Ornithine transcarbamylase deficiency

OTCD is the most common type of urea cycle disorder. An exact incidence is
difficult to calculate, due to the varying clinical presentations of later onset forms
of the disease. Early estimates of the incidence were as high as 1:14,000 live
births, however later studies have decreased these estimates to approximately
1:60,000 - 1:72,000.

Metabolic pathway
When we eat food, our bodies break down proteins into a form that can be used
by our cells. During this process, a waste nitrogen, in the form of ammonia, is
produced. Because too much it is toxic for
the body, the generated ammonia is
processed and excreted in the form of
urea through the action of several
different enzymes in the urea cycle. It
occurs mostly in the liver and, in a lesser
extent, kidneys. Described by Hans Krebs
and Kurt Henseleit, it was the first
Figure 1:
metabolic cycle discovered. It involves both the
Ornithine
mitochondria and other hepatic tissues.

Individuals with childhood or adult onset disease may have a partial enzyme
deficiency. Ornithine transcarbamylase, OTC is the last enzyme in the proximal
portion of the urea cycle, which consists of the reactions that take place in the
mitochondria. The substrates of the reaction catalyzed by ornithine
transcarbamylase are ornithine (Figure 1) and carbamyl phosphate, while the
product is citrulline. (Figure 2)

Figure 2: Action of Ornithine transcarbamylase that catalyses the condensation of

ornithine and carbamyl phosphate

In OTC deficiency, the mitochondrial enzyme ornithine carbamoyl transferase is

not working correctly, hence there is a failure to incorporate citrulline with
ornithine by condensation. With the urea cycle (Figure 4) not being able to
proceed correctly, this results to an increase in hepatic ornithine as reflected in
the elevated serum level and ammonia accumulation in the bloodstream.
Furthermore, an excess of mitochondrial
carbamyl phosphate leaks out into the cytosol.
Acting as substrate for the carbomoyl
phosphate synthetase (CPS) II reaction, orotic
acid is produced, which is a normal intermediate
in pyrimidine biosynthesis.
Because of this, diminished ornithine transport
into mitochondria occurs. This is followed
ornithine accumulation in the cytoplasm which
reduces the ability to clear carbamoyl phosphate and ammonia loads. (Figure 3)
Level of pyrimidines in the body will also elevate due to increase in orotic acid
which can combine with PRPP to form UMP
Figure 3: Blockage of the urea
cycle at action of OTC results in
incompletion, leading to
dangerous ammonia load

Figure 4: The complete urea cycle

Pathogenesis
All the urea cycle disorders are
transmitted genetically as autosomal
recessive genes - each parent
contributes a defective gene to the
child, except for one of the defects,
Ornithine Transcarbamylase Deficiency.
This urea cycle disorder is acquired in
one of three ways: as an X-linked trait
from the mother, who may be an
undiagnosed carrier; in some cases of
female children, the disorder can also be
inherited from the father's Xchromosome; and finally, OTC deficiency
may be acquired as a "new" mutation
occurring in the fetus uniquely.
Mutation of the OTC gene which only
occurs in X chromosome at band p21.1
causes OTCD. (Figure 5) The gene spans
more than 85 kb and is comprised of 10
exons encoding a protein of 1062 amino
Figure 5: X-chromosome showing various
acids. Pathogenic missense variants that bands of genes.
affect residues essential for catalysis,
substrate binding, and folding severely impair or completely abolish OTC enzyme
activity.
Pathogenic nonsense variants, insertions, and deletions that cause frameshift of
the open reading frame and single-nucleotide variants in canonical intronic splice
sites result in complete absence of functional OTC and neonatal-onset disease in
hemizygous males. Through this mutation, babies with OTC deficiency either do
not make enough or make non-working copies of ornithine transcarbamylase.
When ornithine transcarbamylase does not work correctly, the body cannot
remove ammonia through the urine. This causes a dangerous build-up of
ammonia in the body. Mutations that abolish OTC activity completely result in the
severe, neonatal-onset form while mutations leading to decreased OTC activity
result in the late-onset phenotypes.

Figure 6: Genetic pedigree of OTC deficiency, an X-linked

recessive disorder. When the father has the condition,
the daughters will all be carriers and no son will inherit
the mutated gene.

Being an X-linked recessive genetic

condition, this means that males are
affected more often than females, and
that a male must inherit one copy of
the non-working gene from his mother
to have the condition. Females who
carry a defective copy of the gene can
be severely affected or asymptomatic,
largely depending on the random
nature of X-inactivation. if Xchromosome inactivation in their
hepatocytes is skewed in favor of the X
chromosome with the pathogenic
allele, females heterozygous for a
pathogenic variant can develop
symptoms of OTC deficiency later in
life. In most cases, a female must
inherit two copies of the non-working gene, one from each parent, in order to
have the condition. Sometimes, females with one non-working copy of the gene
can still express symptoms associated with the condition.
There is some degree of genotype - phenotype correlation with OTC deficiency,
but this depends on a number of situations. Individuals with milder mutations,
often associated with late onset disease can still present with severe illness when
exposed to sufficient metabolic stress. Correlations are more difficult to ascertain
in females, since the residual activity of OTC in the liver is impacted not only by
the nature of the mutation, but also by the random pattern of X-inactivation.
It is well established that significant medical problems (e.g., neonatal sepsis or
other causes of newborn catabolism) can also cause a severe, early presentation
in an individual with an OTC pathogenic variant typically associated with mild
disease, making it appear that the pathogenic variant is associated with severe
neonatal-onset disease. Amino acid substitutions that decrease OTC enzyme
activity or stability may result in a post-neonatal-onset phenotype in hemizygous
males and heterozygous females.

While having a child with OTC is rare, when

one or both parents carry the non-working
gene, they can have more than one child
with the condition. Female carriers of an Xlinked disorder have a 25% chance with
each pregnancy to have a carrier daughter
like themselves, a 25% chance to have a
non-carrier daughter, a 25% chance to
have a son affected with the disease and a
25% chance to have an unaffected son.
If a male with X-linked disorders is able to
reproduce, he will pass the defective gene
to all of his daughters who will be carriers.
A male cannot pass an X-linked gene to
his sons because males always pass their
Y chromosome instead of their X
chromosome to male offspring.

Figure 7: Genetic pedigree of OTC deficiency, an Xlinked recessive disorder. When the mother is the
carrier, 25% chance the daughter will be
unaffectedand a non-carrier, 25% chance a son
will be affected and a 25% chance the son will be
unaffected.

Recent research has shown that some female carriers of the disease may
become symptomatic with the disorder later in life, suffering high ammonia
levels. Several undiagnosed women have died during childbirth as a result of
high ammonia levels and on autopsy were determined to have been unknown
carriers of the disorder.

Effects
Ammonia is especially damaging to the nervous system, so ornithine
transcarbamylase deficiency causes neurological problems as well as eventual
damage to the liver.
Males with the severe, neonatal-onset type are normal at birth but develop poor
sucking, hypotonia and lethargy after a few days, rapidly progressing into
somnolence and coma. Seizures and hyperventilation may also be present. If
untreated, severe encephalopathy will develop with a high risk for death.
Patients with a milder form can present at any age. In infants, symptoms can be
induced when switching from breast milk to whole milk. In children and adults,
environmental stressors (i.e. fasting, high protein diet, pregnancy and the
postpartum period, intercurrent illness, surgery) can trigger episodes of
hyperammonemic encephalopathy along with nausea, vomiting, headaches,
erratic behavior, delirium and combativeness. These episodes can also result in
hyperammonemic coma. Neurological complications of hyperammonemic coma

include developmental delay and (sometimes) severe cognitive impairment.

Many female carriers are asymptomatic; however they can be affected to the
same extent as males if the degree of X-inactivation of the disease allele is
unfavorable. Coagulopathy is a frequent finding during metabolic
decompensation and sometimes evolves into acute liver failure.
References
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https://scientiaetarte151.wordpress.com/2012/10/01/otcd/
http://www.ncbi.nlm.nih.gov/books/NBK154378/
http://www.omim.org/entry/311250
https://en.wikipedia.org/wiki/Urea_cycle_disorder
http://www.babysfirsttest.org/newborn-screening/conditions/ornithinetranscarbamylase-deficiency
6. http://www.orpha.net/consor/www/cgi-bin/OC_Exp.php?
lng=EN&Expert=664
7. http://rarediseases.org/rare-diseases/ornithine-transcarbamylasedeficiency/
8. http://emedicine.medscape.com/article/950672-overview#a6
9. https://ghr.nlm.nih.gov/condition/ornithine-transcarbamylasedeficiency#sourcesforpage
10.https://en.wikipedia.org/wiki/Ornithine_transcarbamylase_deficiency