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Dr. Samah Kotb Nasr EldeenLecturer of Biochemistry
Cellular Biochemistry and Metabolism
(CLS 333 )
Inborn Errors of Metabolism (IEM)
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Introduction
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Comprise a group of disorders in which a
single gene defect causes a clinically
significant block in a metabolic pathway
resulting either in accumulation of
substrate behind the block or deficiency
of the product.
Inborn Errors of Metabolism (IEM)
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All IEMs are all genetically
transmitted typically in an
autosomal recessive or X-
linked recessive fashion.
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Examples of Inborn errors of metabolism
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1. Phenyl ketonuria
It is most common
hereditary disorder of
phenylalanine metabolism
and indeed of all amino
acids.
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It is due to a defect in the formation of
phenyl alanine hydroxylase enzyme as a
result phenyl alanine is diverted into its
minor pathway and large amounts of phenyl
pyruvate, phenyl lactate, phenyl acetate ,
phenyl acetyl glutamine and even phenyl
alanine itself are excreted in the urine .
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The plasma phenylalanine
level is increased and
principle clinical symptoms
are mental retardation and
convulsion.
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Maple syrup urine
disease is an inherited
disorder in which the
body is unable to
process certain protein
building blocks (amino
acids) properly.
2. Maple syrup urine disease
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The condition gets its name from the distinctive sweet odor of affected infants' urine and is also characterized by poor feeding, vomiting, lack of energy (lethargy), and developmental delay.
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If untreated, maple syrup urine disease can lead to seizures, coma, and death.
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Causes the urine and sweat to smell
like maple syrup . Plasma and urine
levels of all branched chain amino acids
and their corresponding α keto acids
are increased far above normal .
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The biochemical defect is the lack of the α keto acid decarboxylase.
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Intermittent branched
chain ketonuria is a variant
of maple syrup urine
disease in which the α keto
acids decarboxylase
deficiency is much less
severe.
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3. Galactosemia
Is a rare genetic
metabolic disorder
that affects an
individual's ability to
metabolize the sugar
galactose properly.
Galactose
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Galactosemia follows an
autosomal recessive mode
of inheritance that confers
a deficiency in an enzyme
responsible for adequate
galactose degradation.
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Diagnosis
Infants are routinely screened for
galactosemia in the United States, and
the diagnosis is made while the person
is still an infant. Infants affected by
galactosemia typically present with
symptoms of lethargy, vomiting,
diarrhea and jaundice.
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None of these symptoms are specific to galactosemia, often leading to diagnostic delays. Luckily, most infants are diagnosed on newborn screening.
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If the family of the baby has a history of galactosemia, doctors can test prior to birth by taking a sample of fluid from around the fetus (amniocentesis) or from the placenta (chorionic villus sampling or CVS).
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A galactosemia test is a blood test (from the heel of the infant) or urine test that checks for three enzymes that are needed to change galactose sugar that is found in milk and milk products into glucose, a sugar that your body uses for energy.
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A person with galactosemia doesn't have one of these enzymes. This causes high levels of galactose in the blood or urine.
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Treatment
The only treatment for classic galactosemia is eliminating lactose and galactose from the diet. Even with an early diagnosis and a restricted diet, however, some individuals with galactosemia experience long-term complications such as speech difficulties, learning disabilities, neurological impairment (e.g. tremors, etc.), and ovarian failure in females.
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Galactosemia is sometimes confused with lactose intolerance, but galactosemia is a more serious condition. Lactose intolerant individuals have an acquired or inherited shortage of the enzyme lactase, and experience abdominal pains after ingesting dairy products, but no long-term effects. In contrast, a galactosemic individual who consumes galactose can cause permanent damage to their bodies.
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Long term complication of galactosemia includes:
Speech deficitsAtaxiaDysmetriaDiminished bone densityPremature ovarian failureCataract
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4. Hereditary fructose intolerance
Is an inborn error of fructose metabolism caused by a deficiency of the enzyme aldolase. Individuals affected with HFI are asymptomatic until they ingest fructose, sucrose, or sorbitol. If fructose is ingested, the enzymatic block at aldolase causes an accumulation of fructose-1-phosphate.
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This accumulation has downstream effects on gluconeogenesis and regeneration of adenosine triphosphate (ATP).
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Symptoms of HFI include vomiting, hypoglycemia, jaundice, hemorrhage, hepatomegaly, hyperuricemia and potentially kidney failure.
Symptoms
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While HFI is not clinically a devastating condition, there are reported deaths in infants and children as a result of the metabolic consequences of HFI. Death in HFI is always associated with problems in diagnosis.
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HFI is typically suspected based on dietary history, especially in infants who become symptomatic after breast feeding. This suspicion is typically confirmed by molecular analysis. Treatment of HFI is based around strict avoidance of fructose in the diet. Older patients with HFI typically self-select a diet low in fructose, even before being diagnosed.
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Characteristics
The key identifying feature of HFI is the appearance of symptoms with the introduction of fructose to the diet. Affected individuals are asymptomatic and healthy, provided they do not ingest foods containing fructose or any of its common precursors, sucrose and sorbitol. In the past, infants often became symptomatic when they were introduced to formulas that were sweetened with fructose or sucrose.
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Symptoms such as vomiting, nausea, restlessness, pallor, sweating, trembling and lethargy can also first present in infants when they are introduced to fruits and vegetables. These can progress to apathy, coma and convulsions if the source is not recognized early.
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When patients are diagnosed with HFI, a dietary history will often reveal an aversion to fruit and other foods that contain large amounts of fructose. Most adult patients do not have any dental caries.
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Fructose metabolism
After ingestion, fructose is converted to fructose-1-phosphate by the liver by fructokinase. Deficiencies of fructokinase cause essential fructosuria, a clinically benign condition characterized by the excretion of unmetabolized fructose in the urine. Fructose-1-phosphate is metabolized by aldolase into dihydroxyacetone phosphate and glyceraldehyde. HFI is caused by a deficiency of aldolase.
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A deficiency of aldolase results in an accumulation of fructose-1-phosphate, and trapping of phosphate (fructokinase requires adenosine triphosphate (ATP). The downstream effects of this enzyme block are the inhibition of glucose production and reduced regeneration of ATP.
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Diagnosis
Because of the ease of therapy (dietary exclusion of fructose), HFI can be effectively managed if properly diagnosed.
In HFI, the diagnosis of homozygotes is difficult, requiring a genomic DNA screening with allele specific probes or an enzyme assay from a liver biopsy.
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Treatment
Treatment of HFI depends on the stage of the disease, and the severity of the symptoms. Stable patients without acute intoxication events are treated by careful dietary planning that avoids fructose and its metabolic precursors.
Fructose is replaced in the diet by glucose, maltose or other sugars. Management of patients with HFI often involves dietitians who have a thorough knowledge of what foods are acceptable.
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5. Multiple carboxylase deficiency
Multiple carboxylase deficiency is a form of metabolic disorder involving failures of carboxylation enzymes.
The deficiency can be in biotinidase or holocarboxylase synthetase.
These conditions respond to biotin.
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Forms include:
1) Holocarboxylase synthetase deficiency - neonatal;
2) Biotinidase deficiency - late onset;
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If left untreated, the symptoms can include feeding problems, hypotonia, generalized erythematous rash with skin exfoliation and alopecia, seizure, coma, developmental delay, foul smelling urine, metabolic acidosis, ketosis and hyperammonemia.
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• 1. Blood levels of lactic acid
are normally less than 1.2
mM. In lactic acidosis, the
values for blood lactate
may be 5mM or more.
6. Lactic acidosis
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2. The high concentration of lactate
results in lowered blood PH and
bicarbonate levels .
3. High blood lactate levels can result
from increased formation or decreased
utilization of lactate .
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4. Tissue anoxia may occur in
shock and other conditions that
impair blood flow , in
respiratory disorders , and in
severe anemia.
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