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
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