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									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 urine.
• 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
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 tolerate.
  – 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
     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

  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 PKU.
---- Researchers also are exploring the
   possibility of treating PKU using gene
 – 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
 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
• 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 back.
             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 cystine)
  –   Urinalysis (may show cystine crystals)
  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
  – Medications may be prescribed to help dissolve the
    cystine crystals.
  – Analgesics
• Surgery may be needed.

– 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
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 extensive.
• Spleen enlargement and bone marrow replacement cause anemia,
   thrombocytopenia and leukopenia.
• Brain is not affected, but there may be lung and, rarely, kidney
• 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
Type II (or acute infantile neuropathic Gaucher's disease)
 - Age :- typically begins within 6 months of birth
• 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 adulthood
• It is characterized by slowly progressive but milder
   neurologic symptoms compared to the acute or type 2
• Major symptoms include an enlarged spleen and/or liver,
   seizures, poor coordination, skeletal irregularities, eye
   movement disorders, blood disorders including anemia and
   respiratory problems.
         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 Gaucher's:
  – 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 patient’s comfort).
•   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 (α1-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
• Therapy is not appropriate for liver-
  affected patients.
• In severe cases, liver transplantation may
  be necessary.
           Wilson's disease
• Syn. : - Hepatolenticular degeneration
• Wilson's disease is a rare inherited
  disorder that affects about one in 30,000
  people worldwide.
• 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 disease.
• Symptoms usually appear between the ages of 6 and 20
  years, but cases in much older patients have been
• Wilson's disease occurs in 1 to 4 per 100,000 people.
• Wilson's disease is named after Dr. Samuel Alexander
  Kinnier Wilson (1878-1937), the British neurologist who
  first described the condition in 1912.
• Copper acts as a cofactor for a
  number of enzymes such as
  ceruloplasmin, cytochrome c
  oxidase, dopamine β-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                                Cu = copper,
• ATOX1 Copper transport protein       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 disease.
• Copper accumulates in the
  liver tissue; ceruloplasmin is
  still secreted, but in a form
  that lacks copper (termed
  apoceruloplasmin) and
  rapidly degraded in the
                                   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
• 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
• 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
     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
• 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
• 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).

– 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)
– Cardiac arrhythmias (episodes of irregular and/or abnormally fast
  or slow heart beat).

– 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
  (<0.2 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
 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
– Ceruloplasmin < 0.2 g/L
– Serum copper        < 12 µmol/L
– Urine copper        > 1.1 µmol / 24 h as an
  isolated test; > 4 µmol is a more useful
– Urine copper post-penicillamine > 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 urine.
• 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 fatal.

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