2) , Simona Bucerzan1,2) , Camelia Alkhzouz1,2), Ioana Nascu1,3) , Anca Zimmermann4) , Radu Popp,5), Paula Grigorescu-Sido 1,2)

    1) Centrul Regional de Genetica Medicala - Spitalul Clinic de Urgenta pentru Copii, Cluj; 2) Disciplina Pediatrie I - UMF “Iuliu Hatieganu” Cluj; 3) Unitatea de Primire a Urgentelor - Spitalul Clinic de Urgenta pentru Copii, Cluj 4)) Department of Endocrinology and Metabolic Diseases, 1st Clinic of Internal Medicine, Yohannes Gutenberg

    University, Mainz, Germany 5) Catedra de Genetica, Departamentul de Stiinte Moleculare - UMF “Iuliu Hatieganu” Cluj

  • I. Lysosomal storage disease

    - Lysosomal storage disease ← Accumulation of glucocerebrosides in the lysosomes of monocyte-derived

    macrophages

    - more than 70 diseases described

    - incidence in the Caucasian population : 1/7500

  • Sphingolipidoses: Gaucher disease

    Fabry disease etc.

    Mucopolysaccharidosis

    Glycoproteinosis

    Mucolipidosis

    Glycogen storage disease type II (Pompe disease)

    Lysosomal disease

  • - enzima lizozomală

    (hidrolaza acidă –pH optim =5)

    gena - 1q

    β

    acida

    Gaucher disease

    Essential date

  • Glucocerebrosides accumulation Displaced nucleus

    Gaucher cell

  • Hematologic manifestations : - anemia

    - thrombocytopenia type 1

    Hepatosplenomegaly

    Bone involvement

    Neurological involvement: - acute……………..type 2

    - chronic…………...type 3

    Gaucher disease

    Clinical presentation (+/- severe)

    Monogenic disease, AR

  • 12-year-old male with

    Gaucher disease type I

  • 18-year-old female with Gaucher

    disease type 1

  • 3-year-old female with Gaucher disease type 3

  • Specific treatment in Gaucher

    disease Therapy to reduce glycosylceramides accumulation

    1. Enzyme replacement therapy

    2. Substrate reduction therapy

    3. Molecular chaperone therapy

    4. Gene therapy

  • Specific treatment in Gaucher

    disease

    USA Europe Romania

    • Imiglucerase - Cerezyme (Genzyme) 1994 1997 2002

    • Velaglucerase - Vepriv (Shire)* 2010 2010 -

    • Taliglucerase - Protalix (Pfizer) 2012

    * - approved in 2010 at the time of temporary reduction of Cerezyme's production

    capacity compared to world-wide requirement

    1. Enzyme replacement therapy (ERT)

    Obiectives: replacement of enzymes missing from lysosomes

  • 12 Ver 1 Jan 2010

    1880 1900 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010

    Gaucher and Cerezyme Time Line

    1882 – Philippe

    Gaucher describes

    a 32-year-old with

    enlarged spleen

    1985 – Beutler & Ginns

    identify acid

    β-glucocerebrosidase

    gene

    1955 – Lysosome

    discovered by de

    Duve

    1994 – Cerezyme® recombinant

    glucocerebrosidase approved

    in US; 1997 – Cerezyme

    approved in EU

    1965 – Roscoe Brady:

    glucocerebrosidase

    deficiency causes GD

    1991 – Ceredase®

    placental ERT

    approved in US

    and the EU

    1932 – Aghion

    identifies

    glucocrebrosidase

    accumulation as

    cause of GD 1983 – First patient with

    Gaucher treated with

    enzyme purified from

    human placentas

    2002 – Cerezyme

    real-world efficacy

    (1028 pts, 2-5 yrs) Weinreb Am J Med 2002

    2007/8 –

    Cerezyme efficacy

    in bone Charrow Clin Genet 2007;

    Wenstrup J Bone Miner Res

    2007;Sims Clin Genet 2008

    2008 – Cerezyme

    pediatric efficacy

    (887 pts, 8 yrs) Andersson Pediatrics 2008

    Treatment Basics

  • USA Europe Romania

    ● Miglustat (Zavesca)/Actelion Pharmaceuticals 2002 2003 -

    - Imino-N-alkylate sugars :

    - N-butyl-deoxynojirimycin – NB-DNJ

    - 3x100 mg/day, p.o.

    -results: - redused efficacy compared to ERT

    - long-term safety needed to be carefully evaluated

    - adverse effectes- diarrhea; tremor

    ● Eliglustat (Cerdelga)/Genzyme 08.2014 01.2015

    - “EDGE” study: - 19 countries (Romania);

    - 170 pacients (including 2 Romanian patients)

    2. Substrate reduction therapy

    The aim: reducing the biosynthesis of glycosphingolipids

    Specific treatment in Gaucher

    disease

  • Mechanism of Action = Substrate Reduction

    Substrate Reduction Therapy (SRT) restores the imbalance between production and removal of glucosylceramide

    Ceramide + Glucose

    Glucosylceramide

    Synthase

    Acid β-glucosidase

    deficient in

    Gaucher disease

    Eliglustat

    Glucosylceramide

    14

  • - Gene mutation → lysososmal enzyme configuration defects:

    - active sites involvement → enzyme inactivation (a)

    - respecting active sites → active enzyme (b)

    ● Chaperone: • pharmacological: - small molecule, ligand → protecting the

    degradation of lysosomal enzymes that have undergone configuration defect, but

    they are still active (b)

    - allows - correct configuration of enzymes

    - their traffic to lysosomes (where they dissociate from the enzyme:

    reversible binding)

    - cross the blood-brain barrier!

    * Under investigation

    • Chaperone therapy*

  • • Gene therapy*

    - aim: introduction of the GBA gene into:

    - hematopoietic stem cells

    - muscle cells “secretant”

    * Currently under investigation ≥ 1995

  • II. Gaucher disease in Romania.

    Results of The National Health Expertise

    Center for Lysosomal Diseases Cluj :

    - patients data

    - treatment

    - therapy results

  • A. Clinical data of Romanian

    patients with Gaucher disease

    (evaluated in our centre)

  • In Romania

    - specific diagnosis of lysosomal storage disease is available since 1997:

    - enzymatic diagnosis – for the most common 19

    forms of lysosomal storage disease

    - molecular diagnosis - Gaucher disease

    - Genetic Pathology Center Cluj

    (Prof. Dr. Paula Grigorescu-Sido)

    - Biochemistry Department U.M.F. Cluj

    (Conf.Dr.Cristina Drugan)

    * These include the 5 most common types of lysosomal storage diseases with specific treatment Fabry disease

    MPS type I; MPS type II

    Pompe disease

  • Gaucher disease

    79p.

    69,2%

    Other

    Sphingolipi

    doses 20p. 17,5%

    MPS 31p.

    20,3%

    MPS type

    II/III 3p.

    1,9%

    Pacients diagnosed with lysosomal storage disease in

    Center Cluj Napoca (n = 152) :

    120 (78,9%) treatable!!!!

    Type II - 16 p.

    type III B - 6 p.

    type I - 7 p. 31 p Type IVB - 1 p.

    Type VII - 1 p.

    Fabry disesae – 15 p.

    GM1gangliozidosis – 12 p.

    GM2 gangliozidosis – 2 p.

    Niemann-Pick dis. – 5 p.

    Metachromatic – 1 p.

    leukodystrophy

    Gaucher disease

    type 1 – 76 p.

    Type 3 – 3 p.

    75% Sphingolipidosis (114 p.)

    1,9%

    Gliogenosis type II

    Pompe disease 3p.

    79 p

    35

    0,6%

    α Manozidosis 1 p.

    Fabry

    13,15%

  • 79 pacients/62 families nonconsanguineous /30 counties+ Bucuresti

    1-6 pacients/county

    Type 1: 76 pacients

    Type 3: 3 pacients

    Reported

    to International

    Gaucher Registry

    Epidemiologic data of Romanian patients/2017.

    • Diagnosis

    Gaucher disease

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