Wednesday, December 2, 2009

Lab Lines Article published by Duke

Jennifer Goldstein, PhD, Clinical Research Coordinator—Pediatric Medical Genetics
Volume 7, Number 4

In clinical laboratory science, a keen eye for detail can make all the difference to the life of a patient. At first glance, the trace of a specialized urine test for a 12 month-old boy looked normal. However, one peak held the key to the diagnosis, and ultimately a treatment, for this patient.

When he was about 4 months old, the patient’s mother became concerned that he was not developing normally and she noticed some unusual movements of his limbs (choreoathetosis). The pediatrician confirmed her concerns and recommended a neurology evaluation. The neurologist told the parents that lack of oxygen at birth had caused cerebral palsy. While the parents were beginning to adjust to this diagnosis, another doctor, a neurodevelopmental specialist, wondered if the patient’s symptoms might, instead, be caused by an inherited metabolic disorder. There are hundreds of different metabolic disorders, problems caused when the body cannot make or breakdown certain compounds correctly, and most of them are very rare. Many metabolic disorders can be detected by measuring metabolites in urine and blood – so, when the patient was 12 months old, the doctor sent samples to the Duke Biochemical Genetics Laboratory, which performs these specialized tests.

The pattern of peaks of metabolites in the patient’s urine looked normal, but a peak representing a compound called creatinine seemed lower than usual. To make sure that the results were not caused by a lab error, Dr. Sarah Young, assistant director of the Biochemical Genetics laboratory, asked technician Eileen Gilbert to repeat the test. Eileen had just completed her training and this sample was the very first sample she had run independently. The repeat analysis gave exactly the same result. Dr. Young considered another explanation for the patient’s results – that the low creatinine could be a sign of a creatine deficiency syndrome.

Dr. Young recommended to the referring physician another metabolic test that could be performed on the same urine sample. Mixing a small volume of urine with isotope-labeled standards, technician Amie Vaisnins-Carroll performed an assay that measures creatine and its precursor, guanidinoacetic acid (GAA). This test was recently developed by the Biochemical Genetics laboratory to screen for several creatine deficiency disorders. The laboratory is one of a few in the USA that performs this specialized biochemical testing using state-of-the-art tandem mass spectrometry technology. The results confirmed Dr. Young’s suspicion - the patient
did indeed have a rare disorder that affects the synthesis of creatine. Specifically, high amounts of GAA and low creatine showed that the patient was lacking the enzyme that converts GAA to creatine, an enzyme called guanidinoacetate methyltransferase (GAMT).

Why would lack of creatine cause a problem? Creatine is important in providing energy to the brain as well as muscle and other tissues. Lack of creatine in the brain causes a range of neurological symptoms including developmental delay, lack of speech, seizures, movement disorder, mental retardation and autism. Patients with GAMT deficiency also have high levels of GAA, which is thought to be toxic to the nervous system, making the symptoms more severe. GAMT deficiency was not discovered until 1994 and since then about 40 patients worldwide, only a few of them in the USA, have been reported in the medical literature. Researchers
soon recognized that supplementing with creatine, as well as dietary modifications to reduce the amount of GAA, could treat GAMT deficiency. In older patients with GAMT deficiency who had already developed many of the symptoms, seizures disappeared after they started treatment, and movement disorder and behavioral problems also improved.

The patient with GAMT deficiency is now treated in the Metabolic Clinic by Dr. Dwight Koeberl at Duke University Medical Center. The patient’s family has been very conscientious about his treatment, administering the recommended four treatments a day and a low protein diet. Few children have been treated from such a young age, so it is not possible to predict his future outcome. However, treatment is expected to prevent other symptoms of the condition, such as seizures, from occurring, and the patient has already made great developmental progress. His mother feels like her son “has been given another chance at life”, but it is hard for her to think about what would have happened if the disorder had not been diagnosed early.

Creatine deficiency syndromes, including GAMT deficiency, are rare, but they are almost certainly underdiagnosed. Deficiency of the creatine transporter, which is inherited on the X-chromosome, is probably the most common of the three known creatine deficiency syndromes. One of the difficulties in diagnosing these conditions is that the symptoms are variable and also occur in many other disorders. However, with the availability of specialized biochemical tests to measure creatine and GAA, testing for these disorders is straightforward, and can lead to treatment that could be life-changing for patients and their families.

To date, the benefits of treatment in preventing symptoms appear to be greatest when the treatment is started from a young age suggesting that early diagnosis may be critical. This has led researchers to start looking into the possibility of screening all newborn babies in NC for this condition, a move for which families are strongly advocating.


  1. I'm glad I found your blog. I read your article in the paper online. My name is Jennifer and I have a son who has Cerebral Palsy, though he isn't offically diagnosis. He was born the exact same way. The umbilical cord wrapped around the neck, born on his due date, but the hospital waited over an hour while he was in fetal distress to get him out. He suffered from a grand mal seizure an hour after birth. We did genetic testing and some things were low or high. We were told that it could be a metabolic disorder. My husband and I thought it was Cerebral Palsy because of the way he was born. Now I'm looking into doing genetic testing again. He may not have what your son has, I sure do hope he does though, but he may have something metabolic. Thank you for having this blog. I'm glad I found it. I would love to talk to you some time. If you want to check out my son's blog then your more than welcome too. Care Page Name: Tyse. If your interested in emailing me then please do. My email address is on the blog. Thank you and best of luck to you and your family. Glad to hear that things are looking up for your son. That's great news!

  2. There recently was an article in a nearby newspaper about your family. I was immediately brought to tears because of how much this sounded like our situation. Your description of your John sounds exactly like my almost 2 year old son, Cameron. He too had a rough birth and has been through several tests. Our first MRI showed nothing, and the second showed a very minimal amount of brain damage. Honestly, when reading the article and your blog, they read like an exact copy of Cameron's life. We have been through several rounds of genetic testing, and all tests have been normal. However, when reading your article, this past Sunday, we began researching the disorder. We called our doctor (at Children's Hospital of Pittsburgh) to find out if Cameron had been tested for this yet, and he has not. They said that it was something they would test him for eventually. We wanted the test done sooner, and so he had the blood drawn today. We will be anxiously awaiting the results, but I am convinced that this is what he has. He has unfortunately developed the seizures that I am happy for John, never got to happen. I completely relate to everything you said and how you felt about everything. This has been the scariest process, and something I never imagined could happen to my baby. It will take probably a month for the results, and I am afraid to continue to feed him proteins if this is in fact what he has. Thank you for giving us hope, and as much as I don't want my son to have a genetic disorder, at least there is hope. Best of luck to you and your family, and thank you again for the information.

  3. I am so glad to have come across your article. We have a son who recently turned 3 and is very delayed in his speech and has social/behavior issues. He hasn't developed and seizures that we know of and no muscle problems. We have taken him to multiple doctors and the last one at Childrens Hospital was about ready to send us out of the office just to continue with speech therapy and early intervention classes, then she asked if anyone had ordered and lab work. No one prior to her had ordered lab work just an MRI which came back normal. She ordered chromosome test and urine test for his creatine levels. The urine test came back with elevated guanidinoacetate and now he just did another urine test for a recheck. The chromosome results are not currently finished so now we just wait for more results and pray that we have finally found a diagnosis!! Thanks again!

  4. I really hope that they are able to give you a diagnosis. Please let me know how it goes. If you do end up with a diagnosis of GAMT we have a very small support group (4 families) but we share helpful information with each other and we would love to be in contact with you. Best wishes! You can always email me at

  5. Hi there, a couple of days ago my 19-month son was diagnosed with creatine transporter defect and we're slowly digesting the information. He was initially diagnosed with cerebral palsy so it's been a roller coaster ride for us - just as we digested that diagnosis, we received this news. Sigh. We've got a battery of tests coming up to determine his baseline then we will begin supplementation (hopefully in a few weeks). Thank you for your blog, it's comforting to know of other families going through something similar.

  6. Hi Doggles, I tried to look at your profile to see if I could contact you, but it says it is unavailable. I can totally understand the complete roller coaster ride as we lived with the cerebral palsy diagnosis for 7 months. I'm not that familar with creatine transporter and I am curious as to what they are doing for supplementation. Are you giving a creatine supplement or is it something else? If you would like to contact me you can send me an email at and if there is anything I can do to help please let me know.

  7. Hi Missy, we'll begin supplementation (creatine, arginine and glycine) after his baseline has been determined. I'll likely be emailing you soon!

  8. Hi - Just wanted to pass along this information to you. There is a facebook support group for Creatine Disorders if you are interested in joining it. It is for all 3 of the creatine disorders and there are a lot of families on there that have children with the Creatine Transporter. There is also a Dr. on there named Dr. Joseph Clark that is studying Creatine Transporter and is willing to provide information to the group. Here is a link to the group.!/groups/127389967322193/

    August 11, 2011 3:08 PM