Laboratory diagnosis of creatine deficiency syndromes: a technical standard and guideline of the American College of Medical Genetics and Genomics

Abstract: Cerebral creatine deficiency syndromes are neurometabolic conditions characterized by intellectual disability, seizures, speech delay, and behavioral abnormalities. Several laboratory methods are available for preliminary and confirmatory diagnosis of these conditions, including measurement of creatine and related metabolites in biofluids using liquid chromatography–tandem mass spectrometry or gas chromatography–mass spectrometry, enzyme activity assays in cultured cells, and DNA sequence analysis. These guidelines are intended to standardize these procedures to help optimize the diagnosis of creatine deficiency syndromes. While biochemical methods are emphasized, considerations for confirmatory molecular testing are also discussed, along with variables that influence test results and interpretation.

Parent Summary: Sharer et al. reported on recommended laboratory methods to diagnose CCDSs. While the authors noted that magnetic resonance spectroscopy (MRS; a noninvasive technique that allows researchers to study the levels of chemical components of the brain’s tissues) can be used, that approach is expensive, requires children to be sedated, and does not specify which CCDS the patient may have. Thus, the authors recommended measuring creatine, guanidinoacetate, and creatinine levels in urine, plasma, or dried blood spots for initial diagnosis. For AGAT or GAMT deficiency, plasma and/or urine can be used; measurements of creatine and guanidinoacetate levels in plasma are specifically recommended. For CTD, urine is the best option. For some female patients with CTD, genetic analyses are also recommended. In general, the authors recommend that the samples be collected when the patients have fasted. The authors also provided a general reference table for relative levels of guanidinoacetate, creatine, and creatine:creatinine ratios in plasma, urine, and cerebrospinal fluid in patients with AGAT deficiency, GAMT deficiency, and CTD. (Cerebrospinal fluid is a fluid that flows through the brain and spinal cord.) The authors did note that creatinine (by itself) has limited value as a diagnostic marker for CCDSs. Additionally, the authors provided background information on (1) the sources and function of creatine, (2) biochemical/molecular characteristics and clinical descriptions of AGAT, GAMT, and CTD, (3) prevalence and inheritance of CCDSs, and (4) interpretation of test results.

Link to article: https://www.nature.com/articles/gim2016203

PubMed: https://pubmed.ncbi.nlm.nih.gov/28055022/

Authors: J. Daniel Sharer, Olaf Bodamer, MD, Nicola Longo, MD, Silvia Tortorelli, MD, Mirjam M.C. Wamelink, and Sarah Young; a Workgroup of the ACMG Laboratory Quality Assurance Committee

Key Terms: Multiple CCDS, MRS, Diagnostic, In vitro, Basic Science, GAMT, AGAT, CTD