Inborn Errors of Metabolism - PowerPoint PPT Presentation


PPT – Inborn Errors of Metabolism PowerPoint presentation | free to download - id: 513629-MDg4Z


The Adobe Flash plugin is needed to view this content

Get the plugin now

View by Category
About This Presentation

Inborn Errors of Metabolism


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

Number of Views:3062
Avg rating:5.0/5.0
Slides: 55
Provided by: sarahmc7
Learn more at:


Write a Comment
User Comments (0)
Transcript and Presenter's Notes

Title: Inborn Errors of Metabolism

Inborn Errors of Metabolism
  • Dr B.Vahabi

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

  • 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

Enzyme A
Amino acids Carbohydrates Lipids Nucleic acids
Enzyme B
Protein Carriers
Energy Biomolecules
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
  • Subsequently the enzyme is not produced and the
    pathway breaks down.

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
  • The concept of inborn errors of metabolism (IEM)
    was first introduced by Archibald Garrod in 1908.

  • 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
  • Certain IEMs have a race related prevalence
  • e.g Tay-Sachs in Ashkenazi Jews

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

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

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

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

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

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

Pathophysiology of PKU
(No Transcript)
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

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
  • 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.

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.

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

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

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.)

(No Transcript)
Pathways of liver glucose production
Von Gierke disease (GSD type I)
  • Caused by defective liver glucose 6-phosphatase
  • 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

(No Transcript)
Presentation of Von Gierke 1a disease
  • Initial symptoms are due to hypoglycaemia and
  • 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
  • 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

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

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
  • Show progressively degenerative course

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

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

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
  • 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.

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

  • 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

Developmental delay
  • 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

  • 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

  • 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
  • Intended for diagnosis of some amino acid
    disorders, lysosomal storage disorders etc.

  • Prenatal tests
  • Cultured amniotic fluid cells
  • Used for measurement of specific enzyme activity
    using various enzyme assays
  • Used for the study of various metabolic
  • 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

  • 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

  • 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


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

Examples of screening tests
  • Measurement of reducing substances in the urine
    using Clinitest
  • Detects glucose, fructose and galactose in the
  • 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

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
  • A punched sample from the dried blood spot is
    extracted with solvent containing appropriate
  • The extracted metabolites are identified and
    quantified with electrospray ionisation

Disease specific diagnostic tests
  • Key to exclusion or inclusion of an IEM and
  • MRI (Magnetic resonance imaging) can be used for
    detection of demyelination/neuron loss in the
  • 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

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

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
  • 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

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
  • 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

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

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

Treatment of PKU
  • Treatment from birth with a low phenylalanine
    diet largely prevents the deviant cognitive
  • Present treatment relies on a diet low in
  • 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
  • Gene therapy is being used in preclinical trials
    to deliver the PAH gene into liver

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

Key references
  • Blau, N. et al (2010) Phenyketonuria. The Lancet.
  • 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.
  • 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