A CLOSER LOOK AT HURLER SYNDROME

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2 A CLOSER LOOK AT HURLER SYNDROME

3 What is Hurler Syndrme? Hurler Syndrme belngs t a grup f inherited metablic strage disrders in which a persn cannt break dwn chains f sugar mlecules called glycsaminglycan. These cmplex sugars are necessary fr the bdy t build bnes and tissues. In Hurler syndrme, knwn as Mucplysaccharidsis r MPS, critical bdy enzymes (alpha-l-idurnidase) is missing r deficient. Withut this enzyme, the big mlecules build up and prgressively damage parts f the bdy. It is als knwn as Mucplysaccharidsis type I r MPS I as well as Gargylism.

4 Types f Hurler Syndrme? Hurler syndrme, als knwn as Mucplysaccharidsis type I (MPS I). MPS I is divided int three subtypes based n severity f symptms. MPS I Or Hurler Syndrme MPS I-S Or Scheie Syndrme MPS I H-S Or Hurler- Scheie Syndrme The mst severe f the MPS I subtypes. Is the less severe versin f Hurler Syndrme. It is a cnditin characterized by crneal cluding, facial dysmrphism and nrmal lifespan. It is als knwn as "Mucplysaccharidsis type I H-S. It is a cutaneus cnditin, als characterized by mild mental retardatin and crneal cluding.

5 What causes Hurler Syndrme? Peple with Hurler Syndrme usually have a deficiency in the enzyme alpha-l idurnidase, which helps break dwn lng chains f sugar mlecules called glycsaminglycans and the deficient f this enzyme results in affecting varius rgans and tissues in the bdy. Withut the enzyme, glycsaminglycans build up and damage rgans. The absence f alpha L-idurnidase wuld cause a buildup f heparin sulfate and dermatan sulfate causing damage t the rgans, including the heart. Symptms can range frm mild t severe.

6 Epidemilgy f Hurler Syndrme Internatinal Mucplysaccharidsis type I (MPS I) has an estimated incidence f 1 case per 100,000 live births. Mrtality/Mrbidity Lifespan in mucplysaccharidsis type I (MPS I) ranges frm death in early childhd in the mst severe frm t adulthd in the least severe variant. Race Mucplysaccharidsis type I (MPS I) is inherited in an autsmal recessive manner and affects bth sexes. Ref:

7 Symptms f Hurler Syndrme Cmmn symptms f Hurler Syndrme include having a shrt stature mental retardatin difficulty in breathing crneal cluding chrnic runny nse The symptms wuld usually appear between 6 mnths t 2 years f age. Children affected with the cnditin usually live past the age f 5 but unfrtunately d nt survive beynd 10 years f age. It is usually marked by prgressive deteriratin. Enlargement f the liver and spleen are usually prevalent alng with dwarfism and characteristic facial features like shrt nse, flat face and large head. Develpmental delay is usually evident alngside mental retardatin. By age 4, children wuld already stp develping. Physical skills wuld als deterirate. Lss f hearing and enlargement f the tngue is pssible. Carpal tunnel syndrme and limited range f mvement in the jints are als highly likely. Children usually appear larger than nrmal at birth and may have inguinal r umbilical hernias. Height may increase faster in the first year but wuld stunt after reaching 3 years f age.

8 Symptms f Hurler Syndrme Height f children suffering frm Hurler Syndrme wuld usually reach arund 4 feet and the bdy trunk wuld appear shrt with the ribs becming wider and ar-shaped. Unique facial features wuld becme mre nticeable by 2 years f age. Feeding and bwel prblems may be experienced by children. Obstructive airway disease, respiratry tract infectins and cardiac prblems wuld usually be the cause f death by children affected with Hurler syndrme.

9 Hw is Hurler Syndrme diagnsed Hurler Syndrme can be diagnsed thrugh clinical examinatin and a series f tests. Urine tests are undertaken t check excess mucplysaccharides that may be excreted Bld tests and skin samples t check fr the presence f alpha-l idurnidase Genetic tests fr psitive gene mutatin Radigraphic examinatin t check fr damaged spine Electrcardigram r echcardigram t check heart functin and valve prblems Prenatal diagnsis thrugh amnicentesis and chrinic villus sampling wuld determine if a fetus carries a mutated gene, which causes Hurler syndrme

10 Treatment f Hurler Syndrme Enzyme replacement therapy is usually undertaken t prvide the alpha-l idurnidase, which the bdy lacks. This is dne thrugh medicatin like larnidase (Aldurazyme), which is cmmercially prepared by Genzyme. Larnidase has shwn t be effective in imprving prblems assciated with breathing, grwth, heart, bnes and jints. Hwever, enzyme replacement therapy is nt yet advised fr thse children wh have MPS I with mental retardatin like Scheie Syndrme and Hurler-Scheie Syndrme. Bne marrw transplantatin (BMT) and umbilical crd transplantatin (UCBT) are als used t treat MPS. Transplantatin f the bne marrw r the umbilical crd have shwn the capability t halt abnrmal physical features and neurlgic degeneratin. Gene therapy is still under research.

11 Crd Bld transplant fr treatment f Hurler Syndrme Haematpietic stem cell transplants have becme a valuable treatment fr Hurler Syndrme, as transplanted cells can generate new, healthy, enzyme prducing bld cells t replace the diseased cells. These dnr cells will deliver enzymes t all rgans, including the brain and can prevent disease prgressin. Crd bld has been prpsed as an alternative stem cell surce fr children with HS since it has been suggested that crd bld may increase their levels f lyssmal alpha-l-idurnidase, which cnsequently may allw them t live lnger with fewer cmplicatins. REASONS TO CHOOSE CORD BLOOD STEM CELLS A dctr might chse crd bld because f sme f the ways it differs frm marrw r peripheral bld. Mre tlerant matching: A clse match between the patient and the dnr r crd bld unit can imprve a patient's utcme after transplant. If yu have an uncmmn tissue type, yu may nt find a clsely matched adult dnr fr yu. Hwever, a crd bld unit may be the best ptin. Mre quickly available: Crd bld units are stred and ready t use. A crd bld unit can be selected and delivered t the transplant center in less than tw weeks whereas it can take tw mnths r mre t find an unrelated marrw r peripheral bld dnr. Less GVHD: Graft-versus-hst disease (GVHD) is a cmmn cmplicatin after an allgeneic transplant (which uses cells unrelated dnr). GVHD can range frm mild t life-threatening. There is less chance f GVHD when the crd bld transplant is dne using cells frm a family member.

12 Case Studies Crd-Bld Transplants frm Unrelated Dnrs in Patients with Hurler's Syndrme Susan L. Staba et al; N Engl J Med 2004; 350: children (10 bys and 10 girls) received crd-bld transplants frm unrelated dnrs. Pst transplantatin, patients were evaluated every 6 t 12 mnths by multiple pediatric sub specialists in develpmental pediatrics, phthalmlgy, audilgy, cardilgy, pulmnlgy, and rthpedics. Eighty-five percent f the children survived with cmplete dnr chimerism and nrmal peripheralbld alpha-l-idurnidase activity. Haematpietic stem-cell transplantatin arrests the prgressin f Hurler's syndrme, averting death frm cardiac causes and liver disease, imprving grwth and develpment, and prlnging survival

13 Case Studies Hematpietic stem cell transplantatin imprves the high incidence f neutralizing all-antibdies bserved in Hurler s syndrme after pharmaclgical enzyme replacement therapy. Muhammad Ameer Saif et al; Haematlgica September : Develpment f an immunglbulin G enzyme-linked immunsrbent assay as well as in vitr catalytic enzyme inhibitin and cellular uptake inhibitin assays and quantified enzyme inhibitin by all-antibdies. 8 patients were examined fr the impact f these antibdies wh received enzyme therapy befre and during hematpietic stem cell transplantatin. High titer immune respnses were seen in patients fllwing expsure t alpha-l-idurnidase. Allgeneic haematpietic stem cell transplantatin was an effective and rapid immune tlerance inductin strategy.

14 Crd Bld Transplantatin Step 1 Cllectin, strage and crypreservatin f umbilical crd bld Step 2 Day -30 t -11: HLA typing and dnr/recipient matching Step 3 Day -10: Patient admissin and islatin in ICU rm Step 4 Day -8: Pre-transplantatin cnditining regimen fr 8-10 day befre transplantatin Step 5 Day 0: Umbilical crd bld transplantatin in patient Step 6 Day 1 t Day 25: Pst transplantatin fllw up and mnitring

15 Crd Bld Transplantatin STEP 1: COLLECTION OF UMBILICAL CORD BLOOD Umbilical crd bld is cllected by trained paramedic as per standard prcedure and transprted t the strage lcatin. One can als plan secnd child and stre umbilical crd bld fr the treatment f their diseased first child. Cllected crd bld sample is stred at GMP labratry fr future use. STEP 2: HLA TYPING Befre implantatin, HLA typing (Crss matching) is need t d fr checking dnr- recipient cmpatibility. Als attentin requires in the case f Bld Grups f bth dnr- recipient fr ABO incmpatibility. Assessment f medical histry and reprts. STEP 3: HOSPITALIZATION Patient is admitted t the hspital befre 8-10 days f transplantatin date. Patient is cmpletely islated frm the utside and keep in ICU unit t avid cntaminatin. Access is restricted t limited persnnel nly

16 Crd Bld Transplantatin STEP 4: PRE-OPERATIVE REGIMEN Preparative regimen is given t the patient t prepare fr implantatin. This includes medicatin, antibitics and chemtherapy t ablate the patient s immune system and avid GVHD after transplantatin. STEP 5: UMBILICAL CORD BLOOD TRANSPLANTATION Stred umbilical crd bld sample is prcured frm the lab befre transplantatin. Physician transplants the required quantity f umbilical crd bld cells intravenusly int the patients bdy. The intravenus part f the transplant takes apprximately 15 minutes. STEP 6: POST TRANSPLANTATION FOLLOW UP After transplantatin, patient will be under strict mnitring fr 4-5 weeks fr any side effects r cmplicatins. Haematlgical engraftments are checked using bld tests and analysis. It can takes mnths t recver full immune pwer fr patient after transplantatin.

17 Centers where UCB transplantatins are dne: AIIMS, New Delhi Apll Specialty Hspitals, Chennai Glbal Hspitals, Hyderabad Tata Memrial Hspital, Mumbai KDA Hspital, Mumbai Jaslk Hspital, Mumbai Christian Medical Cllege Hspital Sahyadri Speciality Hspital, Pune Ruby Hall Clinic, Pune

18 Muhammad Ameer Saif, Brian W. Bigger, Karen E Brkes, Jean Mercer,Karen L. Tylee, Heather J. Church, Denise K. Bnney, Simn Jnes, J. Ed Wraith,and Rbert F. Wynn Haematlgica September : Baehner F, Schmiedeskamp C, Krummenaver F, Miebach E, Baibui M. Cumulative incidence rate f mucplysaccharidses in Germany. J Inherit Metab Dis. 2005;28: Rubicek M, Gehler J, Spranger J. The clinical spectrum f alpha-l-idurnidase deficiency. Am J Med Genet. 1985;20: Meikle PJ, Ranieri E, Simnsen H, et al. Newbrn screening fr lyssmal strage disrders: clinical evaluatin f a tw-tier strategy. Pediatrics 2004;114(4):