Now, urea cycle relates to a lot
of things in human disease.
We've already seen several examples.
It is believed to be very
underdiagnosed in infant death.
And it may represent as much as 20%
of all the sudden infant death
syndrome deaths that occur.
For people who have the non-lethal form,
problems can be focused on
the accumulation of ammonia
or also on citric acid
And both of those
So, these tables I'll show
in the next two slides
depict some of the urea cycle diseases
and some of the effects of those.
In each case the enzyme I'm describing
as deficient is one of the five enzymes
that we started with in the feeder
reaction or the urea cycle.
The carbamoyl phosphate synthethase was
the enzyme of the feeder reaction.
Deficiency of it leads to the disease
carbamoyl phosphate synthethase I deficiency,
which the name is pretty much
describing exactly what's happening.
And the molecule that accumulates
in this case is ammonium.
The ammonia of course was produced
by the catabolism of amino acids.
So, if this can't be made into carbamoyl
phosphate, ammonia will accumulate.
The symptoms of this disease include
developmental delay and mental retardation
Ornithine transcarbamylase catalyzes
that first reaction of the urea cycle.
And its name also like the other one is
ornithine transcarbamylase deficiency
and that also describes exactly
what has happened here.
The molecules that accumulate with the
deficiency of this enzyme include
and orotic acid.
Now, the symptoms of this
disease are pretty severe.
We're talking about death and
seizures in the severe cases.
But in adults, if it's an adult onset,
there's a very wide spectrum of results
and in some cases can actually
be managed with diet.
The argininosuccinate when it's deficient
leads to argininosuccinate acidemia.
The molecule that accumulates here is
the precursor that can't be converted
by the enzyme and that's citrulline.
In addition to citrulline,
ammonia as is true of all of these
enzyme deficiencies accumulates.
Symptoms of the disease include
lethargy, seizures, liver damage,
and in some case coma
especially among young people.
when it's deficient,
results in argininosuccinic aciduria
and the molecules that accumulate here
are citrulline from two reactions before
and argininosuccinic acid which
is the substrate for this enzyme.
Deficiencies result in the symptoms of
lethargy, lack of appetite, again coma
and mental retardation and
again the more severe effects
occurring when the children
start with the disease.
And the last enzyme
arginase, as I said,
is the one that is the least
likely to be deficient.
It is a disease that creates --
it's a deficiency that creates
the disease argininemia
and the molecule that
accumulates is arginine.
Now, the symptoms here
seem a little less severe.
It may result in leg stiffness and in some
cases slow growth or developmental delay.
In more severe cases, seizures may result.
The treatment for all of these diseases
is the same, balancing protein intake.
Because the more protein and
the more amino acids you have,
the more likely you're
going to have to balance
and get rid of more of those
ammonia and ammonium ions.
There are medications in some
cases to favor the movement
of accumulating molecules to
other alternative pathways.
And in severe cases, liver transplants
can help a person to lead
and live a normal life.