Carbamoylphosphate
Synthetase Deficiency
Metabolism of amino acids generates ammonia,
a highly toxic nitrogen-containing molecule that is
eliminated from the body by its incorporation into urea,
a non-toxic end product excreted through the kidneys.
Carbamyl Phosphate Synthetase (CPS) catalyzes the first
step in the detoxification of ammonia through formation
of carbamyl phosphate, which enters the urea cycle and
ultimately contributes its nitrogen to urea. Deficiency
of CPS results in hyperammonemia and life-threatening
symptoms. CPS is localized to the mitochondrial matrix
and is present in high amount in liver and intestine.
The CPS gene has been cloned and mutations identified
in patients.
Newborns with CPS deficiency appear normal for the first
24 hours. By 72 hours, symptoms of lethargy, vomiting,
hypothermia, respiratory alkalosis and seizures progressing
to coma appear. These patients are frequently thought
to have sepsis. However, a key laboratory abnormality
suggesting a urea cycle defect is low blood urea nitrogen,
which should prompt measurement of ammonia. Patients
who survive the newborn period often have recurrent
episodes of hyperammonemia associated with viral infections
or increased dietary protein intake. A neurologically
damaged outcome is characteristic of CPS deficiency.
Some patients have a later onset with a less severe
course making diagnosis difficult.
This disorder most often follows an autosomal recessive
inheritance pattern. With recessive disorders affected
patients usually have two copies of a disease gene (or
mutation) in order to show symptoms. People with only
one copy of the disease gene (called carriers) generally
do not show signs or symptoms of the condition but can
pass the disease gene to their children. When both parents
are carriers of the disease gene for a particular disorder,
there is a 25% chance with each pregnancy that they
will have a child affected with the disorder.
As with all genetic diseases, genetic counseling may
be appropriate to help families understand recurrence
risks and ensure that they receive proper evaluation
and care.
Argininemia
Argininemia is a rare Urea Cycle defect caused by deficiency
of Arginase in liver and erythrocytes. Arginase is the
final enzyme in the Urea Cycle that catalyzes the breakdown
of arginine to ornithine and urea, which is the major
metabolite carrying waste nitrogen destined for urinary
excretion. Patients with Arginase deficiency have elevated
levels arginine in blood. The deficient Arginase gene
is located on chromosome
Patients with Argininemia may present from two months
to four years of age. Symptoms are progressive spastic
paraplegia, failure to thrive, delayed milestones, hyperactivity
and irritability, with episodic vomiting, hyperammonemia
and seizures. Mental retardation is a result of cerebral
atrophy which leads to microcephaly. Hepatomegaly may
be present.
This disorder most often follows an autosomal recessive
inheritance pattern. With recessive disorders affected
patients usually have two copies of a disease gene (or
mutation) in order to show symptoms. People with only
one copy of the disease gene (called carriers) generally
do not show signs or symptoms of the condition but can
pass the disease gene to their children. When both parents
are carriers of the disease gene for a particular disorder,
there is a 25% chance with each pregnancy that they
will have a child affected with the disorder.
As with all genetic diseases, genetic counseling may
be appropriate to help families understand recurrence
risks and ensure that they receive proper evaluation
and care.
Argininosuccinic
Aciduria
Argininosuccinic aciduria is an inherited disorder that
causes ammonia to accumulate in the blood. Ammonia,
which is formed when proteins are broken down in the
body, is toxic if the levels become too high. The nervous
system is especially sensitive to the effects of excess
ammonia.
Argininosuccinic aciduria usually becomes evident in
the first few days of life. An infant with argininosuccinic
aciduria may be lacking in energy (lethargic) or unwilling
to eat, and have poorly controlled breathing rate or
body temperature. Some babies with this disorder experience
seizures or unusual body movements, or go into a coma.
Complications from argininosuccinic aciduria may include
developmental delay and mental retardation. Progressive
liver damage, skin lesions, and brittle hair may also
be seen.
Occasionally, an individual may inherit a mild form
of the disorder in which ammonia accumulates in the
bloodstream only during periods of illness or other
stress.
Argininosuccinic aciduria occurs in approximately 1
in 70,000 newborns.
Citrullinemia
Citrullinemia is an inherited disorder that causes ammonia
and other toxic substances to accumulate in the blood.
Two forms of citrullinemia have been described; they
have different signs and symptoms and are caused by
mutations in different genes.
Type I citrullinemia (also known as classic citrullinemia)
usually becomes evident in the first few days of life.
Affected infants typically appear normal at birth, but
as ammonia builds up in the body they experience a progressive
lack of energy (lethargy), poor feeding, vomiting, seizures,
and loss of consciousness. These medical problems are
life-threatening in many cases. Less commonly, a milder
form of type I citrullinemia can develop later in childhood
or adulthood. This later-onset form is associated with
intense headaches, partial loss of vision, problems
with balance and muscle coordination (ataxia), and lethargy.
Some people with gene mutations that cause type I citrullinemia
never experience signs and symptoms of the disorder.
Type II citrullinemia chiefly affects the nervous system,
causing confusion, restlessness, memory loss, abnormal
behaviors (such as aggression, irritability, and hyperactivity),
seizures, and coma. In some cases, the signs and symptoms
of this disorder appear during adulthood (adult-onset).
These signs and symptoms can be life-threatening, and
are known to be triggered by certain medications, infections,
surgery, and alcohol intake in people with adult-onset
type II citrullinemia.
The features of adult-onset type II citrullinemia may
also develop in people who as infants had a liver disorder
called neonatal intrahepatic cholestasis caused by citrin
deficiency (NICCD). This liver condition is also known
as neonatal-onset type II citrullinemia. NICCD blocks
the flow of bile (a digestive fluid produced by the
liver) and prevents the body from processing certain
nutrients properly. In many cases, the signs and symptoms
of NICCD resolve within a year. Years or even decades
later, however, some of these people develop the characteristic
features of adult-onset type II citrullinemia.
Type I citrullinemia is the most common form of the
disorder, affecting about 1 in 57,000 people worldwide.
Type II citrullinemia is found primarily in the Japanese
population, where it occurs in an estimated 1 in 100,000
to 230,000 individuals. Type II also has been reported
in other populations, including people from East Asia
and the Middle East.
Homocystinuria
Homocystinuria is an inherited disorder in which the
body is unable to process certain building blocks of
proteins (amino acids) properly. The most common form
of the condition is caused by the lack of an enzyme
called cystathionine beta-synthase. This form of homocystinuria
is characterized by dislocation of the lens in the eye,
an increased risk of abnormal blood clots, and skeletal
abnormalities. Problems with development and learning
are also evident in some cases.
Less common forms of homocystinuria are caused by a
lack of other enzymes involved in processing amino acids.
These disorders can cause mental retardation, seizures,
problems with movement, and a blood disorder called
megaloblastic anemia.
Homocystinuria caused by cystathionine beta-synthase
deficiency affects at least 1 in 200,000 to 335,000
people worldwide. The disorder appears to be more common
in some countries, such as Ireland (1 in 65,000), Germany
(1 in 17,800), Norway (1 in 6,400), and Qatar (1 in
3,000). Other forms of homocystinuria are much rarer,
with a small number of cases reported in the scientific
literature.
Hypermethioninemia
Hypermethioninemia is an excess of a particular protein
building block (amino acid), called methionine, in the
blood. This condition can occur when methionine is not
broken down (metabolized) properly in the body.
People with hypermethioninemia often do not show any
symptoms. Some individuals with hypermethioninemia exhibit
learning disabilities, mental retardation, and other
neurological problems; delays in motor skills such as
standing or walking; sluggishness; muscle weakness;
liver problems; unusual facial features; and their breath,
sweat, or urine may have a smell resembling boiled cabbage.
Hypermethioninemia can occur with other metabolic disorders,
such as homocystinuria, tyrosinemia and galactosemia,
which also involve the faulty breakdown of particular
molecules. It can also result from liver disease or
excessive dietary intake of methionine from consuming
large amounts of protein or a methionine-enriched infant
formula.
Primary hypermethioninemia that is not caused by other
disorders or excess methionine intake appears to be
rare; only a small number of cases have been reported.
The actual incidence is difficult to determine, however,
since many individuals with hypermethioninemia have
no symptoms.
2, 4-Dienoyl-CoA
Reductase Deficiency
One patient has been reported with 2,4-Dienoyl-CoA Reductase
Deficiency. This enzyme is necessary for the degradation
of unsaturated fatty acids having even numbered double
bonds.
The patient was born with a small body habitus, a short
trunk, arms and fingers, and microcephaly. She was readmitted
to the hospital on day 2 of life with symptoms of sepsis,
hypotonia, decreased feeding and intermittent vomiting.
A low carnitine level was found in her plasma. She responded
poorly to treatment in the hospital, and later developed
respiratory acidosis and died at 4 months of age.
This disorder most often follows an autosomal recessive
inheritance pattern. With recessive disorders, affected
patients usually have two copies of a disease gene (or
mutation) in order to show symptoms. People with only
one copy of the disease gene (called carriers) generally
do not show signs or symptoms of the condition but can
pass the disease gene to their children. When both parents
are carriers of the disease gene for a particular disorder,
there is a 25% chance with each pregnancy that they
will have a child affected with the disorder.
As with all genetic diseases, genetic counseling may
be appropriate to help families understand recurrence
risks and ensure that they receive proper evaluation
and care.
5-Oxoprolinuria
(Pyroglutamic Aciduria)
5-Oxoprolinemia is a rare clinical condition caused
by a deficiency of any one of three enzymes in the ?-Glutamyl
Cycle. The Cycle provides antioxidant for the body in
the form of Glutathione. Three enzymes are involved
in the sequential processing of 5-Oxoproline to form
glutathione. A deficiency of any one of the enzymes
causes 5-Oxoprolinemia, and two of the defects lead
to low levels of glutathione. Patients with 5-Oxoprolinemia
have been described in several ethnic groups around
the world.
Clinical presentation of these deficiencies is variable,
from severe to very mild. Glutathione Synthetase Deficiency
is the most common defect, reported in over 40 cases
worldwide. It usually presents in the newborn period
with marked metabolic acidosis, hemolytic anemia, electrolyte
imbalance, and jaundice. Patients who survive the initial
onset may later have episodes of metabolic decompensation
during intercurrent illnesses. They often develop progressive
central nervous system symptoms. 5-Oxoproline can reach
very high levels during illness.
?-Glutamylcysteine Synthetase Deficiency is less severe
than Glutathione Synthetase Deficiency, lacking the
metabolic acidosis and having lower 5-Oxoproline levels
in plasma and urine. Patients have mild compensated
hemolytic anemia as the most consistent finding.
Only a few patients have been reported with 5-Oxoprolinase
Deficiency. Their clinical symptoms vary tremendously
and may not be due to the metabolic defect. They have
normal glutathione levels in erythrocytes and no evidence
of hemolytic anemia.
This disorder most often follows an autosomal recessive
inheritance pattern. With recessive disorders affected
patients usually have two copies of a disease gene (or
mutation) in order to show symptoms. People with only
one copy of the disease gene (called carriers) generally
do not show signs or symptoms of the condition but can
pass the disease gene to their children. When both parents
are carriers of the disease gene for a particular disorder,
there is a 25% chance with each pregnancy that they
will have a child affected with the disorder.
As with all genetic diseases, genetic counseling may
be appropriate to help families understand recurrence
risks and ensure that they receive proper evaluation
and care.
Hyperammonemia
Hyperornithinemia Homocitrullinuria Syndrome (HHH)
Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH)
Syndrome was first described in 1969. In affected patients,
plasma Ornithine is found to be dramatically elevated.
Hyperammonemia is chronically present, but worsens postprandially.
The etiology is a deficiency of a mitochondrial carrier
protein that normally functions to transport Ornithine
into the mitochondria as part of the urea cycle. When
transport is defective, Ornithine accumulates in the
cytosol and the urea cycle is impaired, resulting in
hyperammonemia. The ORNT 1 gene that codes for the transport
protein is located on chromosome 13, and several mutations
have been identified in affected patients.
HHH Syndrome may present at birth, during childhood
or even adulthood. Newborns who are breast fed usually
have an uneventful beginning with intermittent hyperammonemia.
Infants on high protein formula or foods may vomit with
feeding, refuse to eat, become lethargic or develop
hyperammonemic coma. Most affected patients exhibit
some symptoms, such as lethargy, vomiting, ataxia or
chroeoathetosis, impaired growth and delayed development.
Seizures are often reported. Mild to profound mental
retardation is usually apparent by childhood. Over time,
patients will gravitate to a diet low in milk and meat
during childhood.
This disorder most often follows an autosomal recessive
inheritance pattern. With recessive disorders affected
patients usually have two copies of a disease gene (or
mutation) in order to show symptoms. People with only
one copy of the disease gene (called carriers) generally
do not show signs or symptoms of the condition but can
pass the disease gene to their children. When both parents
are carriers of the disease gene for a particular disorder,
there is a 25% chance with each pregnancy that they
will have a child affected with the disorder.
As with all genetic diseases, genetic counseling may
be appropriate to help families understand recurrence
risks and ensure that they receive proper evaluation
and care.
Hyperornithinemia
with Gyrate Atrophy
The first description of a patient with gyrate atrophy
of the choroid and retina, as defined by the characteristic
appearance of the ocular fundus and a typical history
of visual deterioration, was probably made in 1888.
Since that time numerous other case reports have confirmed
this condition as a distinct entity. Hyperornithinemia
and ornithinuria were recognized as the biochemical
marker for this disorder in 1973. Elevations in Ornithine,
a non-protein amino acid, are associated with complete
or partial deficiency of Ornithine Aminotransferase
(OAT) activity.
The major clinical problem in these patients is a slowly
progressive loss of vision leading to blindness, usually
by the fifth decade of life. Myopia and decreased night
vision are early symptoms, usually noted by the first
or second decade. Reduced peripheral vision is typically
present in the second decade, with nearly all patients
ultimately developing cataracts. The combination of
the cataracts and diminished visual fields results in
progressive visual loss, which is frequently well established
by the third decade of life in most patients. However,
there is significant variability in vision and a few
patients retain good visual function into their sixth
or seventh decade.
Younger patients often come to the attention of the
ophthalmologist in late childhood or around the time
of puberty for evaluation of myopia or decreased night
vision. Aside from visual impairment, patients with
gyrate atrophy are for the most part asymptomatic. Some
patients have mild muscle weakness with associated abnormalities
on muscle biopsy and in electromyograms, although creatine
phosphokinase activity is normal. Affected patients
are developmentally normal.
Hyperornithinemia with Gyrate Atrophy is inherited as
an autosomal recessive trait. Both parents are carriers
of one normal gene and one abnormal Hyperornithinemia
gene. An affected child is born when both parents pass
along the Hyperornithinemia gene at conception, resulting
in every cell of the body having the two abnormal genes.
The risk for carrier parents having an affected pregnancy
is one chance in four with every conception. If not
screened at birth, all previous siblings should be tested
to rule out Hyperornithinemia. This disease has been
found in several ethnic groups around the world with
a particularly high incidence in Finland.
Maple Syrup
Urine Disease
Maple syrup urine disease is an inherited disorder in
which the body is unable to process certain protein
building blocks (amino acids) properly. Beginning in
early infancy, this condition is characterized by poor
feeding, vomiting, lack of energy (lethargy), seizures,
and developmental delay. The urine of affected infants
has a distinctive sweet odor, much like burned caramel,
that gives the condition its name. Maple syrup urine
disease can be life-threatening if untreated.
Maple syrup urine disease can be classified by its pattern
of signs and symptoms or by its genetic cause. The most
common and most severe form of the disease is the classic
type, which appears soon after birth. Variant forms
of the disorder appear later in infancy or childhood
and are typically milder, but still involve mental and
physical retardation if not treated.
Maple syrup urine disease affects an estimated 1 in
185,000 infants worldwide. The disorder occurs much
more frequently in the Old Order Mennonite population,
in which the incidence is about 1 in 358 newborns.
Hyperargininemia
due to Arginase
The urea cycle is a series of six reactions necessary
to rid the body of the nitrogen generated by the metabolism,
primarily of amino acids, from the diet or released
as the result of endogenous protein catabolism. Arginase
is the sixth and final enzyme of this cycle. Arginase
catalyzes the conversion of arginine
to urea and ornithine, the latter recycled to continue
the cycle. Hyperargininemia due to
arginase deficiency is inherited in an autosomal
recessive manner and gene for arginase.
This condition rarely presents in the neonatal period
and first symptoms typically present in children between
2 and 4 years of age. First symptoms are often neurologically
based. If untreated, symptoms are progressive with a
gradual loss of developmental milestones.
This disorder most often follows an autosomal recessive
inheritance pattern. With recessive disorders affected
patients usually have two copies of a disease gene (or
mutation) in order to show symptoms. People with only
one copy of the disease gene (called carriers) generally
do not show signs or symptoms of the condition but can
pass the disease gene to their children. When both parents
are carriers of the disease gene for a particular disorder,
there is a 25% chance with each pregnancy that they
will have a child affected with the disorder.
As with all genetic diseases, genetic counseling may
be appropriate to help families understand recurrence
risks and ensure that they receive proper evaluation
and care.
Ornithine
Transcarbamylase Deficiency
Ornithine transcarbamylase deficiency (OTCD), the most
common of the urea cycle disorders, is a rare metabolic
disorder, occurring in one out of every 80,000 births.
OTC is a genetic disorder resulting in a mutated and
ineffective form of the enzyme ornithine transcarbamylase.
Like other urea cycle disorders, OTC affects the body's
ability to get rid of ammonia, a toxic breakdown product
of the body's use of protein. As a result, ammonia accumulates
in the blood causing hyperammonemia. This ammonia travels
to the various organs of the body including the brain,
causing coma, brain damage and death.
Another symptom of OTC is a buildup of orotic acid in
the blood. This is due to an anapleurosis that occurs
with carbamoyl phosphate entering the pyrimidine synthesis
pathway.
Ornithine transcarbamylase deficiency often becomes
evident in the first few days of life. An infant with
ornithine transcarbamylase deficiency may be lacking
in energy (lethargic) or unwilling to eat, and have
poorly-controlled breathing rate or body temperature.
Some babies with this disorder may experience seizures
or unusual body movements, or go into a coma. Complications
from ornithine transcarbamylase deficiency may include
developmental delay and mental retardation. Progressive
liver damage, skin lesions, and brittle hair may also
be seen. Other symptoms include irrational behavior
(caused by encephalitis), mood swings, and poor performance
in school.
In some affected individuals, signs and symptoms of
ornithine transcarbamylase may be less severe, and may
not appear until later in life. Some female carriers
become symptomatic later in life. This can happen as
a result of anorexia, starvation, malnutrition, or even
(in at least one case) as a result of gastric bypass
surgery. It is also possible for symptoms to be exacerbated
by extreme trauma of many sorts, including, (at least
in one case) adolescent pregnancy coupled with severe
stomach flu.
This disorder most often follows an autosomal recessive
inheritance pattern. With recessive disorders affected
patients usually have two copies of a disease gene (or
mutation) in order to show symptoms. People with only
one copy of the disease gene (called carriers) generally
do not show signs or symptoms of the condition but can
pass the disease gene to their children. When both parents
are carriers of the disease gene for a particular disorder,
there is a 25% chance with each pregnancy that they
will have a child affected with the disorder.
As with all genetic diseases, genetic counseling may
be appropriate to help families understand recurrence
risks and ensure that they receive proper evaluation
and care.
This disorder most often follows an autosomal recessive
inheritance pattern. With recessive disorders affected
patients usually have two copies of a disease gene (or
mutation) in order to show symptoms. People with only
one copy of the disease gene (called carriers) generally
do not show signs or symptoms of the condition but can
pass the disease gene to their children. When both parents
are carriers of the disease gene for a particular disorder,
there is a 25% chance with each pregnancy that they
will have a child affected with the disorder.
As with all genetic diseases, genetic counseling may
be appropriate to help families understand recurrence
risks and ensure that they receive proper evaluation
and care.
Arginase
deficiency
Argininemia is a rare Urea Cycle defect caused by deficiency
of Arginase in liver and erythrocytes. Arginase is the
final enzyme in the Urea Cycle that catalyzes the breakdown
of arginine to ornithine and urea, which is the major
metabolite carrying waste nitrogen destined for urinary
excretion. Patients with Arginase deficiency have elevated
levels arginine in blood. The deficient Arginase gene
is located on chromosome 6.
Patients with Argininemia may present from two months
to four years of age. Symptoms are progressive spastic
paraplegia, failure to thrive, delayed milestones, hyperactivity
and irritability, with episodic vomiting, hyperammonemia
and seizures. Mental retardation is a result of cerebral
atrophy which leads to microcephaly. Hepatomegaly may
be present.
This disorder most often follows an autosomal recessive
inheritance pattern. With recessive disorders affected
patients usually have two copies of a disease gene (or
mutation) in order to show symptoms. People with only
one copy of the disease gene (called carriers) generally
do not show signs or symptoms of the condition but can
pass the disease gene to their children. When both parents
are carriers of the disease gene for a particular disorder,
there is a 25% chance with each pregnancy that they
will have a child affected with the disorder.
As with all genetic diseases, genetic counseling may
be appropriate to help families understand recurrence
risks and ensure that they receive proper evaluation
and care.
Biotinaidase
deficiency
Biotinidase deficiency is an inherited metabolic disorder
of biotin (vitamin B) recycling that leads to multiple
carboxylase deficiencies.
Symptoms of untreated biotinidase deficiency may appear
at any time from 1 week to10 years of age. The most
common early symptoms include seizure activity of various
types (myoclonic, grand mal, and focal or infantile
spasms) and hypotonia. Other early symptoms include
breathing problems (tachypnea, hyperventilation, stridor,
apnea), skin rashes and alopecia. Later developmental
delays, speech problems, ataxia, and vision and hearing
problems may occur. Less frequent findings include feeding
difficulties, vomiting/diarrhea, fungal infections,
hepatomegaly and splenomegaly.
This disorder is inherited in an autosomal recessive
pattern. As an autosomal recessive disorder, the parents
of a child with biotinidase deficiency are unaffected,
healthy carriers of the condition and have one normal
gene and one abnormal gene. With each pregnancy, carrier
parents have a 25 percent chance of having a child with
two copies of the abnormal gene, which results in biotinidase
deficiency. Carrier parents have a 50 percent chance
of having a child who is an unaffected carrier and a
25 percent chance of having an unaffected, non-carrier
child. These risks hold true for each pregnancy. All
siblings of infants diagnosed with biotinidase deficiency
should be tested; genetic counseling services should
be offered to the family.
Cystic
Fibrosis
Cystic fibrosis (CF), or mucoviscoidosis, is a hereditary
disease that affects mainly the lungs and digestive
system, causing progressive disability. Formerly known
as cystic fibrosis of the pancreas, this entity has
increasingly been labeled simply cystic fibrosis.
Difficulty breathing and insufficient enzyme production
in the pancreas are the most common symptoms. Thick
mucus production, as well as a less competent immune
system, results in frequent lung infections, which are
treated, though not always cured, by oral and intravenous
antibiotics and other medications. A multitude of other
symptoms, including sinus infections, poor growth, diarrhea,
and potential infertility (mostly in males, due to the
condition Congenital bilateral absence of the vas deferens)
result from the effects of CF on other parts of the
body. Often, symptoms of CF appear in infancy and childhood;
these include meconium ileus, failure to thrive, and
recurrent lung infections.
CF is caused by a mutation in a gene called the cystic
fibrosis transmembrane conductance regulator (CFTCR).
The product of this gene is a chloride ion channel important
in creating sweat, digestive juices, and mucus. Although
most people without CF have two working copies of the
CFTR gene, only one is needed to prevent cystic fibrosis.
CF develops when neither gene works normally. Therefore,
CF is considered an autosomal recessive disease. The
name cystic fibrosis refers to the characteristic 'fibrosis'
(tissue scarring) of the biliary tract ("cystic"
being a generic term for all that is related to the
biliary vesicle and/or the bladder), first recognized
in the 1930s.
Gene therapy holds promise as a potential avenue to
cure cystic fibrosis
STEP 1
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