Blue Diaper Syndrome and Phenylketonuria
Maisa Haddad
Introduction
Blue diaper syndrome is an inborn error of amino acid metabolism. The amino
acid tryptophan is malabsorped in the intestinal lining of newborn infants.
The syndrome is known to be an autosomal recessive trait. It is believed
that a mutation in the tryptophan transport protein causes a baby's diaper
to turn blue once the urine touches the diaper. This was caused by the bacteria
that acted on urine precursor's to produce a compound that turned indigo
blue upon contact with air.Unfortenutely there was limited information on
blue diaper syndrome , but there were other disorders that were caused by
inborn error's of amino acid metabolism.
One of interest and that was not limited on information was the phenylketonuria
(PKU) disorder. This was also caused by inborn error's of amino acid metabolism.
It is caused by the deficiency of the hepatic enzyme phenylalanine hydroxylase
(PAH).The amino acid phenylalanine is malabsorped because there is low concentration's
of the PAH enzyme. Since there are low concentration of this enzyme , the
amino acid is not being absorbed like it normally should. Therefore, there
is an accumulation of the phenylalanine in the serum, which causes mental
retardation in newborns.
Examples and Experiments
The cause of the mutation in blue diaper is not really known, but one might
suggest an explanation or hypothesis. Since there are bacteria that are
activated and begin to act on the precursors of the compound that releases
the blue color, one might speculate that there maybe some kind of mutation
in the gene that transports the amino acid tryptophan or a mutation in the
bacteria that is activated by a specific enzyme that is activated by the
deficiency of the enzyme that absorbs tryptophan. Other mutations may be
caused by base substitutions or by transcription factors that may not start
the transcription process and in turn no translation takes place and the
enzyme may not be made. In this case it would be the enzyme that is required
for absorption. Ways to test this hypothesis is to use gel electrophoresis,
Southern blotting and RFLP's. By isolating the gene that may be mutated,
one might suggest to compare the DNA sequencing of the mutated and the normal
gene. From this, one can tell if there is a base substitution involved.
Restriction enzymes may also be used with vectors to isolate certain fragments
prior to DNA sequencing. Since blue diaper syndrome is inherited, the RFLP
method would be suitable for comparison on the whole family that carries
this syndrome.
The difference with PKU is that there is lots of information on the disorder
and actual experiments that have been done. An example is the RFLP hapotype
analysis of the PAH locus in a German PKU family . A novel MspI site in
one of the mutant alles was observed. The site was caused by a T to C transition
in exon 9 of the gene and resulted in the substitution of leucine by proline
at residue 311 of the protein (Konecki 2882). Mutagenesis and expression
analyses have verified that the amino acid subsitution caused the lack of
accumulation of the corresponding protein and the neucleotide substitution
must represent a novel mutation in the PAH gene that causes PKU(konecki
2883). DNA sequencing of a fragment of the normal and mutant human PAH showed
the T to C transition within the exon 9 gene.
Case Inquiry
The case for Blue diaper syndrome was about Gloria an aunt that has two
nephews named William and Charlie . They both have blue diaper syndrome,
their parents Edith and Archie are carriers. They went to a Doctor and he
told them that they had a 25% chance that their kids would get it. They
did. The doctor also told them that they would not have this problem in
their family anymore. But the aunt, Gloria had fraternal twins with her
husband Michael and they had the syndrome. The question that was asked was
what error did the physician make? The Doctor made an error by saying that
no one in the family would get the syndrome and they did, Gloria 's children
inherited the gene. The pedigree for the family and their unusual disorder
looks like this:
--------- = sisters
+ = Wife and husband
V = children
Micheal+Gloria---------Edith+Archie
B_ B_ Bb Bb
V V
V V
Marshall/ Joey William/ Charlie
bb bb bb bb
Edith and Archie are carriers for the syndrome, Gloria might be a carrier
or have the syndrome. Her husband Micheal may not carry the gene or he might
be a carrier or have the syndrome. But that part is unknown further testing
is required. Gloria and Edith wonder if their grandsons will inherit blue
diaper syndrome? Well they could because Marshall and Joey are recessive
and if they marry someone that is a carrier they would have a half chance
of getting it and if they marry someone that is not a carrier the grandsons
would be carriers. If they marry someone that does have the recessive trait
then there would be a 100% chance of getting it. Eating food that contained
tryptophan (maybe meat- protein) or bacteria that grows in the intestines
would most likely trigger the urine precursors to produce the blue color.
Phenylketonuria is an autosomal recessive gene also, so it would show up
the same way in the family like blue diaper syndrome.
Conclusion
Blue diaper syndrome and phenylketonuria are both inborn errors of amino
acid metabolism. There is malabsorption of the amino acids tryptophan and
phenylalanine. Because of abnormal transport of the amino acid tryptophan
across the small intestinal lining , bacteria act on urine precursors to
produce a compound that turns indigo blue upon contact with the air. The
syndrome is not harmful to newborns but can be disturbing. The classic PKU
is caused by a deficiency of the hepatic enzyme hydroxylase (PAH) and is
a typical example of the inborn errors . The deficiency of the PAH enzyme
leads to the accumulation of phenylalanine which is very dangerous to a
newborn baby because it can cause mental retardation. The PKU disorder is
caused by a base substitution of the exon gene that codes for the PAH enzyme.
Many tests like DNA sequencing, southern blotting and RFLP's have proven
that this mutation causes a deficency in the PAH enzyme. There are probably
other mutations that cause the deficency, but are still unknown.
References
Konecki, L., DiLella, A. Phenylalanine Hydroxylase Deficiency caused by
a single base substitution. (1988) Biochemistry, 27, 2881-2885
Woo, S. Molecular Basis and Population Genetics of Phenylketonuria. (1989)
Biochemistry, 28, 1-6
Yoshiyuki,O, M.D., PH.D., Eisensmeth.,R. Molecular Basis of phenotypic heterogeneity
in PKU (1991) The New England Journal of Medicine, 324, 18, 1232-1238
Levy, H.L, Molecular Genetics of Phenylketonuria and its implications. (1989)
Human Genetics, 45, 667-70
Thorn, Adams, Brwnwald, Isselbacker, Petersdorf, The Principles of Internal
Medicine. 8th edition. CH.320, 1687-1688.
Return Case Studies in Virtual Genetics
1996-1997