2. Inborn errors of metabolism (IEMs)
• They are a large group of rare genetic diseases that generally result
from a defect in an enzyme or transport protein which results in a
block in a metabolic pathway.
• Effects are due to toxic accumulations of substrates before the block,
intermediates from alternative metabolic pathways, defects in energy
production and use caused by a deficiency of products beyond the
block, or a combination of these metabolic deviations.
• Often the central nervous system (CNS) is affected, leading to
3. Inborn errors of metabolism (IEMs)
• Inborn errors of metabolism are now often referred to as congenital
metabolic diseases or inherited metabolic disorders.
• The term inborn errors of metabolism was coined by a British
physician, Archibald Garrod (1857–1936), in 1908.
• The incidence of IEMs, collectively, is estimated to be as high as 1 in
800 live births, but it varies greatly and depends on the population.
• Phenylketonuria (PKU) and medium-chain acyl-CoA dehydrogenase
(MCAD) deficiency with respective incidences of 1 in 10,000 and 1 in
20,000 are among the most prevelant.
• Traditionally the inherited metabolic diseases were classified as
disorders of carbohydrate metabolism, amino
acid metabolism, organic acid metabolism, or lysosomal storage
• In recent decades, hundreds of new inherited disorders of
metabolism have been discovered and the categories have
6. Signs and symptoms of IEMs
• Because of the enormous number of these diseases the wide range of
systems affected badly, nearly every "presenting complaint" to a
healthcare provider may have a congenital metabolic disease as a
possible cause, especially in childhood and adolescence. The
following are examples of potential manifestations affecting each of
the major organ systems.
• Growth failure, failure to grow, loss of weight
• Ambiguous genitalia, delayed puberty, precocious puberty
• Developmental delay, seizures, dementia, encephalopathy, stroke
• Deafness, blindness, pain agnosia(insensitivity to pain)
7. Signs and symptoms of IEMs
• Skin rash, abnormal pigmentation, lacking of pigmentation, excessive
hair growth, lumps and bumps
• Dental abnormalities
• Immunodeficiency, low platelet count, low red blood cell
count, enlarged spleen, enlarged lymph nodes
• Many forms of cancer
• Recurrent vomiting, diarrhea, abdominal pain
• Excessive urination, kidney failure, dehydration, edema
• Dozens of congenital metabolic diseases are now detectable
by newborn screening tests, especially expanded testing using mass
• This is an increasingly common way for the diagnosis to be made and
sometimes results in earlier treatment and a better outcome.
Specific diagnostic tests (or focused screening for a small set of
• Tissue biopsy: liver, muscle, brain, bone marrow
• Skin biopsy and fibroblast cultivation for specific enzyme testing
• Specific DNA testing
• In the middle of the 20th century the principal treatment for some of
the amino acid disorders was restriction of dietary protein and all other
care was simply management of complications.
• In the past twenty years, enzyme replacement, gene therapy, and organ
transplantation have become available and beneficial for many previously
• Some of the more common or promising therapies are listed:
• Dietary restriction
• E.g., reduction of dietary protein remains a mainstay of treatment
for phenylketonuria and other amino acid disorders
• Dietary supplementation or replacement
• E.g., oral ingestion of cornstarch several times a day helps prevent people
with glycogen storage diseases from becoming seriously hypoglycemic.
11. • Vitamins
• E.g., thiamine supplementation benefits several types of disorders
• Intermediary metabolites, compounds, or drugs that facilitate or
retard specific metabolic pathways
• Enzyme replacement E.g. Acid-alpha glucosidase for Pompe disease
• Bone marrow or organ transplantation
• Treatment of symptoms and complications
• Prenatal diagnosis
12. G6PD gene
• The G6PD gene provides instructions for making an enzyme called
• This enzyme, which is active in virtually all types of cells, is involved in
the normal processing of carbohydrates.
• It plays a critical role in red blood cells, which carry oxygen from the
lungs to tissues throughout the body.
• This enzyme helps protect red blood cells from damage and
14. Glucose-6-phosphate dehydrogenase
• Glucose-6-phosphate dehydrogenase deficiency (G6PDD) is
an inborn error of metabolism that predisposes to red blood cell
• Most of the time, those who are affected have no symptoms.
• Following a specific trigger, symptoms such as yellowish skin, dark
urine, shortness of breath, and feeling tired may develop.
• Complications can include anemia and newborn jaundice.
• Some people never have symptoms
15. Glucose-6-phosphate dehydrogenase
• Red blood cell breakdown may be
triggered by infections, certain
medication, stress, or foods such as fava
• Depending on the specific mutation the
severity of the condition may vary.
• Diagnosis is based on symptoms and
supported by blood tests and genetic
• G6PD deficiency is inherited as an X-linked defect.
• Males with a G6PD deficiency mutation on their X chromosome are
• Females with one G6PD deficiency mutation are carriers at a 50% risk
to pass their G6PD deficiency X chromosome to a male child.
• As an X-linked disorder, G6PD deficiency would generally be thought
to affect only males.
• However, females having a G6PD deficiency mutation on both of their
X chromosomes also have clinical symptoms.
• Some carrier females have been reported to have symptoms.
• Therefore, all members of an identified family should have G6PD
testing and genetic counseling.
• The risk for having an affected male pregnancy is one chance in two
for a carrier female.
• G6PD deficiency is found in populations from areas of the world
where malaria is prevalent (It is known that Africa and the Mediterranean basin are
high-risk areas for the infectious disease malaria. Researchers have found evidence that the
parasite that causes this disease does not survive well in G6PD-deficient cells. So they believe that
the deficiency may have developed as a protection against malaria.)
18. Glucose-6-phosphate dehydrogenase
• Avoiding triggers is important.
• Treatment of acute episodes may
include medications for infection,
stopping the offending medication,
or blood transfusions.
• Jaundice in newborns may be treated
with bili lights.
• It is recommended that people be
tested for G6PDD before certain
as primaquine(antimalarial) are taken
19. Glucose-6-phosphate dehydrogenase
• About 400 million people have the condition
• It is particularly common in certain parts of
Africa, Asia, the Mediterranean, and
the Middle East.
• Males are affected more often than
• In 2015 it is believed to have resulted in
20. CLINICAL MANIFESTATIONS
• Babies with G6PD deficiency appear normal at birth.
• They may experience neonatal jaundice and hemolysis that can be so
serious as to cause neurologic damage or even death.
• Excluding such severe complications in the newborn period, infants
with G6PD deficiency generally experience normal growth and
21. CLINICAL MANIFESTATIONS
• Exposure to certain antimalarial drugs and sulfonamides,
infection stress (such as upper respiratory or GI infections),
environmental agents (e.g. moth balls), and eating certain
foods (e.g. fava beans), each of which impact the patient’s
ability to handle oxidative reactions, can cause acute
• Conversely, uniform testing for several years by the United
States military found no significant adverse effects in G6PD
deficient males with their health or military performance
under proper care and avoidance.
Fava Beans "Saim Ki Phali" in Urdu
22. CLINICAL MANIFESTATIONS
• A child with G6PD deficiency who is exposed to a medication or infection
that triggers the destruction of RBCs may have no symptoms at all. In more
serious cases, a child may exhibit symptoms of hemolytic anemia (also
known as a hemolytic crisis), including:
• paleness (in darker-skinned kids, paleness is sometimes best seen in the mouth,
especially on the lips or tongue)
• extreme tiredness
• rapid heartbeat
• rapid breathing or shortness of breath
• jaundice, or yellowing of the skin and eyes, particularly in newborns
• an enlarged spleen
• dark, tea-colored urine
• Once the trigger is removed or resolved, the symptoms of G6PD deficiency
usually disappear fairly quickly, typically within a few weeks.
• Newborn screening for G6PD deficiency can be done by enzyme
analysis or primary DNA screening.
• Confirmatory testing using a quantitative assay should be performed
for diagnosis of G6PD deficiency.
• Infants with G6PD deficiency may be at increased risk for pathological
newborn jaundice and may warrant close monitoring for associated
complications during the newborn period.
• Otherwise, treatment of G6PD deficiency is avoidance.
• For the infant, this means avoidance of several medications routinely
prescribed for infections and illness.
• Strict attention to the ingredients of prepared foods and restaurant
meals is required as fava beans are a frequent addition to prepared
• Patients should not be exposed to moth balls containing naphthalene.
• The adverse affects of infection on patients with G6PD Deficiency can
be acute and life threatening.
• Over exertion from exercise and work leading to dehydration and
hypoglycemia can precipitate clinical symptoms.
• As mentioned above, patients mindful of these limitations can lead a
normal life of exercise and choice of vocation.
• Because the diagnosis and therapy of this disorder is complex, the
pediatrician is advised to manage the patient in close collaboration
with a consulting pediatric hematology specialist.
• It is recommended that parents travel with a letter of treatment
guidelines from the patient’s physician.
• There is no cure for G6PD deficiency, and it is a lifelong condition.
However, most people with G6PD deficiency have a completely
normal life as long as they avoid the triggers
27. Phenylketonuria (PKU)
• Phenylketonuria (fen-ul-key-toe-NU-ree-uh), also called PKU, is a rare
inherited disorder that causes an amino acid called phenylalanine to
build up in the body.
• PKU is caused by a defect in the gene that helps create the enzyme
needed to break down phenylalanine.
• Without the enzyme necessary to process phenylalanine, a dangerous
buildup can develop when a person with PKU eats foods that contain
protein or eats aspartame, an artificial sweetener.
28. Phenylketonuria (PKU)
• This can eventually lead to serious health problems.
• For the rest of their lives, people with PKU — babies, children and
adults — need to follow a diet that limits phenylalanine, which is
found mostly in foods that contain protein.
• Babies in the United States and many other countries are screened
for PKU soon after birth.
• Recognizing PKU right away can help prevent major health problems
29. Phenylketonuria (PKU) Symptoms
• Newborns with PKU initially don't have any symptoms. However,
without treatment, babies usually develop signs of PKU within a few
• PKU signs and symptoms can be mild or severe and may include:
• A musty odor (resembling the odor of wet socks or rotten wood) in the
breath, skin or urine, caused by too much phenylalanine in the body
• Neurological problems that may include seizures
• Skin rashes (eczema)
30. Phenylketonuria (PKU) Symptoms
• Fair skin and blue eyes, because phenylalanine can't
transform into melanin — the pigment responsible for
hair and skin tone
• Abnormally small head (microcephaly)
• Intellectual disability
• Delayed development
• Behavioral, emotional and social problems
• Psychiatric disorders
31. Severity varies
The severity of PKU depends on the type.
• Classic PKU. The most severe form of the disorder is called classic
PKU. The enzyme needed to convert phenylalanine is missing or
severely reduced, resulting in high levels of phenylalanine and severe
• Less severe forms of PKU. In mild or moderate forms, the enzyme
retains some function, so phenylalanine levels are not as high,
resulting in a smaller risk of significant brain damage.
• But most children with the disorder still require a special PKU diet to
prevent intellectual disability and other complications.
32. Pregnancy and PKU
• Women who have PKU and become pregnant are at risk of another
form of the condition called maternal PKU.
• If women don't follow the special PKU diet before and during
pregnancy, blood phenylalanine levels can become high and harm the
developing fetus or cause a miscarriage.
• Even women with less severe forms of PKU may place their unborn
children at risk by not following the PKU diet.
• Babies born to mothers with high phenylalanine levels don't often
inherit PKU. But they can have serious consequences if the level of
phenylalanine is high in the mother's blood during pregnancy.
33. Pregnancy and PKU
Complications at birth may include:
• Low birth weight
• Delayed development
• Facial abnormalities
• Abnormally small head
• Heart defects and other heart problems
• Intellectual disability
• Behavioral problems
34. When to see a doctor
Seek medical advice in these situations:
• Newborns. If routine newborn screening tests show that your baby may
have PKU, your child's doctor will want to start dietary treatment right
away to prevent long-term problems.
• Women of childbearing years. It's especially important for women with a
history of PKU to see a doctor and maintain the PKU diet before becoming
pregnant and during pregnancy to reduce the risk of high blood
phenylalanine levels harming their unborn babies.
• Adults. People with PKU continue to receive care across the life span.
Adults with PKU who have stopped the PKU diet in their teens may benefit
from a visit with their doctors. Returning to the diet may improve mental
functioning and behavior and slow damage to the central nervous system
that can result from high phenylalanine levels.
• A defective gene (genetic mutation) causes PKU, which can be mild,
moderate or severe. In a person with PKU, this defective gene causes
a lack of or deficiency of the enzyme that's needed to process
phenylalanine, an amino acid.
• A dangerous buildup of phenylalanine can develop when a person
with PKU eats protein-rich foods, such as milk, cheese, nuts or meat,
and even grains such as bread and pasta, or eats aspartame, an
artificial sweetener. This buildup of phenylalanine results in damage
to nerve cells in the brain.
• People with PKU must also avoid food products that contain aspartame, as it's
converted into phenylalanine in the body.
• Aspartame is a sweetener found in:
• sugar substitutes such as the artificial sweeteners often used in tea and coffee
• diet versions of fizzy drinks
• chewing gum
• squash and cordial
• some alcopops
• All food products that contain aspartame or a related product should be clearly
• There are also medicines that contain aspartame, such as some children's cold
and flu remedies.
• It's a legal requirement for any medicine that contains aspartame to state it on
the patient information leaflet that comes with the medicine.
• For a child to inherit PKU, both the mother and father must have and
pass on the defective gene. This pattern of inheritance is called
• It's possible for a parent to be a carrier — to have the defective gene
that causes PKU, but not have the disease. If only one parent has the
defective gene, there's no risk of passing PKU to a child, but it's
possible for the child to be a carrier.
• Most often, PKU is passed to children by two parents who are carriers
of the disorder, but don't know it.
38. Risk factors
Risk factors for inheriting PKU
• Having both parents with a defective
gene that causes PKU. Two parents
must pass along a copy of the defective
gene for their child to develop the
• Being of certain ethnic descent. The
gene defect that causes PKU varies by
ethnic groups and it's less common in
African-Americans than in other ethnic
• Untreated PKU can lead to complications in infants, children and adults
with the disorder. When mothers with PKU have high blood phenylalanine
levels during pregnancy, fetal birth defects or miscarriage can occur.
Untreated PKU can lead to:
• Irreversible brain damage and marked intellectual disability beginning
within the first few months of life
• Neurological problems such as seizures and tremors
• Behavioral, emotional and social problems in older children and adults
• Major health and developmental problems
• If you have PKU and are considering getting pregnant:
• Follow a low-phenylalanine diet. Women with PKU can prevent birth
defects by sticking to or returning to a low-phenylalanine diet before
becoming pregnant. If you have PKU, talk to your doctor before you
start trying to conceive.
• Consider genetic counseling. If you have PKU, a close relative with
PKU or a child with PKU, you may also benefit from genetic counseling
before becoming pregnant. A doctor who specializes in medical
genetics (geneticist) can help you better understand how PKU is
passed through your family tree. He or she can also help determine
your risk of having a child with PKU and assist with family planning.
• Galactosemia is a disorder that affects how the body processes a
simple sugar called galactose.
• A small amount of galactose is present in many foods.
• It is primarily part of a larger sugar called lactose, which is found in all
dairy products and many baby formulas.
• The signs and symptoms of galactosemia result from an inability to
use galactose to produce energy.
• Researchers have identified several types of galactosemia.
• These conditions are each caused by mutations in a particular gene
and affect different enzymes involved in breaking down galactose.
43. Classic galactosemia, also known as type I,
• is the most common and most severe form of the condition.
• If infants with classic galactosemia are not treated promptly with a
low-galactose diet, life-threatening complications appear within a few
days after birth.
• Affected infants typically develop feeding difficulties, a lack of energy
(lethargy), a failure to gain weight and grow as expected (failure to
thrive), yellowing of the skin and whites of the eyes (jaundice), liver
damage, and abnormal bleeding.
44. Classic galactosemia, also known as type I,
• Other serious complications of this condition can include
overwhelming bacterial infections and shock.
• Affected children are also at increased risk of delayed development,
clouding of the lens of the eye speech difficulties, and intellectual
• Females with classic galactosemia may develop reproductive
problems caused by an early loss of function of the ovaries
(premature ovarian insufficiency).
45. Galactosemia type II
• (also called galactokinase deficiency) and type III (also called
galactose epimerase deficiency) cause different patterns of signs and
• Galactosemia type II causes fewer medical problems than the classic
• Affected infants develop cataracts but otherwise experience few long-
• The signs and symptoms of galactosemia type III vary from mild to
severe and can include cataracts, delayed growth and development,
intellectual disability, liver disease, and kidney problems.
• This condition is inherited in an autosomal recessive pattern, which
means both copies of the gene in each cell have mutations.
• The parents of an individual with an autosomal recessive condition
each carry one copy of the mutated gene, but they typically do not
show signs and symptoms of the condition.
48. Testing and Treatment
• Every baby born at a U.S. hospital is given what’s called a newborn
screening. A blood sample is taken from a heel stick (a tiny cut in the
baby’s foot) and it is tested for several conditions.
• If your baby shows signs of the illness, your doctor will suggest a
follow-up test to confirm. This test will include both a blood
and urine sample.
• If your child has galactosemia, your doctor will work with you to plan
a diet. Lactose and galactose are taken out of their diet. Instead,
they’re given soy-based formula and must avoid milk or milk
49. Testing and Treatment
• Though a person with galactosemia will never be able to process this
type of sugar, they can live normal lives if the disease is caught early
• Along with eliminating dairy, your doctor may recommend cutting out
some fruits, vegetables, and candies that contain galactose. In
addition, your child may need to take vitamin and
mineral supplements such as calcium, vitamin C, vitamin D,
and vitamin K.
50. Testing and Treatment
• Babies with type II or type III also will have fewer issues than babies
with classic galactosemia.
• However, they still can develop cataracts, kidney and liver issues, and
have delayed growth. Girls with galactosemia may
require hormone treatment when they reach puberty.
• It’s important that parents of a child with galactosemia work with
a health care team to find ways to help them live with the condition
and its effects on their daily life.