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Treatment of Inherited Metabolic Diseases

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Title: Treatment of Inherited Metabolic Diseases Author: rcasey Last modified by: rcasey Created Date: 5/12/2011 4:48:03 AM Document presentation format – PowerPoint PPT presentation

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Title: Treatment of Inherited Metabolic Diseases


1
Treatment of Inherited Metabolic Diseases
  • Robin Casey, MD
  • Pediatric Resident Teaching
  • 12 May 2011

2
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3
Overview of Inherited Metabolic Disease
  • over 700 separate IEM described
  • most present early
  • in utero 8
  • birth - 1 yr 55
  • 1 yr-puberty 32
  • adulthood 5
  • for many, early detection prior to irreversible
    pathology
  • may permit intervention with diet or medical
    therapy
  • to prevent long-term death or disability
  • approaches to early detection
  • symptomatic presentation
  • screening
  • IEM affect about about 1/1000 to 1/2000 persons

4
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5
Untreated Phenylketonuria
  • Signs / Symptoms
  • mental retardation
  • hypopigmentation
  • eczema-like rash
  • autistic-like behavior
  • autosomal recessive
  • high blood
  • phenylalanine levels

6
Metabolism of Phenylalanine
Dietary Protein
Body Protein
PHE
BH4
(PAH)
PPA
qBH2
6-pyruvoyl-BH4
Tyrosine
PAA
PLA
GTP
Phenylactetyl- glutamine
7
PHE levels in the Newborn with PKU
PHE
Screening Possible
NORMAL RANGE
1
2
3
4
Days of Age
8
Treatment of PKU Prevents Mental Retardation
  • Screening
  • screen all babies for increased phenylalanine in
    blood
  • Microbiological Inhibition assay (Guthrie test)
  • newer techniques ie Tandom Mass Spectrometry
  • Treatment
  • phenylalanine restricted diet
  • must meet all nutritional needs not just restrict
    PHE
  • use medical food (restricted in PHE) normal low
    protein content foods to provide the tolerated
    amount of PHE

9
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10
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11
System for Newborn Screening
  • all newborn infants are reached
  • mechanisms exist for determine effectiveness of
    screening under field conditions
  • (false rate / false - rate /threshold
    levels)
  • samples analyzed reliably and promptly and
    results reported promptly
  • Resources for adequate follow-up (diagnosis
    treatment)
  • Physician parent knowledge of screening program
  • Positive cost / benefit ratio if possible

12
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

13
Nutritional Treatment of PKU
  • Diet has two components
  • Must meet all nutritional needs limit intake of
    restricted nutrients to amts sufficient for growth

Medical Formula Contains all nutrientsexcept
those being restricted
Natural Foods Contains some normal nutrients and
all those being restricted

14
Diet Therapy of PKU
PHE level
Low PHE Formula
Natural food with PHE
Total Nutrient Intake
Time On Diet
15
Disorders of Branched Chain Amino Acid
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
16
Case 1 Positive Newborn Metabolic Screen
  • History
  • NMS test result shows elevated Phenylalanine
    (0.75 umole/l normal lt0.125)
  • Term pregnancy
  • Normal P/L/D
  • BWt 3.1 kg,
  • Normal neonatal course
  • Questions
  • Describe briefly what your initial counselling to
    parents would be.
  • What investigations would you under take to
    confirm diagnosis?

17
Results of investigations
  • Results
  • Plasma PHE1.2umole/l tyrosine 0.05 umole/l
  • Urine organic acids increased PPA,PLA,PAA
  • Questions
  • What other tests need to be done to be sure this
    baby needs diet treatment?
  • 2. What is the basis of the diet treatment?

18
PKU Diagnostic work-up
  • Confirm that PHE level is elevated
  • Rule out biopterin deficiency disorders
  • Urine pterin levels
  • Dihydrobiopterin reductase activity
  • Biopterin load test (optional)
  • If present start DOPA/carbiDOPA/5HTP
  • If BH4 disorder not diagnsosed PHE above 0.4
    mM/l, start low PHE diet

19
Nutritional Treatment of PKU
  • Diet has two components
  • Must meet all nutritional needs limit intake of
    restricted nutrients to amts sufficient for growth

Natural Foods Contains some normal nutrients and
all those being restricted
Medical Formula Contains all nutrients except
those being restricted

20
Three Children with Maternal PKU Syndrome
Mother has untreated PKU during pregnancy(ies)
Children are usually not PKU
syndrome IUGR post natal FTT Microcephaly Develop
mental delay Cardiac malformations
21
Case 2 Acute Neonatal Presentation
  • 5 d.o. male
  • Well for 72 hrs then became lethargic, fed
    poorly, began vomiting developed alternating
    flaccidity opisthotonic posturing.
  • Became comatose
  • Developed hyperpnea and respiratoy alkalosis
    progressing to respiratory failure
  • O/E hepatomegaly, hypothermia
  • What tests would you do?

22
Case 2 Acute Neonatal Presentation
  • 5 d.o. male
  • Well for 72 hrs then became lethargic, fed
    poorly, began vomiting developed alternating
    flaccidity opisthotonic posturing.
  • Became comatose
  • Developed hyperpnea and respiratoy alkalosis
    progressing to respiratory failure
  • O/E hepatomegaly, hypothermia
  • Test Results
  • Normal CBC, lytes, bld glucose, lactic acid,
    urinalysis
  • Low urea, arginine, ornithine,
  • High NH3 (350 uM/l), citrulline (1.21 mM/l),
    glutamine, asparagine
  • ? Diagnosis

23
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)
(Arginase)
(ASAS)
(ASAL)
24
Approaches to Therapy of Urea Cycle Disorders
  • Acute Mgmt
  • (based on NH3 level)
  • NPO
  • Dialysis ( prefer. Hemodialysis)
  • IV CHO (68 mg Glc/kg/min)
  • Lipid (3 gm / kg)
  • Alternate Pathway Therapy
  • Oral (Phenylbutyrate AA)
  • IV (Phenylacetate benzoate L-arginine
  • Chronic Mgmt
  • Low protein diet
  • 1.0 to 1.5 gm/kg/d
  • -Cyclinex (ess. AAs)
  • (up to 50 of prot)
  • Phenylbutyrate (Buphenyl)
  • (450-650mg/kg/d)
  • Arg / ornith / citrulline
  • Regular monitoring
  • Liver Transplantation

25
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

26
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

27
Liver transplantation and UCDs
  • 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

28
Maintainence of Euglycemia during Fed Fasting
States
  • Maintenance of blood and tissue glucose levels is
    critical for function
  • CNS function (except in the infant, CNS is almost
    completely dependent on glucose from the blood
    for energy
  • other tissues also require glucose but can
    utilize other energy sources as well ie fatty
    acids and amino acids, glycerol and lactate

29
Requirements to Maintain Euglycemia Under
Fasting Conditions
  • Functioning hepatic gluconeogenic
    glycogenolytic enzyme systems
  • adequate endogenous gluconeogenic substrates
    (amino acids, glycerol, lactate)
  • adequate B-oxidation of fatty acids to synthesize
    glucose ketones
  • functional endocrine system to modulate
    integrate the above system components

30
Phases of Glucose Homeostasis
  • 1.Glucose absorptive phase 3 - 4 hrs after
    glucose ingestion (high insulin)
  • 2.Post absorptive/early starvation 3-12 hrs
  • glucose (from hepatic glycogen) to brain, RBC,
    renal medulla
  • 3. Early / Intermediate Starvation 14 hrs
  • gluconeogenesis (later) lipolysis

31
Case 3 patient liver biopsy
32
Questions
  • What types of disorders might cause this
    appearance?
  • What further historical information may be of
    help?
  • What further studies should you request from the
    pathologist?

33
Questions
  • What types of disorders might cause this
    appearance?
  • Glycogen storage disorders (types 1a 1b, 3, 6)
  • Lysosmal storage disorders (Gaucher,
    Niemann-Pick, MPS, oligosaccharidoses
  • B-oxidation disorders (MCAD, LCHAD, VLCAD)
  • What further historical information may be of
    help?
  • Symptoms of hypoglycemia (relationship to fasting
    including timing)
  • Mother indicates baby can only go about 2-4 hours
    without a bottle
  • What further studies should you request from the
    pathologist?
  • PAS staining /- pretreatment with diastase
  • Electon microscopy

34
GSD-IV
GSD-II ( lysosomal)
GSD-V, GSD-VI, GSD-IX
GSD-0
GSD-III
GSD-1ab
GSD-VII
GSD-X, GSD-XII, GSD-XIII
GSD-XI (LDH)
LIVER
MUSCLE
35
Diagnostic testing
  • Fasting challenge /- feeding challenges
  • Enzyme assays
  • Need fresh liver
  • Need to choose specific enzymes to target based
    on history
  • Molecular testing
  • Now have bank of mutations but expensive

36
Glycogen Storage Disease Controlled Fast
Time After Feed (min) Time After Feed (min) Time After Feed (min) Time After Feed (min) Time After Feed (min) Time After Feed (min) Time After Feed (min)
0 30 60 90 120 150 180
Glucose (mM) 4.5 4.6 4.2 4.0 4.0 3.8 2.1
Lactate (mM) 1.2 1.6 1.8 1.7 1.8 2.1 5.6
37
GSD IA IB
  • Clinical features
  • early onset hypoglycemia
  • lactic acidosis
  • hepatomegaly
  • Fanconi syndrome
  • hyperuricemia
  • hyperlipidemia
  • Diagnosis
  • controlled fast (test BS LA)
  • enzyme (liver biopsy)
  • DNA testing
  • Therapy
  • provide 5 - 10 mg glucose/kg/min
  • continuous .nocturnal infusion of CHO as polycose
    or formula
  • frequent meals during days
  • corn starch days /or nights
  • dont over treat with CHO
  • Neutropenia in Type IB
  • prophylactic antibiotics
  • GCSF
  • Emergency protocols for illness, surgery etc.

38
Case 4 18 month boy with hepatomegaly and
obtundation
  • History
  • The ER physician calls about an 18 month old boy
    who is admitted in stuporous state following
    being found pale sweaty and unarousable by
    parents
  • Had been ill for about 18 hours with refusal to
    eat anything other then a few ice chips
  • Had a seizure in ambulance on way in
  • Initial studies
  • Blood sugar 0.2 mM/l, Na145, K 3.5, Cl-
    104, TCO2 10
  • Urinalysis Normal
  • All other testing including lactate, NH4 LFEs
    normal
  • WHAT IS YOUR INITIAL ASSESSMENT? HOW SHOULD YOU
    PROCEED WITH HIS DIAGNOSTIC STUDIES CARE?

39
Key observations
  • Severe hypoglycemia with hepatomegaly and no
    ketonuria on setting of history of prolonged
    fasting
  • Needs urgent treatment of hypoglycemia
  • Route?
  • How much glucose?
  • ? Significance of no ketones in urine
  • ?diagnostic testing

40
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41
VLCAD,MCAD, SCAD
Trifunctional protein
42
Diagnostic Investigations
  • Plasma acylcarnitnes suggest Medium Chain
    Dehydrogenase deficiency (MCAD)
  • Plasma free carnitine levels low while
    acylcarnitines high
  • 14C- palmitic acid oxidation in leucocutes quite
    reduced
  • Molecular diagnosis indicates homozygosity for
    the common caucasian mutation.

43
MS/MS Analysis of plasma acylcarnitines (? MCAD)
44
Phases of Glucose Homeostasis
  • 1.Glucose absorptive phase 3 - 4 hrs after
    glucose ingestion (high insulin)
  • 2.Post absorptive/early starvation 3-12 hrs
  • glucose (from hepatic glycogen) to brain, RBC,
    renal medulla
  • 3. Early / Intermediate Starvation 14 hrs
  • gluconeogenesis (later) lipolysis

45
Treatment MCAD
  • Avoid fasting
  • L-carnitine if free carnitine low
  • Emergency protocol letter
  • Sick day management
  • Admission to ER/hospital to maintain blood
    glucose with IV infusion to prevent excessive
    lipolysis the would overload the B-oxidation
    pathway

46
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

47
Salla Disease FibroblastsDistended Lysosomes
48
40 Lysosomal Storage Diseases Identified
  • Oligosaccharide Glycopeptidoses
  • Mannosidoses, fucosidosis, Schindlers,
    sialidoses, aspartylglycosaminuria
  • Multiple Enzyme Deficiencies
  • I-cell MLIII, multiple sulfatase deficiency,
    galactosialidosis
  • Transport Deficiencies
  • Cystinosis, Salla disease, ISS
  • Peptidoses
  • Pycnodysostosis, infantile NCLF
  • Sphingolipidoses
  • Tay-Sachs, Sandhoff, GM1 gangliosidosis,
    MLD,Krabbes, Fabry, Gaucher, Farber, Niemann-Pick
  • Mucopolysaccharidoses
  • Hurler/ Hurler-Scheie/Scheie, Hunter, San
    Filippo, Morquio,
  • Maroteau-Lamy, Sly
  • Glycogenoses
  • Pompe
  • Lipid Storage Diseases
  • Wolman, cholesterol ester, NPC

49
LSDs Treatment Approaches
  • Alleviation of symptoms / palliative care
  • Drugs Cystagon in cystinosis
  • Bone marrow transplantn MPS-I
  • Enzyme replacement therapy
  • Biosynthesis inhibitors
  • Chaparone Therapy
  • Gene therapy

50
Cystinosis
  • Inability to transport cysteine out of lysosome
  • short stature,renal failure, corneal clouding,
    hypothyroidism, mild dementia (late-onset)
  • Treatments
  • renal transplant
  • Cystagon phosphocysteamine

51
LSDs Treatment Approaches
  • Enzyme replacement therapy
  • Biosynthesis inhibitors
  • Chaparone Therapy
  • Gene therapy
  • Alleviation of symptoms / palliative care
  • Drugs Cystagon in cystinosis
  • Bone marrow transplantn MPS-I

52
MPS Patients
MPS III
MPS III
MPS 1H
MPS 1H/S
MPS VI
MPS II
MPS VI
MPS IV
53
Distended Lysosomes in MPS Disorders
54
MPSs in extracellular connective tissue
55
  • 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
56
MPS I H Current Therapeutic Interventions
  • Symptomatic
  • Developmental support
  • Hearing myringotomy tubes, hearing aids
  • Pulmonary CPAP, tracheotomy/ventilator
  • VP shunt hydrocephalus
  • Median nerve decompression
  • Spinal decompression
  • Palliative care
  • Intensive Intervention
  • BMT/ Human Stem Cell Transplantation
  • Corneal transplants
  • Orthopedic surgery
  • Enzyme Replacement Therapy

57
BMT / HSCT Therapy
  • Recommended for all patients with severe form
    (MPS1H)
  • Needs to be done early prior to 18 24 mos.
  • Not recommended for patient with significant CNS
    involvement (too late)
  • Mortality 10 25 (graft loss / infection/
    acute Graft vrs Host disease)
  • Needs matched donors ? world-wide search
  • less effective in prevention of orthopedic or
    ocular problems

58
Physiological Basis of BMT / HSCT Therapy in
MPS I
59
MPSI GAG Excretion during ERT BMT/HSCT
Start of ERT
ERT
BMT/HSCT 2
BMT /HSCT 1
60
Summary Likely Use of ERT in Treatment of MPS I
  • In severe MPS I
  • BMT / HSCT recommended (lt 2 years of age no
    CNS problems)
  • ERT may be helpful peri-transplant
  • In moderate MPS I ( MPS I H/S)
  • ERT appears to be of value but efficacy for all
    problems uncertain (bones/dura/cornea)
  • In mild MPS I(MPS I S)
  • Use of BMT/HSCT /or ERT not recommended
  • May need surgical intervention (cornea/joint
    replacement etc)

61
MPS-I Spinal Cord Compression Syndrome
  • Also seen in MPS II,IV,VI VI
  • Can involve
  • Bony abnormalities
  • Thickening of spinal ligaments /or meninges
  • Clinical monitoring / MRI
  • Classical treatment is spinal column
    decompression /- sub-occipital craniectomy
  • Operative / anesthetic risk
  • Risk of recurrence
  • Clinical Trials with intrathecal ERT underway
  • Spinal cord compression
  • Neurological deterioration

62
Other LSDs treatable with HSCT / BMT
  • X- linked adrenoleukodystrophy
  • Krabbe disease
  • MPS VI
  • ? MPS IV
  • Gaucher III, ? Niemann-Pick

63
LSDs Treatment Approaches
  • Enzyme replacement therapy
  • Biosynthesis inhibitors
  • Chaparone Therapy
  • Gene therapy
  • Alleviation of symptoms / palliative care
  • Drugs Cystagon in cystinosis
  • Bone marrow transplantn MPS-I

64
LSDs Treatable with ERT
  • Gaucher Disease
  • Fabry Disease
  • Hurler/Hurler-Scheie Syndromes (MPSI)
  • Pompe Disease
  • Niemann-Pick B
  • Hunter Syndrome (MPS II)
  • Maroteaux-Lamy Syndrome (MPS VI)
  • Wolman / CESD
  • Hypophosphatasia
  • Currently in Calgary

65
Therapy of Gauchers 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

66
ERT Gaucher Disease
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