The Genetics of Argininemia
by James Washington
Arginase is the final enzyme in the urea cycle it is responsible for hydrolyzing
arginine to urea and ornithine. Low levels of arginase cause an accumulation
of arginine and ammonia. The buildup of ammonia poisons the central nervous
system and causes mental retardation. Due to a genetic defect, the body
can be deficient in arginase and the resulting disorder is known as argininemia.
Argininemia can affect both males and females. Even though one is born with
the disease its affects often go unnoticed until the child reaches an age
of two or three.
Argininemia is a genetic disease because the deficiency in arginase is caused
by mutations in DNA. These mutations are inherited from both the mother
and the father of the child, and cause the child to synthesize invalid arginase.
Analyzing the causes of Argininemia is done by amplifying DNA samples from
affected individuals, and their parents by means of the polymerase chain
reaction. The resultant DNA can then be cloned and sequenced. The results
of DNA sequencing of one patient showed that there were mutations on two
different alleles (Uchino, 1992). One allele was inherited from the patients
mother, this allele had a mutation at base 365 where a guanine had been
changed to an adenine. The other allele was inherited from the father and
had a mutation at base 703 where a guanine was changed to a cytosine. This
patient was a compound heterozygote which means that argininemia is heterogeneous.
In a different individual with argininemia the mutations were more severe.
On one allele a four base deletion in exon three caused a frame shift at
amino acid residue 87 and made a new stop codon at residue 132 (Haraguchi,
1990). On the other allele a base deletion occurred in exon 2 causing a
stop codon at amino acid residue 31. The allele with the four base deletion
was inherited from the patients father, and the other from the mother.
There have been cases in which the condition of argininemia was improved
by different treatment techniques. However, because it is a genetic disease
there is no cure for argininemia today. Different drugs that convert nitrogen
to an excretable form can be administered. A high calorie low protein diet
with amino acid supplements is often used as a treatment for argininemia.
This type of controlled diet seems to be more helpful to patients whose
DNA mutations are of a lesser severity such as a single base change rather
than a deletion (Uchino, 1995). Blood transfusion has been used to treat
argininemia. One patient under went a red blood cell replacement, by means
of a blood cell separator (Sakiyama, 1984). The affected blood cells were
exchanged for normal blood cells from a donor. This patient was then able
to excrete the toxins that once poisoned his body, as a result he showed
a significant improvement in cognitive and motor skills.
References
Haraguchi, Y. "Molecular Basis of Argininemia. Identification of Two
Discrete FrameShift Deletions in the LiverType Arginase Gene." 86 (1990):
34750.
Sakiyama, T. "A Successful Trial of Enzyme Replacement Therapy in a
case of Argininemia." 142 (1984): 23948.
Uchino, T. "Molecular Basis of Phenotypic Variation in Patients with
Argininemia." 96 (1995): 25560.
Uchino, T. "Three Novel Mutations in the LiverType Arginase Gene in
Three Unrelated Japanese Patients with Argininemia." 51 (1992): 140612.
Return Case Studies in Virtual Genetics
1996-1997