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    Inborn Errors of Amino Acid Metabolism

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    Santino Majok
    Inborn errors of amino acid metabolism can occur due to mutations in genes encoding enzymes involved in amino acid metabolism. This leads to deficiencies or abnormalities in these enzymes, causing issues with the metabolism of certain amino acids. Some common examples described in the document are phenylketonuria (PKU), maple syrup urine disease, homocystinuria, and cystinuria. Early diagnosis through newborn screening and treatment such as dietary modifications can help prevent neurological damage and other clinical complications in many of these disorders.

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    Inborn Errors of Amino Acid Metabolism

    Uploaded by

    Santino Majok
    116 views65 pages
    Inborn errors of amino acid metabolism can occur due to mutations in genes encoding enzymes involved in amino acid metabolism. This leads to deficiencies or abnormalities in these enzymes, causing issues with the metabolism of certain amino acids. Some common examples described in the document are phenylketonuria (PKU), maple syrup urine disease, homocystinuria, and cystinuria. Early diagnosis through newborn screening and treatment such as dietary modifications can help prevent neurological damage and other clinical complications in many of these disorders.

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    Inborn errors of amino acid metabolism can occur due to mutations in genes encoding enzymes involved in amino acid metabolism. This leads to deficiencies or abnormalities in these enzymes, causing issues with the metabolism of certain amino acids. Some common examples described in the document are phenylketonuria (PKU), maple syrup urine disease, homocystinuria, and cystinuria. Early diagnosis through newborn screening and treatment such as dietary modifications can help prevent neurological damage and other clinical complications in many of these disorders.

    Copyright:

    © All Rights Reserved
    Download as PPTX, PDF, TXT or read online from Scribd
    Download as pptx, pdf, or txt
    116 views65 pages

    Inborn Errors of Amino Acid Metabolism

    Uploaded by

    Santino Majok
    Inborn errors of amino acid metabolism can occur due to mutations in genes encoding enzymes involved in amino acid metabolism. This leads to deficiencies or abnormalities in these enzymes, causing issues with the metabolism of certain amino acids. Some common examples described in the document are phenylketonuria (PKU), maple syrup urine disease, homocystinuria, and cystinuria. Early diagnosis through newborn screening and treatment such as dietary modifications can help prevent neurological damage and other clinical complications in many of these disorders.

    Copyright:

    © All Rights Reserved
    Download as PPTX, PDF, TXT or read online from Scribd
    Download as pptx, pdf, or txt
    of 65

    Inborn Errors

    of
    Amino Acid
    Metabolism
    Inborn errors of metabolism occur when
    some enzyme involved in metabolism is
    abnormal

    The abnormality occurs due to a mutation


    in gene encoding the enzyme

    The affected enzyme may be absent or


    deficient
    Inborn errors may occur in metabolism of
    all nutrients including amino acids

    When an enzyme is absent or deficient,


    metabolism of the concerned amino acid
    becomes abnormal
    Over 50 inborn errors of metabolism of
    amino acids have been discovered

    The clinical abnormalities may occur


    due to:

    Decreased synthesis of products

    Accumulation of intermediates

    Formation of alternate
    metabolites
    Many disorders result in
    neurological abnormalities and mental
    retardation

    Early diagnosis and treatment can


    prevent neurological abnormalities

    Generally, the treatment comprises


    restricted intake or exclusion of the
    affected amino acid from the diet
    Some relatively common inborn errors are:
    • Primary hyperoxaluria
    • Maple syrup urine disease (MSUD)
    • Cystinuria
    • Homocystinuria
    • Phenylketonuria (PKU)
    • Alkaptonuria
    • Tyrosinaemia
    • Albinism
    • Histidinaemia
    • Hartnup Disease
    Primary hyperoxaluria

    Primary hyperoxaluria is a disorder


    of glyoxylate metabolism

    Glyoxylate is formed from hydroxyproline

    Normally, glyoxylate is transaminated


    to glycine or is oxidised to formate
    Glyoxylate is converted into oxalate when:

    Glycine transaminase is deficient

    Oxidation of glyoxylate is impaired

    This leads to hyperoxaluria and recurrent


    formation of oxalate stones in urinary tract
    Maple syrup urine disease (MSUD)

    This is a disorder of the branched-chain


    amino acids, valine, leucine and isoleucine

    Enzymes catalyzing the first two reactions


    in the catabolism these are common
    Branched-chain amino are
    acids transaminated to -keto
    acids first
    oxidative
    The -keto acids undergo
    decarboxylation
    Oxidative decarboxylation is catalysed by -
    ketoisovalerate dehydrogenase

    This enzyme is absent or deficient in MSUD


    Valine Leucine lsoleucine

    Branched-chain amino acid transaminase

    a-Ketoiso­ a-Ketoiso­ a-Keto-p-methyl


    valeric acid caproic acid valeric acid

    a-Ketoisovalermle: ehydrogenase
    ■
    lsobutyryl lsovaleryl a-Methylbutyryl
    CoA CoA CoA
    The enzyme deficiency leads to
    accumu- lation and increased urinary
    excretion of:

    Branched chain amino acids

    Their -keto acid derivatives

    This imparts a typical odour to urine similar


    to that of maple syrup or burnt sugar
    The clinical signs and symptoms
    appear within one week of birth

    Lethargy, vomiting and aversion to


    food are early signs

    These are followed by severe


    brain damage and ultimately death
    The treatment consists of exclusion
    of branched-chain amino acids from diet

    This is required until the plasma levels fall


    to normal

    Thereafter, the intake is restricted so


    as to maintain the plasma levels
    A milder variant of maple syrup urine disease
    is intermittent branched-chain ketonuria

    In this, the decrease in enzyme activity is only


    moderate

    The signs and symptoms are milder


    and appear much later

    The excretion of branched-chain -keto acids


    is intermittently increased
    Cystinuria

    There is a defect in tubular reabsorption


    of cystine

    Urinary excretion of cystine is increased

    Being sparingly soluble, cystine deposits


    in the kidneys and forms cystine stones

    The defect also involves reabsorption


    of lysine, arginine and ornithine
    Homocystinuria

    Cystathionine synthetase is severely


    deficient in homocystinuria

    This impairs the conversion of methionine


    into cysteine

    Homocysteine accumulates and is


    converted into homocystine
    Homocystine is made up of two
    homo- cysteine molecules

    Urinary excretion of homocystine


    is increased

    Plasma methionine and


    homocysteine levels are increased
    The clinical features of homocystinuria are:

    Thrombotic phenomena

    Osteoporosis

    Dislocation of lenses in the eyes

    Mental retardation

    Ischaemic vascular disease


    Accumulation of homocysteine causes:

    Abnormal cross-linking of collagen

    Abnormalities in the ground


    substance of walls of blood vessels

    Increased platelet adhesiveness


    Dislocation of ocular lenses and
    osteo- porosis occur due to abnormal
    collagen

    Thrombotic phenomena occur because


    of abnormalities in the walls of blood
    vessels
    Increased platelet adhesiveness and
    abnormal vessel walls cause:

    Ischaemic heart disease

    Cerebral thrombosis

    Peripheral vascular disease


    Ischaemic vascular diseases occur at a
    young
    age
    Homocysteine has been described as the
    new cholesterol because of its propensity to
    cause ischaemic vascular diseases
    Early diagnosis and treatment prevent
    most of the clinical abnormalities

    The treatment consists of a low-methionine,


    high-cysteine diet

    Pyridoxine supplements may be given


    to activate the residual cystathionine
    synthetase
    Hyperhomocysteinaemia may occur due
    to deficiency of some vitamins also,
    specially folic acid and vitamin B12

    In such cases, vitamin supplements


    correct the abnormality
    Phenylketonuria (PKU)

    Phenylketonuria is the commonest inborn


    error of amino acid metabolism

    It has an incidence of about 1 in 10,000


    live births

    It was the first inborn error of amino acid


    metabolism to be treated successfully by
    diet manipulation
    There is a block in the conversion
    of phenylalanine into tyrosine in PKU

    Two-thirds of the patients suffer from


    PKU, type I

    Phenylalanine hydroxylase is deficient


    in PKU, type I

    Several mutations have been observed


    in the phenylalanine hydroxylase gene
    One third of the cases
    are due to a defect
    in:

    Dihydropteridine
    reductase

    or

    Conversion of GTP into


    tetrahydrobiopterin
    The degree of defect is variable but it
    is severe in majority of the patients

    Plasma phenylalanine concentration


    rises after ingestion of phenylalanine

    When the level exceeds 1 mmol/L, alternate


    metabolites of phenylalanine are formed
    The alternate metabolites include:

    Phenylpyruvate

    Phenyl-lactate

    Phenylacetate

    Phenylacetylglutamine
    Plasma concentration of phenylalanine is
    raised in PKU

    Plasma concentration of its


    alternate metabolites is also raised

    All these are excreted in urine


    Some other amino acids share their transport
    system with phenylalanine

    A high phenylalanine level may inhibit


    their intestinal absorption and renal tubular
    reabsorption

    Uptake of these amino acids by brain may


    also be inhibited
    Synthesis of myelin sheath is decreased

    Synthesis of norepinephrine in brain


    is decreased

    Decreased availability of tyrosine


    may decrease the synthesis of melanin
    Clinical manifestations appear a few days or
    weeks after birth

    Developmental milestones are delayed

    Motor hyperactivity and seizures occur

    Skin is hypopigmented

    Later on, there is severe mental


    retardation
    Early diagnosis (within 3 weeks of birth) and
    treatment prevent the clinical abnormalities

    Since phenylalanine is an essential


    amino acid, it cannot be excluded from the
    diet

    A low-phenylalanine diet is given to keep the


    plasma phenylalanine level below 6 mg/dl
    Tyrosine cannot be synthesized
    endo- genously in PKU

    Hence, tyrosine becomes an


    essential amino acid for patients with
    PKU

    Their diet needs tyrosine supplements


    Dihydropteridine reductase is deficient in
    PKU, type II

    There is a block in the synthesis of tetra-


    hydrobiopterin from GTP in PKU, type III

    These two also result in


    decreased conversion of phenylalanine
    into tyrosine
    Tetrahydrobiopterin is also required
    for hydroxylation of tyrosine and
    tryptophan

    Deficiency of tetrahydrobiopterin
    results in decreased synthesis of:

    Dopamine, norepinephrine and


    epinephrine from tyrosine

    Serotonin and melatonin


    from
    tryptophan
    The clinical abnormalities in phenyl-
    ketonuria, types II and III:

    Are more severe

    Appear early

    Do not improve despite


    diet manipulation
    Alkaptonuria

    Alkaptonuria is an inborn error of tyrosine


    metabolism

    It is due to absence of homogentisate


    oxidase

    Homogentisate, an intermediate in cata-


    bolism of tyrosine, cannot be metabolised
    further
    Homogentisate is excreted in urine

    Freshly voided urine is normal in colour

    Urine becomes dark on exposure to air


    due to oxidation of homogentisate by
    oxygen
    Homogentisate and its oxidation product
    form polymers that bind to collagen

    This leads to generalized pigmentation


    of connective tissues (ochronosis)

    Chemical irritation of collagen causes


    degenerative changes in connective tissue

    Defective cross-linking of collagen also


    adds to the degeneration
    Damage to joint cartilages causes arthritis
    (ochronotic arthritis)

    Arthritis usually occurs in hip, knee


    and shoulder joints and vertebral column

    Pigmented spots may be seen on


    sclera and ears
    Treatment of alkaptonuria is symptomatic

    Ascorbic acid supplements have


    been tried but without much success
    Tyrosinaemia

    This is another inborn error of


    tyrosine metabolism

    Plasma tyrosine level is increased


    in tyrosinaemia

    Tyrosine and its metabolites are excreted


    in urine
    Two distinct genetic defects can
    cause tyrosinaemia

    Deficiency of
    fumarylacetoacetate hydrolase causes
    tyrosinaemia, type I

    Deficiency of tyrosine transaminase


    causes tyrosinaemia, type II
    Tyrosinaemia, type I causes neurological
    abnormalities, liver damage and renal
    tubular dysfunction

    Tyrosinaemia, type II affects eyes


    and skin
    Albinism

    This is another inborn error of


    tyrosine metabolism

    It is due to absence of tyrosinase


    from melanocytes

    This enzyme is required for synthesis


    of melanin
    Melanin is not synthesized in
    patients having albinism

    Their skin, hair and iris become white

    Such patients are called albinos


    Photophobia and skin hypersensitivity are
    common in albinos

    The incidence of skin cancer is also high

    Goggles and sunscreen lotions


    can reduce the discomfort
    Histidinaemia

    This is an inborn error of


    histidine metabolism in which histidase is
    deficient

    Histidine cannot be converted


    into urocanic acid

    Histidine concentration in plasma


    is increased
    Histidine is converted into some alternate
    metabolites:

    Imidazole pyruvate

    Imidazole lactate

    Imidazole acetate

    The alternate metabolites are


    excreted in urine
    Histidinaemia was believed in the past to
    impair development of speech

    This later turned out to be incorrect

    Most of the subjects with histidinaemia


    have no symptoms
    1% of the histidinaemic subjects develop
    behavioural problems, learning disorders
    and intellectual disability

    This usually happens when histidinaemic


    babies are exposed to perinatal hypoxia
    Hartnup Disease

    This disease was first diagnosed in the


    Hartnup family

    It was believed to be a disorder of


    tryptophan metabolism at first

    Later evidence showed a transport defect


    involving all neutral amino acids
    Intestinal absorption of neutral amino
    acids is impaired

    Renal tubular reabsorption of neutral


    amino acids is also impaired

    This leads to massive loss of amino


    acids
    Tryptophan present in gut is converted
    into indole and indoxyl derivatives by
    bacteria

    These are absorbed and are excreted in


    urine
    Decreased availability of tryptophan
    decreases endogenous synthesis of niacin

    This may produce a pellagra-like picture

    The treatment consists of a high-protein


    diet and niacin supplements

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