Blue Diaper Syndrome and Phenylketonuria
Maisa Haddad

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

B_ B_ Bb Bb
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.

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.


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.

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