People with developmental delays, speech delays, seizures, and other undiagnosed symptoms should ask to be screened for a creatine deficiency.
On average, CCDS patients begin to show their first symptom around the age of 1. Unfortunately, most patients don’t receive a CCDS diagnosis until about 3 years of age or later. Early diagnosis of these disorders is essential for prompt initiation of treatment and improved outcomes.
Developmental delay, speech delays, and seizures are the most common symptoms patients experience prior to receiving a CCDS diagnosis. The chart below shows the diverse set of symptoms patients have experienced before receiving a CCDS diagnosis. Please note, there can be variability in the clinical presentation and severity of patients with CCDS.
Genetic testing is the most common method used to confirm a CCDS diagnosis. Often, patients will undergo multiple tests that together confirm a CCDS diagnosis (e.g., biochemical testing and an MRS).
Testing in both urine and plasma is recommended to screen for all three disorders. At a minimum, a urine specimen should be tested.
Creatine transporter deficiency (CTD) will be missed if only plasma is screened because males with this disorder have normal creatine in plasma; urine is needed to make this diagnosis in males.
*Inclusion of urine screening is recommended because CTD can appear normal in plasma screening. Urine creatine can be normal in females heterozygous for CTD. Sequencing of the SLC6A8 gene is needed for the assessment of females for CTD. Urine metabolites are measured relative to creatinine.
Low plasma and urinary creatinine values are a diagnostic clue for AGAT and GAMT deficiency. Generalized pseudo-elevations of urine metabolites normalized to creatinine, such as amino acids and organic acids, may be observed as a result of low urinary creatinine.
Decreased or absent creatine peak is noted for all three disorders
Guanidinoacetate peak in GAMT Deficiency
Gene sequencing of the following genes may be used to confirm a CCDS diagnosis:
GATM gene > AGAT Deficiency
GAMT gene > GAMT Deficiency
SLC6A8 gene > Creatine Transporter Deficiency (CTD)
In 2023, GAMT Deficiency was added to the Recommended Uniform Screening Panel (RUSP), recommending that all babies born in the United States be tested for GAMT as newborns. The RUSP provides state newborn screening programs with a carefully curated list of disorders that meet the committee’s criteria for inclusion. More information can be found here.
Fibroblast assays may be used to measure AGAT and GAMT activity, and to detect creatine uptake for CTD.
The ACD is always looking for experienced clinicians and researchers that share our passion for Cerebral Creatine Deficiency Syndromes. If you would like to be added to our database of CCDS Centers, please submit the form below.
Submit your information if you are willing to be included in our database of CCDS Centers.
*Deletions/Duplications in these genes appear to be extremely rare. However, some of the above laboratories also offer deletion/duplication testing in addition to sequencing, which may need to be ordered separately if desired.
*Whole Exome Sequencing (WES) is also available through many labs, and this test should also detect all three creatine deficiency syndromes.
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van de Kamp JM, Betsalel OT, Mercimek-Mahmutoglu S, Abulhoul L, et al. Phenotype and genotype in 101 males with X-linked creatine transporter deficiency. J Med Genet. 50:463-72, 2013
CreatineInfo Patient Registry and Natural History Study (2023).