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Summary of a presentation by Dr. Richard Koch, Los Angeles Children’s Hospital
Dr. Richard Koch of Los Angeles Children’s Hospital focused on the importance of “large neutral amino acids” in the transport of blood phenylalanine into the brain. We have known for some time that there are certain amino acids, known as the large neutral amino acids (LNAAs), that have a very important function in determining how much phe is transported into the brain.
Phe is actually one of the LNNAs. The others are tyrosine, tryptophan, leucine, isoleucine, histidine, methionine and threonine. All of the LNAAs are “essential amino acids,” (they are critical for growth and development, including brain development and functioning). All of the LNNAs also compete for places on the same “carrier” system for movement into the brain. When blood phe is high, it crowds out LNAAs in the transport system and the amount of LNNAs that are transported into the brain are lower (and vice versa). Researchers believe that the direct effects of elevated brain phe and lowered LNAAs are major causes for disturbed brain development and function in PKU.
While we have been able to measure blood phe easily for many years using a variety of techniques, our ability to measure brain phe is very recent, in the last several years. It is only now that we are discovering more about brain phe and its importance for PKU.
Today, it is possible to assess brain phe through Magnetic Resonance Spectroscopy, a powerful “MRI” machine that uses special computer software to measure the concentration of certain brain chemicals. Dr. Koch describes that molecules of phe give off radiowaves, yielding a pattern of spectroscopy that is measurable with great accuracy.
Through this technique, even carriers of PKU (i.e. PKU parents) have been shown to have slightly higher levels of brain phe than non-carriers. Interestingly, the variability in brain phe for carriers is marked, despite comparable blood phe levels. Dr. Koch reports that this is also true for people with PKU. Based on recent research he has done, some individuals have very low brain concentrations of phe despite higher blood phe levels. This may explain why some people with PKU do better than others with the same blood phe levels: for some as yet unknown reason, certain people are less efficient at transporting phe into their brain, and thus are less susceptible to the damage caused by high phe levels.
Recently, researchers have wondered whether the competitiveness for the brain transport carrier might be used to advantage in PKU. Would increasing the LNNAs in blood ultimately lower the brain phe level? In 1999, a group of researchers in Germany and Switzerland looked at people with PKU who had comparable blood phe levels. After they were given oral loads of phe, their brain phe levels rose dramatically, and electroencephalogram (EEG) analysis showed acutely disturbed brain activity when they did not receive a LNAA supplement. With LNAA supplementation, phe influx was totally blocked and there was no slowing of EEG activity. Based on such research findings, a Danish company has produced tablets called PreKUnil, composed of the LNAAs. They are not for sale in the U.S. yet since they are not approved by the FDA. This may change in the next year or so. These tablets have been used in Denmark for about three years, and may eventually prove to be a helpful adjunct (not a replacement for) diet therapy. Dr. Flemming Güttler in Denmark has observed some patients with phe levels of 15 mg/dl (900 µmol/L) who have been able to keep low brain phe levels with the use of PreKUnil.
Further studies of LNAA supplements in off-diet people with PKU are especially needed. We need to determine whether brain phe concentration can be lowered when blood phe levels are steady (as compared to the study when a high dose of phe was given to 6 adults on diet), and whether brain function can be improved by long-term LNAA supplementation. Studies also need to be done on the effect of LNAA supplementation on other amino acids in the body.
Dr. Koch discussed a serious problem that high phe levels can have on the brain and nervous system. The neurotransmitters dopamine and serotonin are lowered when blood phe levels are high, sometimes leading to clinical depression. His experience with several women showed that returning to diet led to significant improvements without any other medications. Serotonin and dopamine are derived from two of the LNAAs and thus LNAA supplementation should also prevent depression in persons with PKU.