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Inborn errors of metabolism


Inborn errors of metabolism By : - Dr. Sanjeev Phenylketonuria (PKU) It is an autosomal recessive (two copies of an abnormal gene) genetic disorder characterized by a ... – PowerPoint PPT presentation

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Title: Inborn errors of metabolism

Inborn errors of metabolism
  • By - Dr. Sanjeev

Phenylketonuria (PKU)
  • It is an autosomal recessive (two copies of an
    abnormal gene) genetic disorder characterized by
    a deficiency in the hepatic enzyme phenylalanine
    hydroxylase (PAH).
  • Necessary to metabolize the amino acid
    phenylalanine to the amino acid tyrosine.
  • When PAH is deficient, phenylalanine accumulates
    and is converted into phenylpyruvic acid, phenyl
    lactic acid and phenyl acetic acid (also
    known as phenylketone), which is detected in the
  • Elevated blood phenylalanine and detection of
    phenylketones in the urine is diagnostic.

Metabolic pathways
  • ---- Phenylalanine is a large, neutral amino
    acid (LNAA). LNAAs compete for transport across
    the blood-brain barrier (BBB) via the large
    neutral amino acid transporter (LNAAT).
  • ---- Excessive phenylalanine in the blood
    saturates the transporter. Thus, excessive levels
    of phenylalanine significantly decrease the
    levels of other LNAAs in the brain.
  • ---- But these amino acids are required for
    protein and neurotransmitter synthesis,
    phenylalanine accumulation disrupts brain
    development, leading to mental retardation.

  • Symptoms can be mild or severe
  • Mental retardation
  • Behavioral or social problems
  • Seizures, tremors or jerking movements in the
    arms and legs
  • Hyperactivity
  • Stunted growth
  • Skin rashes (eczema)
  • Small head size (microcephaly)
  • Vomiting
  • A musty (smelling of decay) odor in the child's
    breath, skin or urine, caused by too much
    phenylalanine in the body
  • Fair skin and blue eyes, because phenylalanine
    cannot transform into melanin the pigment
    responsible for hair and skin

  • Criteria for PKU are
  • 1. On a normal diet, phenylalanine level in
    excess of 20 mg/ dL/24 hours on two occasions
  • 2. Blood tyrosine level more than 5 mg/dL and
  • 3. Presence of abnormal urinary metabolites of
    phenylalanine detected by guthrie or ferric
    chloride test.

  • Goal of PKU treatment is to maintain the blood
    level of phenylalanine between 2 and 10 mg/dl
  • Mental retardation can be prevented if the baby
    is treated with a special diet that is low in
    phenylalanine. This diet should be started as
    soon as possible after birth, ideally within the
    first seven to 10 days of life . 
  • At first, the baby is fed a special formula that
    contains protein but no phenylalanine. Breast
    milk or infant formula is used to supply only as
    much phenylalanine as the baby needs and can
  • Later, certain vegetables, fruits, some grain
    products (for example, certain cereals and
    noodles) and other low-phenylalanine foods are
    added to the diet.

  • No regular milk, cheese, eggs, meat, fish and
    other high protein foods are ever allowed.
    Because protein is essential for normal growth
    and development, the child must continue to have
    one of the special formulas that is high in
    protein and essential nutrients, but contains
    little or no phenylalanine.
  • Diet drinks and foods that contain the artificial
    sweetener (which contains phenylalanine) must be
    strictly avoided.
  • All affected persons need regular blood tests to
    measure phenylalanine levels. Testing for babies
    may be as frequent as once a week for the first
    year of life, and then once or twice a month
    throughout childhood.
  • Individuals with PKU must remain on a restricted
    diet throughout childhood and adolescence and
    generally for life.

Drugs used to manage PKU
  • Kuvan (sapropterin dihydrocholoride), the first
    drug to help manage PKU .
  • Reduce blood phenylalanine levels in individuals
    with PKU by increasing the activity of the PAH
    enzyme.Kuvan is effective only in individuals
    who have some PAH activity. Individuals who take
    this drug must continue to follow a
    phenylalanine-restricted diet and have blood
    tests to measure phenylalanine levels.

New in PKU research
  • ---- Researchers also are studying the benefits
    of a nutritional supplement called
    Tetrahydrobiopterin (BH4) in individuals with
  • ---- Researchers also are exploring the
    possibility of treating PKU using gene therapy.

  • Synonyms
  • Cistinuria
  • Cystine-Lysine-Arginine-Ornithinuria
  • Cystinuria with Dibasic Aminoaciduria
  • Disorder Subdivisions
  • Cystinuria, Type I
  • Cystinuria, Type II
  • Cystinuria, Type III
  • Hypercystinuria

  • It is an inherited (get it from one's ancestors)
    metabolic disorder characterized by the abnormal
    movement (transport) in the intestines and
    kidneys, of certain amino acids. These include
    cystine, lysine, arginine, and ornithine (LACO).
  • Excessive amounts of undissolved cystine in the
    urine (cystinuria) cause the formation of stones
    (calculi) in the kidney, bladder, and/or ureter.

  • Four subtypes of Cystinuria are recognized.
  • In Type I Cystinuria
  • Defect in the active transport of cystine and the
    dibasic amino acids lysine, arginine, and
    ornithine in the kidneys and small intestine.
  • People who are carriers of the gene for this type
    of the disorder generally have no symptoms.
  • In Type II Cystinuria
  • Cystine and lysine transport is severely
    impaired in the kidneys and only somewhat
    impaired in the intestines.

  • In Type III Cystinuria
  • Kidney transport of cystine and lysine is
    defective intestinal transport is normal.
  • People who are carriers of the gene for this
    variety of the disease typically have slightly
    elevated levels of cystine and lysine in the
  • In Hypercystinuria
  • There is generally a moderate elevation of
    cystine in the urine intestinal absorption of
    cystine and the dibasic amino acids is normal.

  • Cystinuria is caused by excessive levels of an
    amino acid called cystine in the urine.
  • After entering the kidneys, most cystine normally
    dissolves and goes back into the bloodstream. But
    persons with cystinuria have a genetic defect
    that interferes with this process. As a result,
    cystine builds up in the urine and forms crystals
    or stones, which may get stuck in the kidneys,
    ureters, or bladder.
  • Cystinuria affects approximately 1 out of 10,000
  • Cystine stones are most common in young adults
    under age 40.
  • Less than 3 of known urinary tract stones are
    cystine stones.

  • The high levels of the amino acid cystine in the
    urine lead to stone formation.

  • Blood in the urine
  • Flank pain or pain in the side or back
  • Usually on one side rarely felt on both sides
  • Often severe
  • May get increasingly worse over days
  • Pain may also be felt in the pelvis, groin,
    genitals, or between the upper abdomen and the

Exams and Tests
  • The disorder is usually diagnosed after an
    episode of stones. Analysis of the stones shows
    they are made of cystine.
  • Tests that may be done to detect stones and
    diagnose this condition include
  • Abdominal CT scan, MRI, or ultrasound
  • Intravenous pyelogram (IVP)
  • 24-hour urine collection (shows high levels of
  • Urinalysis (may show cystine crystals)

(No Transcript)
  • Goal of treatment
  • to relieve symptoms and prevent the development
    of more stones.
  • Patient with severe symptoms may need to be
    admitted to a hospital.
  • Treatment
  • - Involves drinking plenty of fluids,
    particularly water, so that large amounts of
    urine are produced.
  • - In some cases, fluids may need to be given
    through a vein.
  • Medications may be prescribed to help dissolve
    the cystine crystals.
  • Analgesics
  • Surgery may be needed.
  • Lithotripsy

  • Bladder injury from stone
  • Ureteral obstruction
  • Kidney injury from stone
  • Urinary tract infection

  • Plenty of fluids to regularly produce a high
    amount of urine (allows stones and crystals to
    leave the body before they become large enough to
    cause symptoms).

Gaucher's disease
  • It is an metabolic disorder with autosomal
    recessive inheritance that is caused by a
    deficiency in an enzyme called glucocerebrosidase
    which splits glucose from glucosylceramide.
  • Enzyme acts on a fatty substance glucocerebroside
    (also known as glucosylceramide)

  • Three types
  • Type 1
  • Liver, spleen, bone involvement.
  • Type 2
  • CNS involvement
  • Type 3
  • Liver, spleen and CNS involvement

  • Type I (or non-neuropathic type)
  • - most common form.
  • Symptoms
  • Age early in life or in adulthood
  • enlarged liver and grossly enlarged spleen
    (hepatosplenomegaly) the spleen can rupture and
    cause additional complications.
  • Skeletal weakness and bone disease may be
  • Spleen enlargement and bone marrow replacement
    cause anemia, thrombocytopenia and leukopenia.
  • Brain is not affected, but there may be lung and,
    rarely, kidney impairment.
  • Bruise (due to low levels of platelets) and
    experience fatigue (due to low numbers of red
    blood cells).
  • Depending on disease onset and severity, type 1
    patients may live well into adulthood.
  • Many patients have a mild form of the disease or
    may not show any symptoms.

  • Type II (or acute infantile neuropathic Gaucher's
  • - Age - typically begins within 6 months of
  • Symptoms include an enlarged liver and spleen,
    extensive and progressive brain damage, eye
    movement disorders, spasticity, seizures, limb
    rigidity, and a poor ability to suck and swallow.
  • Affected children usually die by age 2.
  • Type III (the chronic neuropathic form)
  • - Age - at any time in childhood or even in
  • It is characterized by slowly progressive but
    milder neurologic symptoms compared to the acute
    or type 2 version.
  • Major symptoms include an enlarged spleen and/or
    liver, seizures, poor coordination, skeletal
    irregularities, eye movement disorders, blood
    disorders including anemia and respiratory

Signs and symptoms
  • Painless hepatomegaly and splenomegaly the size
    of the spleen can be 1500-3000 ml, as opposed to
    the normal size of 50-200 ml.
  • Hypersplenism the rapid and premature
    destruction of blood cells, leading to anemia,
    neutropenia and thrombocytopenia (with an
    increased risk of infection and bleeding)
  • Neurological symptoms occur only in some types of
  • Type II serious convulsions, hypertonia, mental
    retardation, apnea.
  • Type III muscle twitches known as myoclonus,
    convulsions, dementia, ocular muscle apraxia.
  • Osteoporosis 75 develop visible bony
    abnormalities due to the accumulated

  • Definitive diagnosis is made with genetic
  • Prenatal diagnosis is useful when there is a
    known genetic risk factor.

  • For type 1 and most type 3 patients
  • Enzyme replacement treatment with intravenous
    recombinant glucocerebrosidase (imiglucerase) can
    dramatically decrease liver and spleen size,
    reduce skeletal abnormalities, and reverse other
  • Successful bone marrow transplantation cures the
    non-neurological manifestations of the disease,
    because it introduces a monocyte population with
    active beta-glucosidase.
  • Splenectomy (if the patient is anemic or when
    the enlarged organ affects the patients
  • Blood transfusion.

  • Other patients may require joint replacement
    surgery to improve mobility and quality of life.
  • Other treatment options include -
  • antibiotics for infections,
  • antiepileptics for seizures, and
  • liver transplants.

  • Substrate reduction therapy - may prove to be
    effective in stopping Type 2, as it can cross
    through the blood barrier into the brain. There
    is currently no effective treatment for the
    severe brain damage that may occur in patients
    with types 2 and 3 Gaucher disease.
  • Gene therapy.
  • Miglustat oral drugs,
  • Isofagomine tartrate, is under development.

Alpha 1 antitrypsin deficiency
  • Alpha 1-antitrypsin deficiency (a1-antitrypsin
    deficiency, A1AD or Alpha-1)
  • Genetic disorder caused by defective production
    of alpha 1-antitrypsin (A1AT), leading to
    decreased A1AT activity in the blood and lungs,
    and deposition of excessive abnormal A1AT protein
    in liver cells.
  • Function - A1AD, a protease inhibitor (Pi), is
    synthesized in the liver and protects lung
    alveolar tissues from destruction by neutrophil

  • Phenotypes - PiSS, PiMZ, PiZZ and PiSZ,
  • Blood levels of A1AT are reduced to between 40
    and 60 of normal levels which is sufficient to
    protect the lungs from the effects of elastase in
    people who do not smoke.
  • Individuals with the phenotype PiZZ, A1AT levels
    are less than 15 of normal, and patients are
    likely to develop emphysema at a young age 50
    of these patients will develop liver cirrhosis,
    because the A1AT is not secreted properly and
    instead accumulates in the liver.
  • Cigarette smoke is especially harmful to
    individuals with A1AD. In addition to increasing
    the inflammatory reaction in the airways,
    cigarette smoke directly inactivates alpha
    1-antitrypsin by oxidizing essential methionine
    residues to sulfoxide forms

Signs and symptoms
  • Shortness of breath
  • Recurrent respiratory infections
  • Asthma that does not respond to treatment
  • Emphysema during their thirties or forties even
    without a history of significant smoking, though
    smoking greatly increases the risk for emphysema
  • Cirrhosis and liver failure (15)
  • Wheeze

  • Intravenous infusions of alpha-1 antitrypsin
  • Therapy is not appropriate for liver-affected
  • In severe cases, liver transplantation may be

Wilson's disease
  • Syn. - Hepatolenticular degeneration
  • Wilson's disease is a rare inherited disorder
    that affects about one in 30,000 people
  • In Wilson's disease, the body is unable to
    excrete excess copper.
  • This manifests as neurological or psychiatric
    symptoms and liver disease.

  • The condition is due to mutations in the Wilson
    disease protein (ATP7B) gene.
  • A single abnormal copy of the gene is present in
    1 in 100 people, who do not develop any symptoms
    (they are carriers). If a child inherits the gene
    from both parents, they may develop Wilson's
  • Symptoms usually appear between the ages of 6
    and 20 years, but cases in much older patients
    have been described.
  • Wilson's disease occurs in 1 to 4 per 100,000
  • Wilson's disease is named after Dr. Samuel
    Alexander Kinnier Wilson (1878-1937), the British
    neurologist who first described the condition in

  • Copper acts as a cofactor for a number of enzymes
    such as ceruloplasmin, cytochrome c oxidase,
    dopamine ß-hydroxylase, superoxide dismutase and
  • Copper enters the body through the digestive
    tract. A transporter protein on the cells of the
    small bowel, copper membrane transporter (CMT1),
    carries copper inside the cells, where some is
    bound to metallothionein and part is carried by
    ATOX1 to an organelle known as the trans-Golgi
  • Here, in response to rising concentrations of
    copper, an enzyme called ATP7A releases copper
    into the portal vein to the liver
  • ATOX1 Copper transport protein

Cu copper, CP ceruloplasmin, green ATP7A
  • Liver cells also carry the CMT1 protein, and
    metallothionein and ATOX1 bind it inside the
    cell, but here it is ATP7B that links copper to
    ceruloplasmin and releases it into the
    bloodstream, as well as removing excess copper by
    secreting it into bile.
  • Both functions of ATP7B are impaired in Wilson's
  • Copper accumulates in the liver tissue
    ceruloplasmin is still secreted, but in a form
    that lacks copper (termed apoceruloplasmin) and
    rapidly degraded in the bloodstream.

Cu copper, CP ceruloplasmin, green ATP7B
carrying copper.
  • When the amount of copper in the liver increased
    the proteins that normally bind it, it causes
    oxidative damage through a process known as
    Fenton chemistry this damage eventually leads to
    chronic active hepatitis, fibrosis (deposition of
    connective tissue) and cirrhosis.
  • The liver also releases copper into the
    bloodstream that is not bound to ceruloplasmin.
    This free copper precipitates throughout the body
    but particularly in the kidneys, eyes and brain.

  • In the brain, most copper is deposited in the
    basal ganglia, particularly in the putamen and
    globus pallidus (together called the lenticular
    nucleus) these areas normally participate in the
    coordination of movement as well as playing a
    significant role in neurocognitive processes such
    as the processing of stimuli and mood regulation.
  • Damage to these areas, again by Fenton chemistry,
    produces the neuropsychiatric symptoms seen in
    Wilson's disease.

  • It is not clear why Wilson's disease causes
    hemolysis, but various lines of evidence suggest
    that high levels of free (non-ceruloplasmin
    bound) copper have a direct effect on either
    oxidation of hemoglobin, inhibition of
    energy-supplying enzymes in the red blood cell,
    or direct damage to the cell membrane.

Signs and symptoms
  • Common sites of copper accumulation are the liver
    and the brain, and liver disease and
    neuropsychiatric symptoms are the main features
    that lead to diagnosis.

Liver disease
  • Liver disease
  • Tiredness, increased bleeding tendency or
    confusion (due to hepatic encephalopathy) and
    portal hypertension.
  • Esophageal varices (increased pressure on the
    portal vein )
  • Splenomegaly
  • Ascites

  • About 5 of all patients are diagnosed only when
    they develop fulminant acute liver failure,
  • This leads to abnormalities in protein production
    and metabolism by the liver.
  • Protein metabolism leads to the accumulation of
    waste products such as ammonia in the
    bloodstream. When these irritate the brain, the
    patient develops hepatic encephalopathy
    (confusion, coma, seizures and finally
    life-threatening swelling of the brain).

Neuropsychiatric symptoms
  • Most patients initially have mild cognitive
    deterioration as well as changes in behavior.
  • Specific neurological symptoms then follow, in
    the form of parkinsonism (increased rigidity and
    slowing of routine movements) with or without a
    typical hand tremor, ataxia (lack of
    coordination) or dystonia (twisting and
    repetitive movements of part of the body).
  • Seizures and migraine (more common)
  • Psychiatric problems - behavioral changes,
    depression, anxiety and psychosis.

Other organ systems
  • Eyes Kayser-Fleischer rings (KF rings) visible
    around the iris. They are due to copper
    deposition in Descemet's membrane of the cornea.
  • visible on slit lamp examination.
  • Sunflower cataracts,
  • KF rings occur in 66 of cases, more often in
    those with neurological than with liver problems.

  • Renal tubular acidosis, a disorder of bicarbonate
    handling by the proximal tubules leads to
    nephrocalcinosis (calcium accumulation in the
    kidneys), weakening of the bone (due to calcium
    and phosphate loss) and occasionally
    aminoaciduria (loss of amino acids, needed for
    protein synthesis).
  • Heart
  • Cardiomyopathy (weakness of the heart muscle) is
    a rare but recognized problem in Wilson's
    disease it may lead to
  • Heart failure (fluid accumulation due to
    decreased pump function) and
  • Cardiac arrhythmias (episodes of irregular and/or
    abnormally fast or slow heart beat).
  • Hormones
  • Hypoparathyroidism (failure of the parathyroid
    glands, leading to low calcium levels),
    infertility and habitual abortion.

  • Complete blood count (CBC)
  • Serum ceruloplasmin
  • Serum copper
  • Serum uric acid
  • Urine copper
  • If there are liver problems, lab tests may find
  • High AST and ALT
  • High bilirubin
  • High PTT
  • Low albumin

Other tests
  • 24-hour urine copper test
  • Abdominal x-ray
  • Abdominal MRI
  • CT scan of the abdomen
  • Head CT scan
  • Head MRI
  • Liver biopsy
  • Genetic testing for ATP7B.

  • Gold standard or most ideal test is a liver

  • - Levels of ceruloplasmin are abnormally low
    (lt0.2 gram/liter) in 80-95 of cases.
  • - The combination of neurological symptoms,
    Kayser-Fleisher rings and a low ceruloplasmin
    level is considered sufficient for the diagnosis
    of Wilson's disease.

Serum and urine copper
  • Serum copper is low but urine copper are elevated
  • Urine is collected for 24 hours in a bottle -
  • Levels above 100 µg/24h (1.6 µmol/24h) confirm
    Wilson's disease, and
  • levels above 40 µg/24h (0.6 µmol/24h) are
    strongly indicative.
  • In children, the penicillamine test -
  • A 500 mg oral dose of penicillamine is
    administered, and urine collected for 24 hours.
    If this contains more than 1600 µg (25 µmol), it
    is a reliable indicator of Wilson's disease.

  • Ceruloplasmin lt 0.2 g/L
  • Serum copper lt 12 µmol/L
  • Urine copper gt 1.1 µmol / 24 h as an
    isolated test gt 4 µmol is a more useful
  • Urine copper post-penicillamine gt 25 µmol/24 h

  • Goal of treatment is to reduce the amount of
    copper in the tissues.
  • done by a procedure called chelation medicine
    that bind to copper and remove it through the
    kidneys or gut. Treatment must be lifelong.
  • Drugs used
  • Penicillamine (Cuprimine, Depen) binds copper and
    leads to increased release of copper in the
  • Trientine (Syprine) binds the copper increases
    its release through the urine.
  • Zinc acetate (Galzin) blocks copper from being
    absorbed in the intestinal tract.

low-copper diet
  • Foods to avoid include
  • Chocolate
  • Dried fruit
  • Liver
  • Mushrooms
  • Nuts
  • Shellfish
  • Drink distilled water because most tap water
    flows through copper pipes.
  • Liver transplant

  • Anemia
  • Central nervous system complications
  • Cirrhosis
  • Fatty liver
  • Hepatitis
  • Bone fractures
  • Jaundice
  • Muscle atrophy
  • Liver failure and damage to the central nervous
    system (brain, spinal cord) are the most common
    and dangerous effects of the disorder. If not
    diagnosed and treated early, Wilson's disease is