CREATININE GIVES CLUE TO DIAGNOSIS OF A TREATABLE
RARE INHERITED NEUROLOGICAL DISORDER
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.