Treatment of Inherited Metabolic Diseases

Robin Casey, MDRobin Casey, MD

Pediatric Resident TeachingPediatric Resident Teaching

12 May 201112 May 2011

Overview of Overview of InheritedInherited Metabolic Disease Metabolic Disease

over 700 separate IEM describedover 700 separate IEM described most present early:most present early:

in uteroin utero 8 % 8 %birth - 1 yrbirth - 1 yr 55 %55 %1 yr-puberty1 yr-puberty 32 %32 %adulthoodadulthood 5 %5 %

for many, for many, early detectionearly detection prior to irreversible pathology prior to irreversible pathology may permit interventionmay permit intervention with diet or medical therapy with diet or medical therapy to to prevent long-term death or disabilityprevent long-term death or disability

approaches to early detection: approaches to early detection: symptomatic presentation symptomatic presentation screeningscreening

IEM affect about about 1/1000 to 1/2000 personsIEM affect about about 1/1000 to 1/2000 persons

Untreated PhenylketonuriaUntreated Phenylketonuria

Signs / Symptoms Signs / Symptoms mental retardationmental retardation hypopigmentationhypopigmentation eczema-like rasheczema-like rash autistic-like autistic-like

behaviorbehavior autosomal recessiveautosomal recessive high bloodhigh blood

phenylalanine levelsphenylalanine levels

Metabolism of PhenylalanineMetabolism of Phenylalanine

PHE

Dietary Protein

Body Protein

Tyrosine

PPA

PLA PAA

Phenylactetyl- glutamine

BH4

qBH2

(PAH)6-pyruvoyl-

BH4

GTP

PHE levels in the Newborn with PKUPHE levels in the Newborn with PKU

PHE

Days of Age

1 2 3 4

NORMAL

RANGE

Screening Possible

Treatment of PKU Treatment of PKU Prevents Mental RetardationPrevents Mental RetardationScreeningScreening

screen all babies for screen all babies for increased increased phenylalanine in bloodphenylalanine in blood

Microbiological Microbiological Inhibition assay Inhibition assay (“Guthrie test)(“Guthrie test)

newer techniques ienewer techniques ieTandom Mass Tandom Mass

SpectrometrySpectrometry

TreatmentTreatment phenylalanine restricted

diet must meet all must meet all

nutritional needs not nutritional needs not just restrict PHEjust restrict PHE

use medical food use medical food (restricted in PHE) + (restricted in PHE) + normal low protein normal low protein content foods to content foods to provide the tolerated provide the tolerated amount of PHEamount of PHE

System for Newborn ScreeningSystem for Newborn Screening

all newborn infants are reachedall newborn infants are reached mechanisms exist for determine effectiveness of mechanisms exist for determine effectiveness of

screening under field conditions:screening under field conditions: (false + rate / false - rate /threshold levels) (false + rate / false - rate /threshold levels)

samples analyzed reliably and promptly and results samples analyzed reliably and promptly and results reported promptlyreported promptly

Resources for adequate follow-up (diagnosis & Resources for adequate follow-up (diagnosis & treatment)treatment)

Physician & parent knowledge of screening programPhysician & parent knowledge of screening program Positive cost / benefit ratio if possiblePositive cost / benefit ratio if possible

Approaches to Treatment Restriction / supplements / medications

PKU & other aminoacidopathies Urea cycle disorders Organic acidopathies (MMA,PA, IVA etc.)

Ensure nutrient availability Glycogen storage disorders B-oxidation disorders

Enhancement of organelle function mitochondrial disorders

Cell / organ replacement lysosomal storage disorders Fabry disease & cystinosis

Diet has two components:Diet has two components:

Must meet all nutritional needs + limit intake Must meet all nutritional needs + limit intake of restricted nutrients to amts sufficient for of restricted nutrients to amts sufficient for growthgrowth

Medical Formula

Contains all nutrientsexcept

those being restricted

Natural Foods

Contains some normal nutrients

and all those being restricted

Nutritional Treatment of PKUNutritional Treatment of PKU

+

Diet Therapy of PKUDiet Therapy of PKU

Low PHE Formula

Natural food with PHE

Total Nutrient Intake

PHE

level

Time On Diet

Disorders of Branched Chain Amino Disorders of Branched Chain Amino Acid Metabolism: Isovaleric AcidemiaAcid Metabolism: Isovaleric Acidemia

Isovaleryl-CoA Dehydrogenase

Deficiency

Treat by controlling intake of leucine to

meet essential needs for growth and

to provide all other nutrients in adequate

amounts

Case 1: Case 1: Positive Newborn Metabolic ScreenPositive Newborn Metabolic ScreenHistoryHistory: : NMS test result shows elevated Phenylalanine NMS test result shows elevated Phenylalanine

(0.75 umole/l; normal <0.125)(0.75 umole/l; normal <0.125) Term pregnancyTerm pregnancy

Normal P/L/DNormal P/L/D BWt 3.1 kg, BWt 3.1 kg, Normal neonatal courseNormal neonatal course

Questions:Questions:1.1. Describe briefly what your initial counselling to parents Describe briefly what your initial counselling to parents

would be.would be.2.2. What investigations would you under take to confirm What investigations would you under take to confirm

diagnosis?diagnosis?

Results of investigationsResults of investigations

ResultsResults Plasma PHE=1.2umole/l; Plasma PHE=1.2umole/l;

tyrosine = 0.05 umole/ltyrosine = 0.05 umole/l

Urine organic acids Urine organic acids increased PPA,PLA,PAAincreased PPA,PLA,PAA

QuestionsQuestions

1.1. What other tests need to What other tests need to be done to be sure this be done to be sure this baby needs diet baby needs diet treatment?treatment?

2.2. What is the basis of the What is the basis of the diet treatment?diet treatment?

PKU: Diagnostic work-up PKU: Diagnostic work-up

Confirm that PHE level is elevatedConfirm that PHE level is elevated Rule out biopterin deficiency disordersRule out biopterin deficiency disorders

Urine pterin levelsUrine pterin levels Dihydrobiopterin reductase activityDihydrobiopterin reductase activity Biopterin load test (optional)Biopterin load test (optional) If present start DOPA/carbiDOPA/5HTPIf present start DOPA/carbiDOPA/5HTP

If BH4 disorder not diagnsosed & PHE If BH4 disorder not diagnsosed & PHE above 0.4 mM/l, start low PHE dietabove 0.4 mM/l, start low PHE diet

Natural Foods

Contains some normal nutrients

and all those being restricted

Nutritional Treatment of PKUNutritional Treatment of PKU

Diet has two components:Diet has two components:

Must meet all nutritional needs + limit intake of Must meet all nutritional needs + limit intake of restricted nutrients to amts sufficient for growthrestricted nutrients to amts sufficient for growth

Medical Formula

Contains all nutrients

except those being restricted

+

Three Children with Three Children with Maternal PKU Maternal PKU

SyndromeSyndrome

Mother has untreated PKU during pregnancy(ies)

Children are usually not PKU

syndrome

IUGR

post natal FTT

Microcephaly

Developmental delay

Cardiac malformations

Case 2: Acute Case 2: Acute Neonatal Presentation Presentation

5 d.o. male5 d.o. male Well for 72 hrs then Well for 72 hrs then

became lethargic, fed became lethargic, fed poorly, began vomiting & poorly, began vomiting & developed alternating developed alternating flaccidity & opisthotonic flaccidity & opisthotonic posturing.posturing.

Became comatoseBecame comatose Developed hyperpnea Developed hyperpnea

and respiratoy alkalosis and respiratoy alkalosis progressing to respiratory progressing to respiratory failurefailure

O/E: hepatomegaly, O/E: hepatomegaly, hypothermiahypothermia

What tests would you do?What tests would you do?

Case 2: Acute Case 2: Acute Neonatal Presentation Presentation

5 d.o. male5 d.o. male Well for 72 hrs then became Well for 72 hrs then became

lethargic, fed poorly, began lethargic, fed poorly, began vomiting & developed vomiting & developed alternating flaccidity & alternating flaccidity & opisthotonic posturing.opisthotonic posturing.

Became comatoseBecame comatose Developed hyperpnea and Developed hyperpnea and

respiratoy alkalosis respiratoy alkalosis progressing to respiratory progressing to respiratory failurefailure

O/E: hepatomegaly, O/E: hepatomegaly, hypothermiahypothermia

Test ResultsTest Resultso NormalNormal: CBC, ‘lytes’, bld : CBC, ‘lytes’, bld

glucose, lactic acid, glucose, lactic acid, urinalysisurinalysis

o LowLow: urea, arginine, : urea, arginine, ornithine, ornithine,

o HighHigh: NH3 (350 uM/l), : NH3 (350 uM/l), citrulline (1.21 mM/l), citrulline (1.21 mM/l), glutamine, asparagineglutamine, asparagine

? Diagnosis? Diagnosis

Detoxification of NH3 by Urea Cycle Benzoate Dietary Protein Gut Bacteria Endogenous Protein Catab Buphenyl

NH4 PAA

NH4 + CO2 GLN

Carbamoyl Phosphate GluA PhAcGluNH2

Hippuric Acid

Ornithine Citrulline

Aspartate

Urea

Arginine Argininosuccinic Acid

Fumarate

Arginine

(CPS)

(OTC)

(ASAS)

(ASAL)

(Arginase)

Approaches to Therapy of Urea Cycle Approaches to Therapy of Urea Cycle DisordersDisorders

Acute MgmtAcute Mgmt(based on NH3 level)(based on NH3 level)

NPONPO DialysisDialysis ( prefer. ( prefer.

Hemodialysis)Hemodialysis) IVIV: CHO (6–8 mg : CHO (6–8 mg

Glc/kg/min)Glc/kg/min) Lipid (3 gm / kg)Lipid (3 gm / kg)

Alternate Pathway Alternate Pathway TherapyTherapy

Oral (Phenylbutyrate + AA)Oral (Phenylbutyrate + AA) IV (Phenylacetate + IV (Phenylacetate +

benzoate + L-argininebenzoate + L-arginine

Chronic MgmtChronic Mgmt Low protein dietLow protein diet

––1.0 to 1.5 gm/kg/d1.0 to 1.5 gm/kg/d-Cyclinex (ess. AA’s)-Cyclinex (ess. AA’s) (up to 50 % of prot)(up to 50 % of prot)

PhenylbutyratePhenylbutyrate (Buphenyl) (Buphenyl) (450-650mg/kg/d)(450-650mg/kg/d)

Arg / ornith / citrullineArg / ornith / citrulline Regular monitoringRegular monitoring

Liver Transplantation

Organ Transplantation (to provide metabolic capability)

Liver Urea Cycle disorder Familial Hypercholesterolemia (LDL-cholesterol receptor deficiency) Tyrosinemia Glycogen Storage Disease (Type I) Primary hyperoxaluria *

Kidney Fabry Disease Cystinosis Primary hyperoxaluria *

Bone Marrow Various lysosomal storage diseases ie. Hurler syndrome (MPSI)

Cornea Cystinosis, Fabry disease

Liver Transplantation

For disorders where liver is the primary organ involved

“cure” means the transplant prevents the disease

process

4% of pediatric liver failure is of metabolic origin

Liver transplantation and UCD’s

Corrects protein tolerance… can enjoy normal diet

Eliminates hyperammonemic crises

Needs to be performed as early as possible to prevent irreversible brain damage

Other organ involvement ie. CNS

Maintainence of Euglycemia Maintainence of Euglycemia during Fed & Fasting Statesduring Fed & Fasting States

Maintenance of blood and tissue glucose levels Maintenance of blood and tissue glucose levels is critical for functionis critical for function

CNS function (except in the infant, CNS is CNS function (except in the infant, CNS is almost completely dependent on glucose from almost completely dependent on glucose from the blood for energythe blood for energy

other tissues also require glucose but can utilize other tissues also require glucose but can utilize other energy sources as well ie fatty acids and other energy sources as well ie fatty acids and amino acids, glycerol and lactateamino acids, glycerol and lactate

Requirements to Maintain Euglycemia Requirements to Maintain Euglycemia Under “Fasting” ConditionsUnder “Fasting” Conditions

Functioning hepatic gluconeogenic & Functioning hepatic gluconeogenic & glycogenolytic enzyme systemsglycogenolytic enzyme systems

adequate endogenous gluconeogenic substrates adequate endogenous gluconeogenic substrates (amino acids, glycerol, lactate)(amino acids, glycerol, lactate)

adequate B-oxidation of fatty acids to synthesize adequate B-oxidation of fatty acids to synthesize glucose & ketonesglucose & ketones

functional endocrine system to modulate & functional endocrine system to modulate & integrate the above system components integrate the above system components

Phases of Glucose HomeostasisPhases of Glucose Homeostasis

1.1.Glucose absorptive phaseGlucose absorptive phase: 3 - 4 hrs after : 3 - 4 hrs after glucose ingestion (high insulin)glucose ingestion (high insulin)

2.2.Post absorptive/early starvationPost absorptive/early starvation: 3-12 hrs: 3-12 hrs

glucose (from hepatic glycogen) to brain, RBC, glucose (from hepatic glycogen) to brain, RBC, renal medullarenal medulla

3.3. Early / Intermediate StarvationEarly / Intermediate Starvation: 14+ hrs: 14+ hrs

gluconeogenesis & (later) lipolysis gluconeogenesis & (later) lipolysis

Case 3: patient & liver biopsy

QuestionsQuestions

1.1. What types of disorders might cause this appearance?What types of disorders might cause this appearance?

2.2. What further historical information may be of help?What further historical information may be of help?

3.3. What further studies should you request from the What further studies should you request from the pathologist?pathologist?

QuestionsQuestions

1.1. What types of disorders might cause this appearance?What types of disorders might cause this appearance?• Glycogen storage disorders (types 1a & 1b, 3, 6)Glycogen storage disorders (types 1a & 1b, 3, 6)• Lysosmal storage disorders (Gaucher, Niemann-Pick, MPS, Lysosmal storage disorders (Gaucher, Niemann-Pick, MPS,

oligosaccharidoses oligosaccharidoses • B-oxidation disorders (MCAD, LCHAD, VLCADB-oxidation disorders (MCAD, LCHAD, VLCAD))

2.2. What further historical information may be of help?What further historical information may be of help?• Symptoms of hypoglycemia (relationship to fasting including timing)Symptoms of hypoglycemia (relationship to fasting including timing)• Mother indicates baby can only go about 2-4 hours without a “bottle”Mother indicates baby can only go about 2-4 hours without a “bottle”

3.3. What further studies should you request from the What further studies should you request from the pathologist?pathologist?

• PAS staining +/- pretreatment with diastasePAS staining +/- pretreatment with diastase• Electon microscopyElecton microscopy

GSD-0

GSD-IV

GSD-1a&b

GSD-V, GSD-VI, GSD-IX

GSD-II ( lysosomal)

GSD-III

GSD-VII

GSD-X, GSD-XII, GSD-XIII

GSD-XI (LDH)

LIVER

MUSCLE

Diagnostic testingDiagnostic testing

Fasting challenge +/- feeding challengesFasting challenge +/- feeding challenges Enzyme assays Enzyme assays

Need fresh liverNeed fresh liver Need to choose specific enzymes to target Need to choose specific enzymes to target

based on historybased on history Molecular testingMolecular testing

Now have bank of mutations but expensive Now have bank of mutations but expensive

Glycogen Storage Disease: Controlled FastGlycogen Storage Disease: Controlled Fast

Time After Feed (min)Time After Feed (min)

00 3030 6060 9090 120120 150150 180180

GlucoseGlucose

(mM)(mM)

4.54.5 4.64.6 4.24.2 4.04.0 4.04.0 3.83.8 2.12.1

LactateLactate

(mM)(mM)

1.21.2 1.61.6 1.81.8 1.71.7 1.81.8 2.12.1 5.65.6

GSD IA &IBGSD IA &IB

Clinical featuresClinical features early onset hypoglycemiaearly onset hypoglycemia lacticlactic acidosisacidosis hepatomegalyhepatomegaly Fanconi syndromeFanconi syndrome hyperuricemiahyperuricemia hyperlipidemiahyperlipidemia

DiagnosisDiagnosis controlled fast (test BS & LA)controlled fast (test BS & LA) enzyme (liver biopsy)enzyme (liver biopsy) DNA testingDNA testing

TherapyTherapy provide 5 - 10 mg provide 5 - 10 mg

glucose/kg/minglucose/kg/min continuous .nocturnal infusion continuous .nocturnal infusion

of CHO as polycose or formulaof CHO as polycose or formula frequent meals during daysfrequent meals during days corn starch days &/or nightscorn starch days &/or nights don’t over treat with CHOdon’t over treat with CHONeutropenia in Type IBNeutropenia in Type IB prophylactic antibioticsprophylactic antibiotics GCSFGCSFEmergency protocols for Emergency protocols for

illness, surgery etc.illness, surgery etc.

Case 4: 18 month boy with hepatomegaly and obtundation

History:History: The ER physician calls about an 18 month old boy who is admitted in The ER physician calls about an 18 month old boy who is admitted in

stuporous state following being found pale & sweaty and unarousable by stuporous state following being found pale & sweaty and unarousable by parentsparents

Had been ill for about 18 hours with refusal to eat anything other then a few Had been ill for about 18 hours with refusal to eat anything other then a few ice chipsice chips

Had a seizure in ambulance on way inHad a seizure in ambulance on way in

Initial studies:Initial studies: Blood sugar = 0.2 mM/l, NaBlood sugar = 0.2 mM/l, Na++=145, K=145, K++ =3.5, Cl =3.5, Cl-- =104, TCO=104, TCO2 2 = 10= 10 Urinalysis = NormalUrinalysis = Normal All other testing including lactate, NH4 & LFE’s normalAll other testing including lactate, NH4 & LFE’s normal

WHAT IS YOUR INITIAL ASSESSMENT? HOW SHOULD YOU PROCEED WHAT IS YOUR INITIAL ASSESSMENT? HOW SHOULD YOU PROCEED WITH HIS DIAGNOSTIC STUDIES & CARE?WITH HIS DIAGNOSTIC STUDIES & CARE?

Key observationsKey observations

Severe Severe hypoglycemiahypoglycemia with with hepatomegalyhepatomegaly and and no no ketonuria ketonuria on setting of on setting of history of prolonged fasting history of prolonged fasting

Needs urgent treatment of hypoglycemia Needs urgent treatment of hypoglycemia Route?Route? How much glucose?How much glucose?

? Significance of no ketones in urine? Significance of no ketones in urine ?diagnostic testing?diagnostic testing

Trifunctional protein

VLCAD,MCAD, SCAD

Diagnostic InvestigationsDiagnostic Investigations

Plasma acylcarnitnes suggest Medium Plasma acylcarnitnes suggest Medium Chain Dehydrogenase deficiency (MCAD)Chain Dehydrogenase deficiency (MCAD)

Plasma free carnitine levels low while Plasma free carnitine levels low while acylcarnitines highacylcarnitines high

1414C- palmitic acid oxidation in leucocutes C- palmitic acid oxidation in leucocutes quite reducedquite reduced

Molecular diagnosis indicates homozygosity Molecular diagnosis indicates homozygosity for the common caucasian mutation.for the common caucasian mutation.

MS/MS Analysis of plasma MS/MS Analysis of plasma acylcarnitines (?= MCAD)acylcarnitines (?= MCAD)

270 300 330 360 450 480 510 540

50

100

% Intensity C2

INTERNAL STANDARDS

C3C4

C8

C16

C18:1C16

C3

C2

C14:1

390 420

C8

C6

C10

C10:1

MS/MS PS 85

Phases of Glucose HomeostasisPhases of Glucose Homeostasis

1.1.Glucose absorptive phaseGlucose absorptive phase: 3 - 4 hrs after : 3 - 4 hrs after glucose ingestion (high insulin)glucose ingestion (high insulin)

2.2.Post absorptive/early starvationPost absorptive/early starvation: 3-12 hrs: 3-12 hrs

glucose (from glucose (from hepatic glycogen) to brain, RBC, glycogen) to brain, RBC, renal medullarenal medulla

3.3. Early / Intermediate StarvationEarly / Intermediate Starvation: 14+ hrs: 14+ hrs

gluconeogenesis & (gluconeogenesis & (later) lipolysislater) lipolysis

Treatment: MCADTreatment: MCAD

Avoid fasting Avoid fasting L-carnitine if free carnitine lowL-carnitine if free carnitine low Emergency protocol & letterEmergency protocol & letter

Sick day managementSick day management Admission to ER/hospital to maintain blood Admission to ER/hospital to maintain blood

glucose with IV infusion to prevent excessive glucose with IV infusion to prevent excessive lipolysis the would overload the B-oxidation lipolysis the would overload the B-oxidation pathwaypathway

Lysosomal Storage Diseases

Characterized by excessive accumulation of undigested large molecules in the lysosome

Caused by: Lack of a single or a group of lysosomal hydrolase

degradative enzymes in lysosme Inability to transport material out of lysosome into

cytoplasm

Due to genetic mutations affecting important proteins including enzymes or transport proteins

Salla Disease FibroblastsDistended Lysosomes

Oligosaccharide & Glycopeptidoses

Mannosidoses, fucosidosis, Schindlers, sialidoses, aspartylglycosaminuria

Multiple Enzyme DeficienciesI-cell & MLIII, multiple sulfatase

deficiency, galactosialidosisTransport Deficiencies

Cystinosis, Salla disease, ISSPeptidoses

Pycnodysostosis, infantile NCLF

40+ Lysosomal Storage Diseases Identified

Sphingolipidoses

Tay-Sach’s, Sandhoff, GM1 gangliosidosis, MLD,Krabbes, Fabry, Gaucher, Farber, Niemann-Pick

MucopolysaccharidosesHurler/ Hurler-Scheie/Scheie, Hunter, San Filippo, Morquio,Maroteau-Lamy, Sly

GlycogenosesPompe

Lipid Storage DiseasesWolman, cholesterol ester, NP”C”

LSD’s: Treatment Approaches

Alleviation of symptoms / palliative care

Drugs: Cystagon in cystinosis

Bone marrow transplant’n –MPS-I

Enzyme replacement therapy

Biosynthesis inhibitors

Chaparone Therapy

Gene therapy

Cystinosis

Inability to transport cysteine out of lysosome

short stature,renal failure, corneal clouding, hypothyroidism, mild dementia (late-onset)

Treatments: renal transplant Cystagon &

phosphocysteamine

LSD’s: Treatment Approaches

Alleviation of symptoms / palliative care

Drugs: Cystagon in cystinosis

Bone marrow transplant’n –MPS-I

Enzyme replacement therapy

Biosynthesis inhibitors

Chaparone Therapy

Gene therapy

MPS PatientsMPS Patients

MPS 1H MPS 1H/SMPS III MPS III

MPS II MPS IV MPS VI MPS VI

Distended Lysosomes in MPS DisordersDistended Lysosomes in MPS Disorders

MPS’s in extracellular connective tissueMPS’s in extracellular connective tissue

MPS IH (Hurler Syndrome)

Dysmorphism•Coarse – thick alae nasi, lips, ear lobes, tongue•Macrocephaly•Hypertrichosis •thatch-like scalp hair

Deficient a-L-Iduronidase enzyme activity

•4p16.3•Dermatan sulfate, Heparan sulfate in lysosomes & urine

Hurler syndrome

Hurler syndrome

MPS I H: Current Therapeutic MPS I H: Current Therapeutic InterventionsInterventions

SymptomaticSymptomatic

Developmental supportDevelopmental support Hearing: myringotomy Hearing: myringotomy

tubes, hearing aidstubes, hearing aids Pulmonary: CPAP, Pulmonary: CPAP,

tracheotomy/ventilatortracheotomy/ventilator VP shunt: hydrocephalusVP shunt: hydrocephalus Median nerve Median nerve

decompression decompression Spinal decompressionSpinal decompression Palliative carePalliative care

Intensive InterventionIntensive Intervention

BMT/ Human Stem Cell BMT/ Human Stem Cell TransplantationTransplantation

Corneal transplantsCorneal transplants

Orthopedic surgeryOrthopedic surgery

Enzyme Replacement Enzyme Replacement TherapyTherapy

BMT / HSCT TherapyBMT / HSCT Therapy Recommended for all patients with severe form Recommended for all patients with severe form

(MPS1H)(MPS1H) Needs to be done early – prior to 18 – 24 mos.Needs to be done early – prior to 18 – 24 mos. Not recommended for patient with significant CNS Not recommended for patient with significant CNS

involvement (too late) involvement (too late) Mortality: 10 – 25 % (graft loss / infection/ acute Mortality: 10 – 25 % (graft loss / infection/ acute

Graft vrs Host disease)Graft vrs Host disease) Needs “ matched donors” ? world-wide searchNeeds “ matched donors” ? world-wide search less effective in prevention of orthopedic or ocular less effective in prevention of orthopedic or ocular

problems problems

Physiological Basis of Physiological Basis of BMT / HSCT Therapy in MPS IBMT / HSCT Therapy in MPS I

MPSIMPSI GAG Excretion during GAG Excretion during

ERT + BMT/HSCTERT + BMT/HSCT

BMT /HSCT #1

BMT/HSCT #2

Start of ERTERT

Summary: Likely Use of ERT in Summary: Likely Use of ERT in Treatment of MPS ITreatment of MPS I

In severe MPS IIn severe MPS I BMT / HSCT recommended (< 2 years of age & no BMT / HSCT recommended (< 2 years of age & no

CNS problems)CNS problems) ERT may be helpful peri-transplantERT may be helpful peri-transplant

In moderate MPS I ( MPS I H/S)In moderate MPS I ( MPS I H/S) ERT appears to be of value but efficacy for all ERT appears to be of value but efficacy for all

problems uncertain (bones/dura/cornea)problems uncertain (bones/dura/cornea) In mild MPS I(MPS I S)In mild MPS I(MPS I S)

Use of BMT/HSCT &/or ERT not recommendedUse of BMT/HSCT &/or ERT not recommended May need surgical intervention (cornea/joint May need surgical intervention (cornea/joint

replacement etc) replacement etc)

MPS-I: Spinal Cord Compression MPS-I: Spinal Cord Compression SyndromeSyndrome

Also seen in MPS II,IV,VI & VIAlso seen in MPS II,IV,VI & VI Can involve:Can involve:

Bony abnormalitiesBony abnormalities Thickening of spinal ligaments &/or meningesThickening of spinal ligaments &/or meninges Clinical monitoring / MRIClinical monitoring / MRI

Classical treatment is spinal column decompression +/- sub-Classical treatment is spinal column decompression +/- sub-occipital craniectomyoccipital craniectomy

Operative / anesthetic riskOperative / anesthetic risk Risk of recurrenceRisk of recurrence

Clinical Trials with intrathecal ERT underwayClinical Trials with intrathecal ERT underway Spinal cord compressionSpinal cord compression Neurological deteriorationNeurological deterioration

Other LSD’s treatable with HSCT / BMT

X- linked adrenoleukodystrophy Krabbe disease

MPS VI ? MPS IV

Gaucher III, ? Niemann-Pick

LSD’s: Treatment Approaches

Alleviation of symptoms / palliative care

Drugs: Cystagon in cystinosis

Bone marrow transplant’n –MPS-I

Enzyme replacement therapy

Biosynthesis inhibitors

Chaparone Therapy

Gene therapy

LSD’s Treatable with ERT

o Gaucher Disease *o Fabry Disease *o Hurler/Hurler-Scheie Syndromes (MPSI)* o Pompe Disease *o Niemann-Pick :B”

o Hunter Syndrome (MPS II)*o Maroteaux-Lamy Syndrome (MPS VI)*o Wolman / CESDo Hypophosphatasia

* Currently in Calgary

Therapy of Gaucher’s disease with Enzyme Replacement Therapy

Recombinant human B- glucocerebosidase (now three products)

IV infusion biweekly (In hospital/home/ treatment)

Major impact on bone pain, well being, anemia, thrombocytopenia & / progression of cortical bone lesions

ERT: Gaucher Disease