IEM 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.
3. X-linked recessive inheritance is a mode of
inheritance in which a mutation in a gene on
the X chromosome causes the phenotype to be
expressed in males and in females who are
homozygous for the gene mutation.
Autosomal recessive is one of several ways that a
trait, disorder, or disease can be passed down
through families.
An autosomal recessive disorder means two copies of
an abnormal gene must be present in order for the
disease or trait to develop.
4. Amino Acid Disorders
Inability to metabolize a certain essential amino acid.
No metabolism of amino acid can be toxic for body. These
disorders are:
Phenylketonuria
Maple syrup urine disease
Homocystinuria
Tyrosinemia
5. Defect or total absence of any of the enzymes or the cofactors used
in the urea cycle.
Lead to accumulation of ammonia in the blood.
The urea cycle converts waste nitrogen into urea and excretes it
from the kidneys.
Since there are no alternate pathways to clear the ammonia.
Dysfunction of the urea cycle results in neurologic damages.
Citrullinemia
Argininosuccinic aciduria
Carbamoyl phosphate synthetase i deficiency
6. This group of disorders includes an enzyme deficiency or its cofactor
that affects the catabolism or anabolism of carbohydrate.
Carbohydrate disorders are complex and affect neurological,
physical, and nutritional status and these are as:
Galactosemia
Glycogen storage disease type I
Glycogen storage disease type II
Glycogen storage disease type III
Glycogen storage disease type IV (Andersen Disease)
Glycogen storage disease type V
Glycogen storage disease type VI
Hereditary Fructose Intolerance
7. Excretion of non-amino organic
acids in the urine.
Caused by a deficient enzyme
involving the catabolism of
specific amino acid.
The non-metabolized substance
accumulates due to the blockage
of the specific metabolic
pathway
Which is toxic to certain organs
and may also cause damage to
the brain.
Isovaleric acidemia
3-Methylcrotonyl-CoA
carboxylase deficiency
Glutaric acidemia type I
Glutaric acidemia type II
3-hydroxy-3-methylglutaryl-
coenzyme A lyase deficiency
Multiple carboxylase
deficiency (Biotinidase
deficiency, Holocarboxylase
synthetase deficiency)
Methylmalonic acidemia
Propionic acidemia
Beta-ketothiolase deficiency
8. Enzyme defect in the process of
mitochondrial fatty acid
oxidation (FAO) system.
The biochemical characteristic
of all fao defects is abnormal
low ketone production as a
result of the increased energy
demands.
This results in fasting
hypoglycemia with severe
acidosis secondary to the
abnormal accumulation of
intermediate metabolites of fao,
which can result in death.
Medium-chain acyl-coa
dehydrogenase deficiency
Long-chain 3-hydroxyacyl-coa
dehydrogenase deficiency
Trifunctional protein deficiency
type 1 (lchad deficiency)
Trifunctional protein deficiency
type 2 (mitochondrial
trifunctional protein deficiency)
Carnitine uptake defect (primary
carnitine deficiency)
Very long-chain acyl-coa
dehydrogenase deficiency
9. Peroxisomes are small organelles found in cytoplasm of all cells.
They carry out oxidative reactions which generate hydrogen peroxides.
They also contain catalase (peroxidase), which is important in detoxifying
ethanol, formic acid and other toxins.
There are two types of peroxisomal disorders:
a) Single peroxisomal enzyme deficiencies (dysfunction of a specific
enzyme, such as acyl coenzyme a oxidase deficiency) and
b) Peroxisomal biogenesis disorders. (By multiple peroxisome enzymes such
as zellweger syndrome and neonatal adrenoleukodystrophy).
These disorders cause severe seizures and psychomotor retardation.
Adrenoleukodystrophy (x-ald)
Zellweger syndrome spectrum
10. They occur when any defect or total absence of any of the
enzymes or the cofactors used in the urea cycle results in the
accumulation of ammonia in the blood.
The urea cycle converts waste nitrogen into urea and excretes it
from the kidneys.
Since there are no alternate pathways to clear the ammonia,
dysfunction of the urea cycle results in neurologic damages.
Citrullinemia
Argininosuccinic aciduria
Carbamoyl phosphate synthetase I deficiency
11. Mitochondrial Disorders are
caused by the dysfunction of the
mitochondrial respiratory chain, or
electron transport chain (ETC).
The ETC dysfunction increases free
radical production, which causes
mitochondrial cellular damage,
cell death and tissue necrosis and
further worsens ETC dysfunction
and thus forms a vicious cycle.
The disorders can affect almost all
organ systems. Brain and muscles
(skeletal and cardiac) are most
affected due to high energy
demand.
Leber hereditary optic
neuropathy
Mitochondrial
encephalomyopathy, lactic
acidosis, and stroke-like
episodes (MELAS)
Mitochondrial
neurogastrointestinal
encephalopathy disease
(MNGIE)
Myoclonic epilepsy with
ragged-red fibers (MERRF)
Neuropathy, ataxia, and retinitis
pigmentosa (NARP)
Pyruvate carboxylase deficiency
13. Phenylketonuria (PKU)
o A rare disease in which body can’t process an amino
acid called phenylalanine.
o Phenylalanine is one of the essential amino acids.
o The liver uses an enzyme called phenylalanine
hydroxylase with a catalyst, (tetrahydrobiopterin,
BH4) to change some of the Phenylalanine to a non-
essential amino acid called tyrosine.
14. o Tyrosine is used to build proteins and to make
a neurotransmitter (chemical messenger) in
the brain called dopamine.
o Phenylalanine mainly comes from protein-
rich foods such as meat, eggs, nuts, Beans,
milk, and cheese.
21. Inborn error in the degradation of the tyrosine. People
have problems breaking down an amino acid tyrosine
from the food they eat.
Hereditary – autosomally recessive.
Three types:
a) Type I – deficiency of the enzyme fumarylacetoacetate
hydrolase (FAH).
b) Type II – deficiency of the enzyme tyrosine
aminotransferase (TAT).
c) Type III – deficiency of the enzyme 4-
hydroxyphenylpyruvate dioxygenase (HPPD).
22. Autosomal recessive is one of several ways that a trait, disorder, or
disease can be passed down through families.
An autosomal recessive disorder means two copies of an
abnormal gene must be present in order for the disease or trait to
develop.
Parents of
children with
tyrosinemia
rarely have the
condition
themselves.
Instead, each
parent has a
single non-
working gene
for the
condition. They
are called
carriers.
Carriers do not
have the
condition
because the
other gene of
this pair is
working
correctly.
23. Tyrosinemia 1 occurs when an enzyme, called fumarylacetoacetase
(FAH), is either missing or not working properly.
There is a mutation in the FAH gene that encodes for the FAH enzyme.
When FAH is not working, it cannot break down tyrosine. Tyrosine
and other harmful substances then build up in the blood.
Can be either chronic or acute.
◦ Acute – infancy
◦ Chronic – later in life
24. Failure to gain weight or grow
Diarrhea, bloody stools and
vomiting
Jaundice of skin and eyes
Cabbage-like odor to the skin
or urine
Increased tendency to bleed
(esp. Nosebleeds)
Extreme sleepiness
Irritability
Enlarged liver
Yellowing of the skin
Tendency to bleed and bruise
easily
Swelling of the legs and
abdomen
Liver cirrhosis and/or
hepatocellular carcinoma
(chronic)
Kidney problems
Rickets
Delays in walking
25.
26.
27. Caused by a mutation in the TAT gene that encodes for the
hepatic (liver) TAT enzyme.
Also known as “Richner-Hanhart syndrome”
TAT gene –Tyrosine Amino Transferase
Which is responsible for converting tyrosine to 4-
hydroxyphenylpyruvate. TAT is the enzyme involved in the
first of a series of five reactions of tyrosine degradation.
Occurs in cytosol
Pyridoxal 5’-phosphate (PLP) dependent enzyme
28. • Elevated serum and plasma tyrosine levels
• Lesions of skin and eyes
• Due to clumping of cellular tyrosine crystals.
• Excessive tearing, abnormal sensitivity to light (photophobia),
lacrimation, burning eye pain, inflamed conjunctiva
• Microcephaly - Mental retardation (caused by elevated blood
tyrosine levels)
• Blistering lesions on the palms and soles
• delay behavioral problems and self injurious behaviors also
occurring frequently
• Symptoms often begin in early childhood
29. • Deficiency of 4-hydroxyphenylpyruvate dioxygenase (HPPD)
• Caused by a mutation in the HPPD gene that encodes for the enzyme
HPPD
• Second enzyme involved in tyrosine catabolism pathway
30. • Mild mental retardation
• Seizures
• Loss of balance and coordination (intermittent ataxia)
• High blood and urine concentrations of tyrosine and HPP
31.
32. • Newborn screen
Tandem mass spectrometry
• Maintaining tyrosine levels below 800µmol/l appears to be
protective against pathology including neurological squeal
33. Vitamin D supplements are sometimes used to treat children who have
rickets.
The special medical formula gives babies and children the nutrients and
protein they need while helping keep their tyrosine levels within a safe
range.
Liver transplant (popular in 1980s)
There is a need to limit foods such as:
cow’s milk
meat
eggs and cheese
regular flour
dried beans
Nuts and peanut butter
34.
35.
36. * MSUD formula supplemented
* Frequent monitoring of blood levels
* Does not include any high protein foods such as meat,
nuts, eggs, and most dairy products.
* There is no age at which diet treatment can be
stopped.
* Lifelong therapy is essential for an optimal outcome.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47. Incidence
• Type 1: 1/30,000 to 1/60,000 for classic
galactosemia
• Age: Neonatal onset, some complications evident
later on in life
48. SIGNS AND SYMPTOMS
At birth: Jaundice after milk
consumption
Feeding difficulties
Vomiting and diarrhea
Aminoaciduria: High levels of
amino acids in urine and/or
plasma
Hepatomegaly
Hypoglycemia
Ascites - fluid accumulation in
the abdomen
High Galactose concentrations
in blood and urine
49. Clinical Findings in Galactosemic
Patients Infants
Poor weight gain
Feeding difficulties
Jaundice
Vomiting
Diarrhea
Refusal to feed, vomiting,
Jaundice and lethargy.
Hepatomegaly, edema and
Ascites may follow.
Death from sepsis may follow.
Diarrhea
Lethargy
Hypotonia
Hepatomegaly
Sepsis
Hemolytic anemia
If untreated - cataract ,
mental retarda4on , kideny
dysfunction, liver cirrhoses and
death in many infants because
of infection and hepatic failure.
Death from sepsis may follow
within days but it has been
noted as early as 3 days of age.
Cataracts appear within days
or weeks
50. DIAGNOSIS
By the presence of galactose in urine and blood
with normal or low blood sugar while the infant
is being fed breast milk or a formula containing
lactose.
A simple urine test ( Benedict test ) indicates
the presence of a reducing substances.
Measurement of enzyme activity in the red blood
cells (fluorometric assay and Beutler assay).
Prenatal diagnosis by direct measurement of the
enzyme galactose-1-phosphate uridyl
transferase in in cultured amniotic cells.
51. TREATMENT
Removal of galactose from diet. Avoid milk
products and anything containing lactose or
galactose. For infants, milk can be substituted
with lactose-free formula or soya formula.
Calcium and vitamin supplements are
recommended.
Pregnant women at risk should restrict intake of
galactose to protect an affected fetus .
Neonatal screening for diagnosis and treatment
of classical galactosemia , is very important to
prevent life threatning complications.
52. fructose intolerance
▪ Hereditary fructose intolerance is a hereditary
condition caused by a deficiency of liver enzymes
that metabolise fructose.
▪ The deficient enzyme is aldolase-B (ALDOB),
which converts fructose-1-phosphate to DHAP
and glyceraldehyde.
▪ This means that the fructose cannot be further
metabolised beyond fructose-1-phosphate.
53.
54.
55.
56.
57.
58. Fruits that may be tolerated Fruits to stay away from
avocado
bananas, ripe
blackberries, blueberries
cantaloupe
grapefruit
kiwi fruit
lemon
lime
orange
papaya
pineapple
raspberries
rhubarb
star fruit (carambola)
Strawberries
apple, applesauce, apple juice,
cider*
apricots*
cherries*
coconut milk and cream
dried fruit (raisins, figs)
fruit juice
guava
grapes
lychee*
mango
peach*
pears and pear juice*
plums and prunes*
watermelon
* These fruits contain natural sugar alcohols and may cause symptoms.