Inborn errors of metabolism

Compiled by
Dr. V. MAGENDIRA MANI
Assistant Professor of Biochemistry
Islamiah College (Autonomous)
Vaniyambadi
Vellore District
Mail: magendiramani@rediffmail.com
Download Science at: https://tvuni.academia.edu/mvinayagam
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PHENYLKETONURIA
Phenylketonuria (PKU) is a rare genetic condition that causes an amino acid called
phenylalanine to build up in the body. Amino acids are the building blocks of protein.
Phenylalanine is found in all proteins and some artificial sweeteners. Phenylalanine
hydroxylase is an enzyme convert phenylalanine into tyrosine, which needs to create
neurotransmitters such as epinephrine, norepinephrine, and dopamine. PKU is caused by a defect
in the gene that helps create phenylalanine hydroxylase. When this enzyme is missing, our body
can’t break down phenylalanine. This causes a buildup of phenylalanine in our body.
The condition is uncommon, only affecting about 1 in 10,000 to 15,000 newborns each year. The
severe signs and symptoms of PKU are rare, as early screening allows treatment to begin soon
after birth. Early diagnosis and treatment can help relieve symptoms of PKU and prevent brain
damage.
Symptoms of phenylketonuria
PKU symptoms can range from mild to severe. The most severe form of this disorder is known
as classic PKU. An infant with classic PKU may appear normal for the first few months of their
life. If the baby isn’t treated for PKU during this time, they’ll start to develop the following
Symptoms
 Seizures (sudden occurrence of diseases)
 Tremors, or trembling and shaking (involuntary vibration)
 Stunted growth
 Hyperactivity
 Skin conditions such as eczema)
 A musty odor of their breath, skin, or urine
If PKU isn’t diagnosed at birth and treatment isn’t started quickly, the disorder can cause:
 Irreversible brain damage and intellectual disabilities within the first few months of life
 Behavioral problems and seizures in older children

Causes of phenylketonuria
PKU is an inherited condition
caused by a defect in the PAH
gene. The PAH gene helps create
phenylalanine hydroxylase, the
enzyme responsible for breaking
down
dangerous
phenylalanine.
buildup
A
of
phenylalanine can occur when
someone eats high-protein foods,
such as eggs and meat. Both
parents must pass on a defective
version of the PAH gene for their child to inherit the
disorder. If just one parent passes on an altered gene, the
child won’t have any symptoms, but they’ll be a carrier of
the gene.
Diagnosis
Screening for PKU involves the following:
 This test involves taking a sample of blood and
analyzing it for the presence of the enzyme needed to
break down phenylalanine.
 Determination of phenylalanine levels: The standard
amino acid analysis done by means of ion exchange
chromatography or tandem mass spectrometry.
 The Guthrie test as a bacterial inhibition assay:
Formerly used, but now being replaced by tandem
mass spectrometry.

Treatment options
People with PKU can relieve their symptoms and prevent complications by following a special
diet and by taking medications.
Diet
The main way to treat PKU is to eat a special diet that limits foods containing phenylalanine.
Infants with PKU may be fed breast milk. When your baby is old enough to eat solid foods, you
need to avoid letting them eat foods high in protein. These foods include:
 eggs
 cheese
 nuts
 milk
 beans
 chicken
 beef
 pork
 fish
To make sure that they still receive an adequate amount of protein, children with PKU need to
consume PKU formula. It contains all the amino acids that the body needs, except for
phenylalanine. There are also certain low-protein, PKU-friendly foods that can be found at
specialty health stores.
TYROSINOSIS
A very rare, possibly heritable disorder of tyrosine metabolism that may be caused by defective
formation of p-hydroxyphenylpyruvic acid oxidase or of tyrosine transaminase;
characterized by enhanced urinary excretion of p-hydroxyphenylpyruvic acid and of other
tyrosyl metabolites upon ingestion of tyrosine or proteins containing that amino acid; of
autosomal recessive inheritance.
Type 1 tyrosinemia, also known as hepatorenal tyrosinemia or tyrosinosis, is the most severe
form of tyrosinemia, a buildup of too much of the amino acid tyrosine in the blood and tissues
due to an inability to metabolize it. It is caused by a deficiency of the enzyme
fumarylacetoacetate hydrolase.

Fumarylacetoacetate hydrolase catalyzes the final step in the degradation of tyrosine -
fumarylacetoacetate to fumarate, acetoacetate and succinate. Fumarylacetoacetate accumulates in
hepatocytes and proximal renal tubal cells and causes oxidative damage and DNA damage
leading to cell death and dysfunctional gene expression which alters metabolic processes like
protein synthesis and gluconeogenesis. The increase in fumarylacetoacetate inhibits previous
steps in tyrosine degradation leading to an accumulation of tyrosine in the body. Tyrosine is not
directly toxic to the liver or kidneys but causes dermatologic and neurodevelopmental problems.
Symptoms
Type 1 tyrosinemia typically presents in infancy as failure to thrive and hepatomegaly. The
primary effects are progressive liver and kidney dysfunction. The liver disease causes cirrhosis,
conjugated hyperbilirubinemia, elevated AFP, hypoglycemia and coagulation abnormalities. This
can lead to jaundice, ascites and hemorrhage. There is also an increased risk of hepatocellular
carcinoma. The kidney dysfunction presents as Fanconi syndrome: Renal tubular acidosis,
hypophosphatemia and aminoaciduria. Cardiomyopathy, neurologic and dermatologic
manifestations are also possible. The urine has an odor of cabbage or rancid butter.
Treatment
The primary treatment for type 1 tyrosinemia is nitisinone (Orfadin) and restriction of tyrosine in
the diet. Nitisinone inhibits the conversion of 4-OH phenylpyruvate to homogentisic acid by 4-

Hydroxyphenylpyruvate dioxygenase, the second step in tyrosine degradation. By inhibiting this
enzyme, the accumulation of the fumarylacetoacetate is prevented. Previously, liver
transplantation was the primary treatment option and is still used in patients in whom nitisinone
fails.
ALKAPTONURIA
Alkaptonuria (black urine disease, black bone disease, or alcaptonuria) is a rare inherited genetic
disorder in which the body cannot process the amino acids phenylalanine and tyrosine, which
occur in protein.
Alkaptonuria is a rare inherited disorder. It occurs when your body can’t produce enough of an
enzyme called homogentisic dioxygenase (HGD). This enzyme is used to break down a toxic
substance called homogentisic acid. When you don’t produce enough HGD, homogentisic acid
builds up in your body.
The buildup of homogentisic acid causes your bones and cartilage to become discolored and
brittle. This typically leads to osteoarthritis, especially in your spine and large joints. People with
alkaptonuria also have urine that turns dark
brown or black when it’s exposed to air.
Symptoms of Alkaptonuria
Dark stains on a baby’s diaper are one of the
earliest signs of alkaptonuria. There are few
other symptoms during childhood.
Other symptoms of alkaptonuria include:
 dark spots in the sclera (white) of
your eyes
 thickened and darkened cartilage in
your ears
 blue speckled discoloration of your skin, particularly around sweat glands
 dark-colored sweat or sweat stains

 black earwax
 kidney stones and prostate stones
 arthritis (especially hip and knee joints)
Alkaptonuria can also lead to heart problems. The buildup of homogentisic acid causes your
heart valves to harden. This can keep them from closing properly, resulting in aortic and mitral
valve disorders. In severe cases, heart valve replacement may be necessary. The buildup also
causes your blood vessels to harden. This raises your risk of high blood pressure.
CausesAlkaptonuria
Alkaptonuria is caused by a mutation on your homogentisate 1,2-dioxygenase (HGD) gene. It’s
an autosomally recessive condition. This means that both of your parents must have the gene in
order to pass the condition on to you. Alkaptonuria is a rare disease. According to the National
Organization of Rare Disorders (NORD), the exact number of cases is unknown. It is estimated
to occur in 1 of every 250,000 –1 million live births in the United States. However, it’s more
common in certain areas of Slovakia, Germany, and the Dominican Republic.
Diagnosis
If your urine turns dark brown or black when it’s exposed to air, they may also test you for the
condition if you develop early onset osteoarthritis.
Treatment
There’s no specific treatment for alkaptonuria. You may be put on a low-protein diet. Also
recommend large doses of ascorbic acid, or vitamin C, to slow down the accumulation of
homogentisic acid in your cartilage. However, NORD warns that long-term use of vitamin C has
generally proven ineffective for treating this condition. Other treatments for alkaptonuria are
focused on preventing and relieving possible complications, such as:
 arthritis
 heart disease
 kidneystones

For example, anti-inflammatory medications or narcotics for joint pain. Physical and
occupational therapy may help you maintain flexibility and strength in your muscles and joints.
You should also avoid activities that put a lot of strain on your joints, such as heavy manual
labor and contact sports.
MAPLE SYRUP URINE DISEASE
 Maple syrup urine disease (MSUD) is a rare metabolic disorder that develops from
inheriting a mutated gene from each parent.
 People who have the disease produce urine that has a distinctive maple syrup odor.
 If left untreated, MSUD can cause significant physical and neurological problems.
Maple syrup urine disease (MSUD) is a rare, inherited metabolic disorder. The disease prevents
your body from breaking down certain amino acids.
Amino acids are what remain after your body digests protein from the food you eat. Special
enzymes process amino acids so they can be used to maintain all of your body functions. If some
of the necessary enzymes are missing or defective, the amino acids and their byproducts, called
keto acids, collect in your body. As the levels of these substances increase, it can result in:
 neurological damage
 coma
 life-threatening conditions
In MSUD, the body lacks an enzyme called BCKDC (branched-chain alpha-keto acid
dehydrogenase complex). The BCKDC enzyme processes three important amino acids: leucine,
isoleucine, and valine, also called BCAAs (branched-chain amino acids). BCAAs are found in
foods rich in protein, such as meat, eggs, and milk.
When untreated, MSUD can cause significant physical and neurological problems. MSUD can
be controlled with dietary restrictions. The success of this method can be monitored with blood
tests. Early diagnosis and intervention improve the chance of long-term success.

Symptoms of MSUD
Some initial symptoms characteristic of classic MSUD are:
 lethargy (inactivity)
 poor appetite
 weight loss
 weak sucking ability
 irritability
 a distinctive maple sugar odor in earwax, sweat, and urine
 irregular sleep patterns
 alternating episodes of hypertonia (muscle rigidity) and hypotonia (muscle limpness)
 high-pitched cry
Signs of intermediate and thiamine-response MSUD include:
 seizures (sudden occurrence of diseases)
 neurological deficiencies
 developmental delays
 feeding problems
 poor growth
 a distinctive maple sugar odor in earwax, sweat, and urine
Diagnosis
Identifying the presence of MSUD at birth is critical to preventing long-term damage. In cases
when both parents are carriers and their child’s test is negative for MSUD, additional tests may
be advised to confirm the findings and prevent the onset of symptoms.
When symptoms show up after the newborn period, diagnosis of MSUD can be made by a urine
analysis or blood test. A urine analysis can detect a high concentration of keto acids, and a blood
test can detect a high level of amino acids. The diagnosis of MSUD also can be confirmed with
an enzyme analysis of white blood cells or skin cells.

Complications of MSUD
Complications from undiagnosed and untreated MSUD can be severe and even fatal. Even babies
in a treatment plan can experience incidents of extreme sickness, called metabolic crises.
Metabolic crises occur when there is a sudden and intense increase of BCAAs in the system. If
untreated, the situation can lead to serious physical and neurological damage. A metabolic crisis
usually is indicated by:
 extreme fatigue or lethargy
 loss of alertness
 irritability
 vomiting
When MSUD is undiagnosed, or metabolic crises are untreated, the following severe
complications can occur:
 seizures
 swelling of the brain
 lack of blood flow to the brain
 metabolic acidosis — a situation in which the blood contains high levels of acidic
substances
 coma
When these conditions occur, they can result in:
 severe neurological damage
 intellectual disability
 blindness
 spasticity, or uncontrolled muscle tightness
Eventually, life-threatening complications can develop and lead to death, especially if they go
untreated.

Treatment of MSUD
If your infant is diagnosed with MSUD, prompt medical treatment can avoid serious medical
problems and intellectual disability. Initial treatment involves reducing the levels of BCAAs in
your baby’s blood.
Typically, this involves intravenous (IV) administration of amino acids that don’t contain
BCAAs, combined with glucose for extra calories. The treatment will promote the utilization of
existing leucine, isoleucine, and valine in the body. At the same time it will reduce the BCAA
level and provide necessary protein.
Your physician will create a long-term treatment plan for your child with MSUD in conjunction
with a metabolic specialist and a dietitian. The goal of the treatment plan is to provide your child
with all the protein and nutrients needed for healthy growth and development. The plan will also
avoid allowing too many BCAAS to collect in their blood.
Prevention
Genetic counseling is suggested for people who want to have children and who have a family
history of maple syrup urine disease. Many states now screen all newborns with blood tests for
MSUD.
If a screening test shows that your baby may have MSUD, a follow-up blood test for amino acid
levels should be done right away to confirm the disease.
HARTNUPDISEASE
Hartnup disease (also known as "pellagra-like dermatosis" and "Hartnup disorder") is an
autosomal recessive metabolic disorder affecting the absorption of nonpolar amino acids
(particularly tryptophan that can be, in turn, converted into serotonin, melatonin, and niacin).
 Hartnup disease is a hereditary metabolic disorder.
 It affects your body’s ability to absorb certain amino acids.
 Complications of this condition are rare, but there are treatments to control symptoms

Hartnup disease is also referred to as Hartnup disorder. It’s a hereditary metabolic disorder. It
makes it difficult for your body to absorb certain amino acids from your intestine and reabsorb
them from your kidneys. Amino acids are essential building blocks for creating protein in your
body.
Hartnup disease was named for the Hartnup family of England, who were featured in a 1956
study of the condition. Four out of eight family members were found to have excessive amounts
of amino acids in their urine. They also had skin rash and a lack of coordination of their
voluntary muscle movements, known as ataxia. These are the signs and symptoms characteristic
of Hartnup disease, which typically affects the skin and brain.
The National Organization for Rare Disorders reports that Hartnup disease is estimated to affect
about one in 30,000 people in the United States. Symptoms normally start to appear in infancy or
the first few years of life. Symptoms last for about two weeks when there is an ―attack.‖ The
frequency of these attacks decreases with age.
Symptoms of Hartnup disease
 skin rash
 anxiety
 rapid mood swings
 delusions
 hallucinations
 intention tremor
 speech difficulties
 unsteady wide-based gait, in which you walk with your legs farther apart than normal
 abnormalities in muscle tone, in which your muscles become tighter or lose tone
 short stature
 sensitivity to light
A skin rash called ―pellagra‖ is a common symptom. It usually results from exposure to
sunlight. It’s an intermittent red and scaly rash that typically appears over your face, neck,
hands, and legs. It’s initially red, but over time it can progress to an eczematous-like rash.
With prolonged sun exposure, the changes in your skin pigmentation can become permanent.

Sunlight, poor nutrition, sulfonamide drugs, or emotional or physical stress may trigger
symptoms.
Although symptoms usually begin to appear in infancy or early childhood, they may also
appear in early adulthood. Acute attacks of symptoms generally become less frequent as you
get older.
Hartnup disease diagnosed
Laboratory to measure the amount of amino acids excreted through your urine. If there are
high levels of ―neutral‖ amino acids in your urine, it may be a sign of Hartnup disease.
Treatment
If you’re diagnosed with Hartnup disease, your doctor will likely advise you to change your
diet, avoid sunlight, and avoid sulfonamide drugs.
Dietary changes
Since those with Hartnup disease can’t produce enough niacin, consuming foods that contain
niacin can significantly reduce your symptoms. Good sources of niacin include:
 red meat
 poultry
 fish
 peanut butter
 fortified grains
 whole grains
 potatoes
Red meat, poultry, fish, and peanuts are also excellent sources of protein. Choose lean cuts of
red meat and skinless poultry. The fat and skin of meat and poultry are rich sources of
saturated fat. Eating too much saturated fat can raise your risk of high cholesterol.

Supplements
Your doctor may also suggest taking vitamin B complex or niacin supplements, such as
nicatonic acid. Your recommended supplement dosage will depend on the severity of your
niacin deficiency.
Sun avoidance
Your doctor may also advise you to avoid direct exposure to the sun. For example, they may
encourage you to wear sunscreen and protective clothing.
HOMOCYSTINURIA
Homocystinuria is a disorder of methionine metabolism, leading to an abnormal
accumulation of homocysteine and its metabolites (homocystine, homocysteine-cysteine
complex, and others) in blood and urine. Homocystinuria is an inherited disorder that keeps
the body from processing the essential amino acid methionine. Amino acids are the building
blocks of protein. Methionine occurs naturally in various proteins. Infants need it for growth,
and adults need it to maintain their body’s nitrogen balance.
The illness usually affects infants during the first few years of life, and the more rare forms
of the disorder can lead to children being underweight. If it’s left untreated, homocystinuria
can have serious and sometimes fatal complications.
Symptoms
The symptoms will depend on the type of homocystinuria. Symptoms generally develop
during the first years of life. However, some people experience symptoms during adulthood.
Symptoms are often vague and difficult to detect. The most common forms of this disorder
may involve the following symptoms:
 dislocation of the lenses in the eyes
 nearsightedness
 abnormal blood clots
 osteoporosis, or weakening of the bones
 learning disabilities
 developmental problems

 chest deformities, such as a protrusion or a caved-in appearance of the breastbone
 long, spindly arms and legs
 scoliosis
Less common variations involve these additional signs and symptoms:
 megaloblastic anemia, an anemia involving larger-than-normal red blood cells
 seizures
 failure to thrive
 intellectual disabilities
 movement and gait abnormalities
Types of Homocystinuria
Numerous variations of homocystinuria exist. They range from common to rare. No specific
names exist for these variations. Instead, they’re distinguished by their symptoms.
Infants who are affected by the common form of this disorder generally experience mild
symptoms. In fact, they may not even have symptoms that require treatment until they’re older.
However, the less common forms of this disorder have been known to cause more serious
developmental problems, including impaired intellectual capability.
Causes
Certain genetic mutations present at
birth cause this disease. More than 150
mutations that cause homocystinuria
have been found in the gene
cystathionine beta-synthase, which is
also known as the CBS gene. The CBS
gene holds instructions for making an
uses vitamin B-6 toenzyme that
metabolize
homocysteine
mutations prevent
the amino
and serine.
the
acids
The
normal

functioning of the CBS gene. This results in a buildup of homocysteine and other toxins that
damage the nervous system, which includes the brain, and the vascular system.
In rare cases, mutations in other genes like MTHFR, MTR, or MTRR cause the disorder.
Homocystinuria is an autosomal recessive trait. This means that for a child to have the signs or
symptoms of this condition, they would need to inherit the mutated gene from both parents.
Diagnosis
An eye examination can reveal a dislocated lens if your child experiences double or significantly
impaired vision.
Treatment
There’s no cure for homocystinuria. High doses of vitamin B-6 are a successful treatment for
about half of the people with this disorder. If you respond well to this supplementation, it’s likely
that you’ll have to use daily vitamin B-6 supplements for the rest of your life.
Alternatively, if you don’t experience positive results from this therapy, your doctor may
recommend eating a diet low in foods containing the amino acid methionine. People diagnosed at
an early stage have had positive responses after switching to this diet.
Your doctor may also recommend taking betaine (Cystadane). Betaine is a nutrient that works to
remove homocysteine from the blood. Taking a folic acid supplement and adding the amino acid
cysteine to the diet are helpful.
ALBINISM
 Albinism is an inherited disorder that’s present at birth. Children are at risk of being born
with albinism if they have parents with albinism, or parents who carry the gene for
albinism.
 Albinism is an inherited disease characterized by a substantially lower rate of melanin
production.
 Melanin is the pigment responsible for the color of the skin, hair, and eyes.
 In general, but not always, people with albinism have lighter colored skin and hair than
the other members of their family or ethnic group.

 Regardless of skin or hair tone, people with albinism always have some level of
dysfunction with their vision.
 Because melanin normally protects the skin from UV (ultraviolet) damage, people with
the disorder are more sensitive to sun exposure and have an increased risk of skin cancer.
Types of albinism
Albinism is split into a number of subgroups depending on the specific genes that are affected.
These subgroups include the following:
Oculocutaneous albinism (OCA): caused by a mutation in 1 of 4 genes, OCA is further split into
seven types depending on the mutations. These subdivisions include:
OCA type 1: individuals tend to have milky skin, white hair, and blue eyes. With age, some
individuals' skin and hair may darken.
OCA type 2: similar to type 1 and occurs most often in sub-Saharan Africans, African-
Americans, and Native Americans.
OCA type 3: occurs mostly in black South Africans.
OCA type 4: occurs most often in East Asian populations.
Inheritance of albinism
Most types of albinism are inherited in an autosomal recessive inheritance pattern, the exception
being X-linked ocular albinism which is passed on in an X-linked inheritance pattern.
Autosomal recessive inheritance
 With autosomal recessive inheritance, an individual must receive faulty copies of a gene
from the mother and father to develop albinism.
 If both parents carry the gene, there is a 1 in 4 chance that their offspring will have
albinism and a 1 in 2 chance that the offspring will become a carrier (without symptoms).
 An estimated 1 in 70 people carry the genes associated with albinism but are not affected
by themutations.
X.linked inheritance
 X-linked recessive conditions predominantly affect males.

 Because females carry two X chromosomes, if one gene damaged, the other can often
make up the shortfall.
 Females can still carry and pass on the gene.
 Men, however, have one X and one Y chromosome, so any albino mutations in their
singular X chromosome will generate the condition.
 If the mother has an X-linked mutation, each daughter will have a 1 in 2 chance of
becoming a carrier and each son will have a 1 in 2 chance of developing albinism.
Symptoms
People with albinism will have the following symptoms:
 an absence of color in the hair, skin, or eyes
 lighter than normal coloring of the hair, skin, or eyes
 patches of skin that have an absence of color
Albinism occurs with vision problems, which may include:
 strabismus (crossed eyes)
 photophobia (sensitivity tolight)
 nystagmus (involuntary rapid eye movements)
 impaired vision or blindness
 astigmatism
Diagnosis
The most accurate way to diagnose albinism is through genetic testing to detect defective genes
related to albinism. Less accurate ways of detecting albinism include an evaluation of symptoms
by your doctor or an electroretinogram test. This test measures the response of the light-sensitive
cells in the eyes to reveal eye problems associated with albinism.
Treatment
There is no cure for albinism. Treatment for albinism can relieve symptoms and prevent sun
damage. Treatment may include:

 sunglasses to protect the eyes from UV rays
 protective clothing and sunscreen to protect the skin from UV rays
 prescription eyeglasses to correct vision problems
 surgery on the muscles of the eyes to correct abnormal eye movements
A UREA CYCLE DISORDER
In urea cycle disorders, the nitrogen accumulates in the form of ammonia, a highly toxic
substance, resulting in hyperammonemia (elevated blood ammonia). Ammonia then reaches the
brain through the blood, where it can cause irreversible brain damage, coma and/or death.
The urea cycle
Five catalytic enzymes:
synthetase I Carbamoylphosphate
(CPS1)
 Ornithine transcarbamylase (OTC)
 Argininosuccinic acid synthetase
(ASS1)
 Argininosuccinic acid lyase (ASL)
 Arginase (ARG1)
 One cofactor-producing enzyme: N-
acetyl glutamate synthetase (NAGS)
Two amino acid transporters:
Ornithine translocase (ORNT1; ornithine/citrulline carrier; solute carrier family 25, member 15)
Citrin (aspartate/glutamate carrier; solute carrier family 25, member 13)
Urea cycle disorders (UCDs) result from inherited deficiencies in any one of the six enzymes or
two transporters of the urea cycle pathway (CPS1, OTC, ASS1, ASL, ARG1, NAGS, ORNT1, or
citrin).
A urea cycle disorder is a genetic disorder caused by a mutation that results in a deficiency of
one of the six enzymes in the urea cycle. These enzymes are responsible for removing ammonia

from the blood stream. The urea cycle involves a series of biochemical steps in which nitrogen, a
waste product of protein metabolism, is removed from the blood and converted to a compound
called urea in the blood. Normally, the urea is transferred into the urine and removed from the
body. In urea cycle disorders, the nitrogen accumulates in the form of ammonia, a highly toxic
substance, resulting in hyperammonemia (elevated blood ammonia). Ammonia then reaches the
brain through the blood, where it can cause irreversible brain damage, coma and/or death.
The onset and severity of urea cycle disorders is highly variable. This depends on the specific
mutation involved and correlates with the amount of urea cycle enzyme function. Severe
mutations result in zero to very little enzyme function and ability to detoxify ammonia, and cause
severe urea cycle disorders. Mild to moderate mutations represent a broad spectrum of enzyme
function, providing some ability to detoxify ammonia, and result in mild to moderate urea cycle
disorders.
Urea cycle disorders occur in both children and adults. Newborns with severe mutations become
catastrophically ill within 36-48 hours of birth. Children with less severe mutations present
outside the newborn period or can remain undiagnosed because symptoms are not appropriately
recognized. Adults often go undiagnosed because they have mild urea cycle disorders which
allow them to produce enough of the urea cycle enzymes to effectively remove ammonia until a
stressor interferes with enzyme function, or causes massive amounts of ammonia to be produced.
These adults may have subtle symptoms in their lifetime that go unrecognized or unheeded.
Metabolic stressors -- viruses, high protein intake, excessive exercise or dieting, surgery, or a
drug (valproic acid, prednisone or other corticosteroid -- can create excessive ammonia in the
body and overwhelm the individual's urea cycle enzyme function, resulting in severe
neurological symptoms. Seemingly normal adults with undiagnosed urea cycle disorders may
present at emergency rooms with staggering, confusion, combativeness and disorientation that is
mistaken for alcohol or drug intoxication. Ammonia quickly rises if untreated and causes coma
and death. Some undiagnosed adults may suffer from psychiatric symptoms like schizophrenia or
bipolar disorder.
Urea cycle disorders are included in the category of inborn errors of metabolism. Although there
is no cure, liver transplant corrects the disorder in most cases. Inborn errors of metabolism

represent a substantial cause of brain damage and death among newborns and infants. The
estimated incidence of urea cycle disorders is 1 in 8500 births. Because many cases of urea cycle
disorders remain undiagnosed and/or infants born with the disorders die without a definitive
diagnosis, the exact incidence of these cases is unknown and underestimated. It is believed that
up to 20% of Sudden Infant Death Syndrome (SIDS) cases may be attributed to an undiagnosed
inborn error of metabolism such a urea cycle disorder. Some children with autism spectrum and
behavioral disorders may have have undiagnosed urea cycle disorders.
Urea cycle disorders Carbamoyl Phosphate synthetase (CPS-1) deficiency
Along with OTC deficiency, deficiency of CPS-I is the most severe of the urea cycle disorders.
Defects in the enzyme carbamoyl phosphate synthase I are responsible for the relatively rare
(estimated frequency 1:62,000) metabolic disease termed "hyperammonemia type 1." Individuals
with complete CPS-I deficiency rapidly develop hyperammonemia in the newborn period.
Children who are successfully rescued from crisis are chronically at risk for repeated bouts of
hyperammonemia.

Ornithine Transcarbamoylase deficiency (OTC deficiency)
The disease is characterized as X linked dominant because most females are also somewhat
affected. A significant number of carrier females have hyperammonemia and neurologic
compromise. The risk for hyperammonemia is particularly high in pregnancy and the postpartum
period. The disease is much more severe in males than in females. The enzyme activity can range
from 0% to 30% of the normal.
Citrullinemia (ASS deficiency)
The hyperammonemia in this disorder is quite severe. Affected individuals are able to
incorporate some waste nitrogen into urea cycle intermediates, which makes treatment slightly
easier.
Argininosuccinic aciduria (ASL deficiency)
This disorder also presents with rapid-onset hyperammonemia in the newborn period. This
enzyme defect is past the point in the metabolic pathway at which all the waste nitrogen has been
incorporated into the cycle. Treatment of affected individuals often requires only
supplementation of arginine. Affected individuals can also develop trichorrhexis nodosa, a node-
like appearance of fragile hair, which usually responds to arginine supplementation. ASL
deficiency is marked by chronic hepatic enlargement and elevation of transaminases.
Arginase deficiency (hyperargininemia; ARG deficiency)
This disorder is not typically characterized by rapid-onset hyperammonemia. Affected
individuals develop progressive spasticity and can also develop tremor, ataxia, and
choreoathetosis. Growth is affected.
NAG Synthase deficiency
Deficiency of this enzyme has been described in a number of affected individuals. Symptoms
mimic those of CPSI deficiency; since CPSI is rendered inactive in the absence of NAG N-
Acetyl glutamate is essential for Carbamoyl phosphate synthase I activity. The NAGS gene
encodes N-acetyl glutamate synthase, which catalyzes the condensation of acetyl-CoA with

glutamate. Defects in the NAGS gene result in severe hyperammonemia, which in this specific
instance may respond to administered Nacetyl glutamate.
Ornithine Transporter deficiency
Hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome (HHH syndrome) results
from mutation of the ORNT1 gene that encodes the mitochondrial membrane ornithine
transporter. The failure to import cytosolic ornithine into the mitochondrial matrix renders the
urea cycle inoperable, with consequent hyperammonemia, and the accompanying accumulation
of cytosolic ornithine results in Hyperornithinemia. In the absence of its normal acceptor
ornithine, mitochondrial carbamoyl phosphate carbamoylates lysine to homocitrulline with a
resulting homocitrullinuria.
Clinical manifestations in urea cycle disorders
Infants with a urea cycle disorder often appear normal initially but rapidly develop cerebral
edema, lethargy, anorexia, hyperventilation or hypoventilation, hypothermia, slurring of the
speech, blurring of vision, seizures, neurologic posturing and coma.
Clinical manifestations in urea cycle disorders
In milder (or partial) urea cycle enzyme deficiencies, ammonia accumulation may be triggered
by illness or stress at almost any time of life, resulting in multiple mild elevations of plasma
ammonia concentration; the hyperammonemia is less severe and the symptoms are more subtle.
In individuals with partial enzyme deficiencies, the first recognized clinical episode may be
delayed for months or years.
Laboratory diagnosis of UCD
The diagnosis of a urea cycle disorder (UCD) is based on evaluation of clinical, biochemical, and
molecular genetic data. A plasma ammonia concentration of 150 mmol/L or higher is a strong
indication for the presence of a UCD. Plasma quantitative amino acid analysis can be used to
diagnose a specific urea cycle disorder
Plasma concentration of Citrulline helps discriminate between the proximal and distal urea cycle
defects as Citrulline is the product of the proximal enzymes (OTC and CPSI) and a substrate for

the distal enzymes (ASS, ASL, ARG). Urinary Orotic acid is measured to distinguish CPSI
deficiency and NAGS (N-Acetyl Glutamate Synthase) deficiency from OTC deficiency. The
combination of family history, clinical presentation, amino acid and Orotic acid testing, and, in
some cases, molecular genetic testing is often sufficient for diagnostic confirmation, eliminating
the risks of liver biopsy.
Treatment
The mainstays of treatment for urea cycle disorders include Dialysis to reduce plasma ammonia
concentration, Intravenous administration of arginine chloride and nitrogen scavenger drugs to
allow alternative pathway excretion of excess nitrogen Excess nitrogen is removed by
intravenous phenyl acetate and that conjugate with glutamine and glycine, respectively, to form
phenylacetylglutamine and Hippuric acid, water-soluble molecules efficiently excreted in urine.
Arginine becomes an essential amino acid (except in arginase deficiency) and should be provided
intravenously to resume protein synthesis.
If these measures fail to reduce ammonia, hemodialysis should be initiated promptly. Restriction
of protein for 24-48 hours to reduce the amount of nitrogen in the diet, providing calories as
carbohydrates (intravenously as glucose) and fat (intra-lipid or as protein-free formula) to reduce
catabolism, Physiologic stabilization with intravenous fluids. Chronic therapy consists of a
protein-restricted diet, phenyl butyrate (a more palatable precursor of phenyl acetate), arginine,
or Citrulline supplements, depending on the specific diagnosis. Liver transplantation should be
considered in patients with severe urea cycle defects that are difficult to control.
Genetic counseling
Deficiencies of CPSI, ASS, ASL, NAGS, and ARG are inherited in an autosomal recessive
manner. OTC deficiency is inherited in an X-linked manner. Prenatal testing using molecular
genetic testing is available for five of the six urea cycle disorders
BENCE JONES PROTEIN
A Bence Jones protein (BJP) is a monoclonal globulin protein or immunoglobulin light chain
found in the urine, with a molecular weight of 22-24 kDa. Detection of BJP may be suggestive of
multiple myeloma or Waldenström's macroglobulinemia a type of cancer. An abnormal Bence-

Jones test result is also linked with malignant lymphomas, renal failure, lytic (or "punched out")
bone lesions, anemia, or large numbers of plasma cells in the bone marrow of patients. Bence
Jones proteins are present in 2/3 of multiple myeloma cases. Multiple myeloma is a blood cancer
of the plasma cells. The proteins are immunoglobulin light chains (paraproteins) are produced by
neoplastic plasma cells. They can be kappa (most of the time) or lambda. The light chains can be
immunoglobulin fragments or single homogeneous immunoglobulins. They are found in urine as
a result of decreased kidney filtration capabilities due to renal failure, sometimes induced by
hypercalcemia from the calcium released as the bones are destroyed or from the light chains
themselves. The light chains have historically been detected by heating a urine specimen and
now by electrophoresis of concentrated urine. More recently, serum free light chain assays have
been superiority over the urine tests, particularly for patients producing low levels of monoclonal
free light chains, as seen in nonsecretory multiple myeloma and AL amyloidosis. This is
primarily because of the re-absorption of free light chains in the kidneys, creating a threshold of
light chain production which must be exceeded before measurable quantities overflow into the
urine. As such, urinalysis is a fickle witness to changing free light chain production.
COMPILED BY
Dr. V. MAGENDIRA MANI
ASSISTANT PROFESSOR OF BIOCHEMISTRY
ISLAMIAH COLLEGE (AUTONOMOUS)
VANIYAMBADI, TAMILNADU, INDIA
DOWNLOAD NOTES AT: http://tvuni.academia.edu/mvinayagam

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