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Inborn Errors of Metabolism

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Inborn Errors of Metabolism Dr B.Vahabi * * * * * * * * Suspicion An important key to diagnosing IEM is thinking about the possibility in the first place The symptoms ... – PowerPoint PPT presentation

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Title: Inborn Errors of Metabolism


1
Inborn Errors of Metabolism
  • Dr B.Vahabi

2
Lecture outcomes
  • Understand the general pathophysiology underlying
    the inborn errors of metabolism (IEMs)
  • Review some important IEMs
  • Understand the genetic inheritance of IEMs
  • Review the general diagnostic methods used for
    detection of IEMs
  • Discuss the current treatment options for people
    suffering from IEMs

3
Metabolism
  • Metabolism is the sum of all the chemical
    reactions in the body
  • Some chemical reactions are involved in breaking
    down molecules, others are involved in building
    up (synthesis)
  • A metabolic pathway consists of SEVERAL STAGES
    involved in the conversion of one metabolite to
    another.

4
Metabolism
Food
Enzyme A
Amino acids Carbohydrates Lipids Nucleic acids
Enzyme B
Protein Carriers
Energy Biomolecules
5
Errors in Metabolism
  • If an error occurs in the gene that codes for the
    enzyme a FAULT occurs.
  • This fault is caused by a mutation in the genetic
    code.
  • Subsequently the enzyme is not produced and the
    pathway breaks down.
  • These are called INBORN ERRORS OF METABOLISM.

6
Metabolite D
Enzyme 1
Enzyme 2
Metabolite C
Metabolite B
Metabolite A
Accumulation of substances present in small amount
Deficiency of specific final products
Deficiency of critical intermediary products
7
  • The concept of inborn errors of metabolism (IEM)
    was first introduced by Archibald Garrod in 1908.

8
Incidence
  • More than 300 human diseases are known today that
    are caused by IEM
  • Overall prevalence of 1 in 5000
  • However the prevalence of each disease has many
    variables
  • Certain IEMs have a race related prevalence
  • e.g Tay-Sachs in Ashkenazi Jews

9
Inheritance
  • Majority IEMs are autosomal recessive
  • Some IEMs are X-linked (Mothers are carriers)
  • Mitochondrial diseases have also been detected

10
Usual clinical presentation of IEMs
  • Young Children
  • Recurring vomiting
  • Dysmorphic features
  • (characteristic facial expression, slant of eyes)
  • Developmental delay (milestones)
  • Seizures
  • Mental retardation
  • Neonates
  • Poor feeding
  • Vomiting
  • Apnoea (breathing disorder)
  • Irritability
  • Abnormal tone
  • Seizures

11
Categories of IEMs
  • Amino acid metabolism disorders
  • Carbohydrate metabolism disorders
  • Lysosomal storage disorders
  • Fatty acid oxidation disorders
  • Urea cycle defects
  • Peroxisomal disorders
  • Mitochondrial disorders

12
Amino acid metabolism disorders
  • A heterogeneous group of disorders
  • Block at early step of metabolic pathway
    resulting in accumulation of amino acids
  • Block at later stages of metabolic pathway
    resulting in accumulation of metabolites
  • Defect in transport mechanism of amino acids
    resulting in decreased intestinal transport and
    increased urinary excretion

13
Amino acid metabolism disorders
  • Examples
  • Phenylketonuria- phenylalanine
  • Homocysteinuria- methionine
  • Maple syrup urine disease- Leucine, isoleuscine
    and valine
  • Tyrosinaemia- Tyrosine

14
Phenyketonuria (PKU)
  • Most prevalent disorder caused by inborn errors
    of amino acid metabolism
  • Caused by mutations in phenyalanine hydroxylase
    (PAH) gene
  • PAH converts phenyalanine into tyrosine and
    requires the cofactor tetrahydrobiopterin (BH4),
    molecular oxygen and iron
  • Loss of PAH activity ? increased concentrations
    of phenyalanine in blood an d toxic
    concentrations in the brain

15
Pathophysiology of PKU
16
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17
Molecular genetics and classification
  • The PAH gene consists of 13 exons
  • PKU arises when both alleles are mutated (548
    separate mutations)
  • Some mutations only partly inhibit the enzyme
    activity? mild PKU
  • About 1-2 of cases of PKU are due to mutations
    in genes coding for enzymes involved in BH4
    biosynthesis

18
Pathophysiology of PKU
  • Phenylalanines entry into the brain is mediated
    by the large neutral aminoacid carrier
    L-aminoacid transporter (LAT1)
  • Raised phenylalanine concentration can induce
    damage in the brain by
  • Reducing formation of myeline in brain white
    matter
  • Inhibition of LAT1 carriers and neutral amino
    acids from entering the brain
  • Reduced activity of pyruvate kinase
  • Disturbed glutamatergic neurotransmission
  • Reduced activity of the enzyme 3-hydroxy-3-methylg
    lutaryl coenzyme reductase.

19
Presentation of PKU
  • Developmental Delay
  • Musty odour
  • Mental Retardation (decreased Myelin formation)
  • Epilepsy
  • Autism
  • Hypopigmentation (decreased melanin)
  • Blood phenylalanine concentrations gt1200µMol/Lit
  • Detected by newborn screening (heel prick test)
  • Can be dietary controlled.

20
Carbohydrate metabolism disorders
  • A heterogeneous group of disorders
  • Caused by inability to metabolize specific
    sugars, aberrant glycogen synthesis or disorders
    of gluconeogenesis
  • Manifest with hypoglycemia, hepatosplenomegaly,
    lactic acidosis or ketosis

21
Carbohydrate metabolism disorders
  • Examples
  • Glycogen storage diseases
  • Galactosemia
  • Fructose intolerance
  • Fructose 1,6-diphosphate deficiency

22
Glycogen storage diseases (GSDs)
  • Characterized by abnormal inherited glycogen
    metabolism in the liver, muscle and brain.
  • Lead to build up of glycogen in tissues
  • Categorised numerically (0-X)
  • (e.g. Type II, Type III etc.)

23
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24
Pathways of liver glucose production
25
Von Gierke disease (GSD type I)
  • Caused by defective liver glucose 6-phosphatase
    activity
  • Mutations can either be in
  • Gene coding for the liver glucose-6-phosphatase
  • Gene coding for endoplasmic reticulum substrate
  • Product transport proteins of the
    glucose-6-phosphatase system

26
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27
Presentation of Von Gierke 1a disease
  • Initial symptoms are due to hypoglycaemia and
    include
  • Tremor, irritability, hyperventilation, apnea,
    convulsions, paleness, sweating, cerebral edema,
    coma and death
  • Older infants may present with
  • Doll-like facial appearance, frequent lethargy,
    difficult arousal from sleep, overwhelming
    hunger, protuberant abdomen, relatively thin
    extremities.
  • With ageing the patient presents
  • Poor growth, short stature, and rachitic changes
  • Most striking laboratory findings
  • Hypoglycaemia, lactic acidosis, hyperlipidemia,
    hyperuricaemia, mosaic pattern of the liver, pale
    staining of the tissue and swollen hepatocytes

28
Presentation of Von Gierke 1b disease
  • In addition to clinical symptoms seen in GSD-1a
  • Recurrent infections
  • Neutropenia
  • Neutrophil dysfunction
  • Inflammatory bowl disease
  • Fever
  • Diarrhea
  • Perioral and anal ulcers

29
Lysosomal storage disorders
  • Are caused by accumulation of glycoproteins,
    glycolipids or glycosaminoglycans within
    lysosomes in various tissues
  • Usually present later in infancy with
    organomegaly, facial coarseness and
    neurodegeneration
  • Show progressively degenerative course

30
Lysosomal storage disorders
  • Examples
  • Tay-Sachs
  • Niemann-Pick disease
  • Gauchers disease

31
Tay-Sachs disease
  • Lack of lysosomal ß-hexosaminidase A (Hex-A)
    enzyme activity
  • Hex-A is responsible for production of
    hexosaminidase A
  • Hexosamindase A breaks down a fatty acid
    substance called GM2 ganglioside in nerve cells
  • Accumulation of GM2-ganglioside has a toxic
    effect on cells? neuronal deterioration ? mental
    and motor retardation

32
Presentation of Tay-Sachs disease
  • Infant appears normal at birth but within few
    weeks may become less visually attentive,
    hypotonic and easily startled by sound, light or
    touch
  • By 6-8 months developmental delay becomes obvious
  • Fundiscopic examination of retina reveals a
    whitish surrounding? lipid deposition
  • By 1 year ? marked reduction in purposeful
    movement, child becomes spastic and lethargic
  • Vision deteriorates
  • Frequent seizures
  • By age 2 years the child is in a vegetative state
    and requires constant care
  • Feeding difficulty
  • A light cherry red spot in the middle of the eye
  • The brain increases in weight and size but
    shows generalized atrophy and reduction
    in nerves
    and white matter
  • Deafness
  • Usually death before age of 5.

33
Diagnosis and Management
  • There are 3 important steps in the diagnosis and
    management of IEM
  • Suspicion
  • Evaluation
  • Treatment

34
Suspicion
  • An important key to diagnosing IEM is thinking
    about the possibility in the first place
  • The symptoms are very common and non-specific
  • Screening allows for the differential diagnosis

35
Developmental delay
36
Evaluation-1
  • Once the possibility of an IEM is suspected,
    how should it be evaluated?
  • History
  • An important clue is a history of deterioration
    after an initial period of good health
  • Developmental delay
  • Change in diet and unusual dietary preferences
  • Family history
  • Most IEMs are autosomal recessive any other
    siblings with the same condition?
  • Consanguineous marriages increases the
    incidence of recessive disease

37
Evaluation-2
  • There are two different types of testing for
    metabolic conditions screening tests and
    disease-specific diagnostic testing
  • Initial screening tests
  • Prenatal tests
  • Ability to detect IEMs prenatally has increased
  • Biochemical methods
  • Detection of metabolites in amniotic fluid
  • Enzyme assays
  • DNA analysis
  • Detection of genetic mutations

38
  • Prenatal tests
  • Choice of sample can be dictated by which
    disorder is to be tested for.
  • Amniocentesis
  • Best carried out at 15-16 weeks
  • Used for analysis of specific metabolites by gas
    chromatography with mass spectroscopy, tandem
    mass spectroscopy, etc
  • Used for detection genetic defects using DNA
    technology
  • Intended for diagnosis of some amino acid
    disorders, lysosomal storage disorders etc.

39
  • Prenatal tests
  • Cultured amniotic fluid cells
  • Used for measurement of specific enzyme activity
    using various enzyme assays
  • Used for the study of various metabolic
    pathways
  • Major disadvantage is the delay in waiting for
    sufficient number of cells to grow
  • Chorionic villous sampling (CVS)
  • Offers a greater advantage over amniocentesis
  • Samples are taken at around 11-week gestation
  • Used for determination of enzyme activity using
    various enzyme assays

40
  • Prenatal tests
  • Foetal blood and Foetal tissue
  • Foetal blood is rarely used
  • Sample taken late in pregnancy
  • Used when there has been a failure in amniotic
    fluid analysis
  • Liver biopsies are used when enzyme deficiencies
    are not expressed in CVS
  • Very risky
  • Used for diagnosis of conditions where enzyme
    deficiency is expressed in the liver
  • Testing of Pre-implantation embryos

41
  • Postnatal Tests
  • The investigation of IEM should begin with simple
    urine and blood analysis.
  • Screening tests allow you to detect the presence
    of a particular class of conditions and includes
  • Serum electrolytes (looking for evidence of
    acidosis), glucose ammonia levels
  • Blood and urine amino acids for disorders of
    amino acid metabolism
  • Urine organic acids for disorders of organic acid
    metabolism, Acylcarnitine profile for disorders
    of fatty acid
  • Blood lactate and pyruvate for disorders of
    carbohydrate metabolism and mitochondrial
    disorders

42

43
Odours attributed to IEMs
  • Phenylketonuria (PKU) Musty, mousy
  • Tyrosinemia Musty, Cabbage like
  • Maple syrup urine disease Sweet, Maple syrup
  • Isovaleric acidemia Sweaty feet
  • Multiple carboxylase deficiency Cat urine

44
Examples of screening tests
  • Measurement of reducing substances in the urine
    using Clinitest
  • Detects glucose, fructose and galactose in the
    urine.
  • Clinitest tablets are used which contain copper
    salts dissolved in hot solution.
  • Reducing substances react with the copper and
    produce colour
  • Colour in compared with a chart

45
Examples of screening tests
  • Tandem mass spectroscopy
  • Used for measurement of amino acids and
    acylcarnitines in blood
  • Used for detection of disorders of amino-acid,
    organic acid and fatty-acid metabolism.
  • Potential of simultaneous multi-disease screening
  • Blood taken from newborn babies are absorbed by
    filter paper (can also be used in the Guthrie
    test).
  • A punched sample from the dried blood spot is
    extracted with solvent containing appropriate
    isotopes
  • The extracted metabolites are identified and
    quantified with electrospray ionisation

46
Disease specific diagnostic tests
  • Key to exclusion or inclusion of an IEM and
    include
  • MRI (Magnetic resonance imaging) can be used for
    detection of demyelination/neuron loss in the
    brain
  • MRS (Magnetic resonance spectroscopy) can be used
    for detection of lactate levels in individuals
    with mitochondrial disorder
  • Study of cells and tissues obtained via biopsies
    to establish the nature of accumulated material,
    organelle alterations and specific markers

47
Treatments/ Management of IEMs
  • Treatment depends on the clinical manifestation
    and type of metabolites accumulated
  • The basic principal for treatment is reduction of
    the substrate that accumulates due to deficient
    enzyme activity
  • This can be mediated by an increasing number of
    therapeutic approaches
  • Prevent Catabolism
  • Limit the intake of the offending substance
  • Increase excretion of toxic metabolites
  • Enzyme-replacement therapy
  • Increase the residual enzyme activity
  • Reduce substrate synthesis
  • Replacement of the end products
  • Transplantation and gene therapy

48
Treatments/ Management of IEMs
  • Prevent Catabolism
  • Controlling the administration of calories used
    to prevent endogenous protein breakdown and
    induction of anabolism
  • 2) Limit the intake of offending substance
  • Restriction of certain dietary components.
  • E.g. restriction of intake of galactose and
    fructose to prevent galactosaemia and fructose
    intolerance
  • E.g. Neonates with PKU should be given protein
    substitute that is phenyalanine-free.
  • 3) Increase the excretion of toxic metabolites
  • Rapid removal of toxic metabolites can be
    achieved by exchange transfusion, peritoneal
    dialysis, haemodialysis, forced diuresis etc.
  • E.g. Haemodialysis is considered mandatory for
    hyperammonaemia

49
Treatments/ Management of IEMs
  • 4) Enzyme replacement therapy
  • Replacement of the deficient enzyme
  • E.g.Human alpha glucosidase enzyme is used for
    treatment of pompes disease
  • 5) Increase the residual enzyme activity (if
    possible)
  • Usually accomplished by administration of
    pharmacological doses of vitamin cofactor for the
    defective enzyme
  • 6) Reduce substrate synthesis
  • Inhibiting the synthesis of a substrate that can
    not be converted to the end products
  • E.g used for treating lysosomal storage disorders
    in order to reduce the rate of glycosphingolipid
    breakdown.

50
Treatments/ Management of IEMs
  • 7) Replacement of end products
  • Replacement of a product due to an enzyme defect
  • E.g. in patients with glycogen storage disease,
    hypoglycaemia is prevented with frequent feeds
    during the day and nasogastric feeding during
    night in infants and young children.
  • 8) Transplantation and gene therapy
  • Bone marrow transplantation (BMT) has been used
    as effective therapy for selected IEMs
  • Mainly Lysosomal storage diseases and peroxisomal
    disorders are treated by BMT.
  • The main rationale is based on provision of
    correcting enzymes by donor cells within and
    outside the blood compartment.
  • In most gene therapy procedures a "normal" gene
    is inserted into the genome to replace an
    "abnormal," disease-causing gene

51
Diagnosis and treatment of PKU
  • Prenatal diagnosis
  • Prenatal diagnosis is less commonly performed for
    PKU due to good prognosis on treatment
  • Few have been undertaken by DNA analysis
  • Postnatal diagnosis
  • Gutherie test using the ability of phenylalanine
    to facilitate bacterial growth in a culture
    medium with an inhibitor.
  • The Guthrie assay is sensitive enough to detect
    serum phenylalanine levels of 180-240 µmol/L (3-4
    mg/dL). In healthy normal people, phenylalanine
    levels are usually under 120 µmol/L.
  • Tandem mass spectroscopy
  • Have a sensitivity of 3umol/l for phenyalanine
  • Discrimination is further enhanced by
    simultaneous measurement of tyrosine.
  • Defects in BH4 synthesis should also be checked

52
Treatment of PKU
  • Treatment from birth with a low phenylalanine
    diet largely prevents the deviant cognitive
    phenotype
  • Present treatment relies on a diet low in
    phenylalanine
  • Tyrosine supplementation in the diet
  • Enzyme replacement therapy is being investigated
  • Pharmacological doses of exogenous BH4
  • Drug based therapeutics using sapropterin
    dihydrochloride which is a synthetic cofactor for
    PAH.
  • Gene therapy is being used in preclinical trials
    to deliver the PAH gene into liver

53
Summary
  • Individually rare but collectively important
  • Present a wide variety of metabolic disorders
  • Can be present at different stages of development
  • Can be fatal!!

54
Key references
  • Blau, N. et al (2010) Phenyketonuria. The Lancet.
    3761417-1427
  • Martins, A.M. (1999) Inborn errors of metabolism
    a clinical overview. Sao Paulo Med J/Rev Paul
    Med. 117251-65
  • Myerowitz, R (1997) Tay-Sachs Disease-Causing
    Mutations and Neutral Polymorphisms in the Hex A
    Gene. Human Mutation. 9195-208
  • Bayraktar, Y. (2007) Glycogen storage
    diseasesNew perspective. World J Gastreonterol.
    132541-2553
  • Shin, Y.S. (2006) Glycogen Storage Disease
    Clinical, Biochemical, and Molecular
    Heterogeneity. Semin Pediatr Neurol. 13 115-120
  • Low, L.C.K. (1996) Inborn errors of metabolism
    clinical approach and management. HKMJ. 2274-281
  • Saudubray, J.M. et al (2002) Clinical approach to
    inherited metabolic disorders in neonates an
    overview. 73-15
  • Besley, G.T.N in Walker, J.M Rapley, R. (Eds
    2001) Medical biomedthods handbook. Humana press
    Inc. Totowa, N.J.
  • Burchell, A (2003) Von Gierke disease.
    Encyclopedia of Genetics. 2120-2122
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