Creatine Synthesis & Transporter Defects
Creatine plays a role in energy metabolism and is synthesized in the liver, kidney and pancreas. 95% of creatine is stored
in the skeletal muscles and the remaining is in the brain, heart and testes In healthy patients, it is transported via the blood
stream to the muscles, heart and brain by the creatine transporter. Creatine synthesis defects, affecting boys and girls,
were discovered in Europe in the 1990s using MRS. Since then, about two dozen persons have been recognized with
synthesis defects. However, when two boys were identified with creatine transporter defects within a nine-month period at
Cincinnati Children’s, clinicians and researchers felt the syndrome may be more common.
Meat and Fish are the major sources of creatine.
Creatine => Creatinine => Urine
Broken down Eliminated
Speech Language are affected
As per researchers from Cincinnati Children’s Hospital in 2000 they identified Creatine transporter deficiency. According
to them it may be more common X-linked genetic disorder. Affected males have mental retardation with severe expressive
language impairment. They discovered this unexpectedly in a 6-yr old patient with developmental delay, but no specific
diagnosis, being followed for epilepsy. The boy’s head appeared to be growing too fast, so he underwent MRI with
magnetic resonance spectroscopy. They found a severe abnormality, no creatine was present in the boy’s Brain. Essential
for energy storage and transfer. Creatine is transported to the brain via the blood stream by the creatine transporter.
Creatine synthesis deficiency – the child couldn’t make creatine due to an inborn error of metabolism.
However when Dr deGrauw measured creatine levels in the boys blood they were in the normal range. He could make
creatine, but it wasn’t getting to the brain due to the transport problem. To find the gene responsible for creatine transport
and further investigate the workings of the gene, the researchers collaborated with a molecular biologist in Amsterdam.
They established that the creatine transporter gene was located on the X Chromosome and its malfunction was due to
mutations. With this information they identified creatine transporter deficiency.
After the first patient was diagnosed, Dr. Cecil was able to perform MR spectroscopy on additional children with
developmental and speech delays who were already undergoing MRI. MR spectroscopy adds approximately three
minutes to a routine MRI of the brain. "Spectroscopy is performed to answer a specific question," as per Dr Cecil. "That's
how we found six families in Cincinnati with creatine disorders. Among them, eight people have creatine synthesis disorder
and five have creatine transporter deficiency."
Dr deGrauw have found that speech delay is the only common defect among those with creatine synthesis disorder and
creatine transport deficiency.
Researchers unsuccessfully treated three male patients with high doses of creatine in an effort to increase creatine levels in
the brain. However, preliminary results show that a 14-year-old girl with learning disabilities, carrier of the x-linked
creatine transporter deficiency, may be responding to high-dose creatine treatment. Dr deGrauw feels “In males, we think
the transport deficiency and the blood-brain barrier keep creatine out of the brain. But we are hopeful that women can be
treated more successfully”
Creatine : From Muscles to Brain
Creatine is a organic molecule which was discovered in the first half of the 19th century from a meat extract resembling the
beef broth. A century later , in the first half of the 20th century , another substance was found this time in the frog extract,
phosphocreatine – or creatine with phosphate group stuck on it. It was found that Creatine and phosphocreatine are part
of the intracellular energy management system and have a remarkable history since. Even though Athletes consume a 2.5
kg of creatine yearly to help their physical endurance and strength it appears that creatine is far more important for brain
rather than mucles. Individuals deficient in creatine suffer from severe intelligent deficits, speech deficits, speech problems
and epilepsy.
The Biochemical Background
Cells need constant energy flow in order to stay alive. Within the cells this energy is handled in the form of high energy
phosphate bonds. The principle behind this is that some chemical bonds need lot of energy for association.
High energy bond is created by adding one phosphate (P) group to adenosine-mono-phosphate which results in a
Adenosine diphosphate (ADP) group. Repeating of the above step results in Adenosine Triphosphate (ATP)
ADP => Adenosine + (2) Phosphate
ATP = > Adenosine + (3) Phosphate
Conversely if we have ATP and remove one P, we get ADP , P and some energy, which in turn many be used for all sorts
of energy requiring tasks, like ion pumping or contracting special proteins.
ATP/ADP cycle constantly runs in the body and is done mainly by mitochondria.
Creatine(Cr) can also form high energy phosphate bonds, which result in Phosphocreatine (PCr). Certain cell types like
neuron and muscle cells maintain a intracellular Cr & PCr pools in addition to ADP and ATP cycle.
The main reason for this is neuron and muscle cells have large fluctuating energy requirements. Muscles need energy to be
able to contract repeatedly on command for any body movement like running, walking etc. Neurons need the potential to
fire away suddenly and sustain ably. Thus there is a abrupt energy demand on the ATP-ADP cycle and to alleviate this
strain cells use backup , which is the PCr-Cr system.
Advantages of PCr-Cr system work
Creatine can take our phosphate group from ATP and store it in PCr. When required it may return the phosphate group to
ADP and generate one ATP. Thus this allows cells to store additional energy, increase ATP generation on short term
basis. PCr is more effective as a transport vehicle for high energy bonds than ATP, as Creatine is a smaller size molecule
as compared to Adenosine which is a large one. Thus it makes Adenosine hard to transverse the distance between the
mitochondria and the ion pumps within the cells.
This involvement in the cellular energy metabolism leds to the idea that getting more creatine in the muscles will improve
strength and endurance.
How does creatine get into muscle and brain?
Creatine is present in the fluid surrounding the cells. It uptake is effected by a special carrier Creatine Transporter or
CreaT. We get creatine into the fluid from food sources like meat and fish. The meat is digested and creatine is selectively
picked out by the gut and transferred to the bloodstream, which delivers it to muscles and the brain. However, creatine is
also synthesised in the body, mainly in the kidney and liver.
|
Creatine Synthesis
|
|
|
Figure 1. Creatine Biosynthesis (from Wikipedia)
|
Creatine is synthesised by a two step process. In a first step, two amino acids (= constituents of proteins), arginine and
glycine, are used to create an intermediary product called guanidinoacetic acid. This is also found in the bloodstream. In a
second step, guanidinoacetic acid reacts with a methyl group donated by a molecule called SAM, resulting in creatine.
These steps are catalysed by two specific enzymes, the first is called GATM (Guanidinoacetate N-methyltransferase, also
known as AGAT or L-arginine:glycine amidinotransferase), the second is called GAMT (or S-adenosyl-L-methionine:N-
guanidinoacetate methyltransferase) (Figure 1) [3]. This will become important because all three mediators of creatine
metabolism in the body, CreaT, AGAT, and GAMT may be impaired on the basis of defective genes coding for them.
Creatine degrades spontaneously after a while to creatinine which leaves the cells, enters the bloodstream and is excreted
by the kidneys.
Research in Germany
In 1994 a patient was presented to a pediatric clinic in Goettingen, Germany. He was specifically diagnosed with a
deficiency of creatine in the brain[4]. The boy was fine till the age of 4 months, and from then his development stopped, his
muscles lost tension, his head started nodding, his movements were uncontrollable were jerky and almost violent. At 22
months he was unable to sit or roll over, eating was difficult due to uncoordintaed swallowing. Biochemical investigations
revealed very low plasma levels of creatinine, the degradation product of creatine. Yet, the symptoms of this patient
seemed largely due to some malfunction of the brain. To investigate further the patient underwent a procedure called
proton NMR spectroscopy. It revealed the complete absence of creatine.
This raises three questions.
(a)why is there no creatine?
(b)can the lack of creatine explain the symptoms?
(c)can his condition be improved by providing him with additional creatine?
A hint for the answer to the first question was found in the fact that the concentration of guanidinoacetate was elevated in
the brain of the patient.
Looking at the pathway for creatine biosynthesis (Figure 1), this suggests that GAMT may not be working properly, and
guanidinoacetate accumulates because it can no longer be processed. Genetic analysis indeed confirmed that the patient
had two mutant GAMT alleles, i.e. no functional gene for this enzyme [5]. The whole situation suggested that creatine
synthesis in the organism is important for brain function and development. However, the reason for this is still unknown.
Raised guanidinoacetate levels in brain can also cause some aspects of the overall menu of symptoms. Creatine
supplementation led to a remarkable improvement of the symptoms. After two months on creatine the infant’s jerky
movements had disappeared, he started to develop again, he learned to sit and to crawl, and at 4.5 years he was able to
walk. Creatine levels in the brain increased in parallel with these improvements [6].
References:
[1]http://www.cincinnatichildrens.org/research/about/horizons/2004-1/creatine.htm
[2]http://www.asnr.org/press/PR_HunterCecil4-29-03.doc
[3]http://www.scq.ubc.ca/?p=194
[4] S. Stockler, U. Holzbach, F. Hanefeld, I. Marquardt, G. Helms, M. Requart, W. Hanicke, J. Frahm, Creatine deficiency in the brain: a new, treatable inborn error of metabolism,
Pediatr Res 36 (1994) 409-413.[5] S. Stockler, D. Isbrandt, F. Hanefeld, B. Schmidt, K. von Figura, Guanidinoacetate methyltransferase deficiency: the first inborn error of creatine
metabolism in man, Am J Hum Genet 58 (1996) 914-922.[6] S. Stockler, F. Hanefeld, J. Frahm, Creatine replacement therapy in guanidinoacetate methyltransferase deficiency, a
novel inborn error of metabolism, Lancet 348 (1996) 789-790
|
|
