Creatine and guanidinoacetate reference values in a French population

Highlights

• Creatine and guanidinoacetate are biomarkers of creatine metabolism pathophysiology.

• Their laboratory blood and urine values varying with age are given within age ranges.

• The age ranges are given on a statistical and not medical or developmental basis.

• Gender differences in urine values might be explained by hormonal effects on SLC6A8.

Abstract

Creatine and guanidinoacetate are biomarkers of creatine metabolism. Their assays in body fluids may be used for detecting patients with primary creatine deficiency disorders (PCDD), a class of inherited diseases. Their laboratory values in blood and urine may vary with age, requiring that reference normal values are given within the age range. Despite the long known role of creatine for muscle physiology, muscle signs are not necessarily the major complaint expressed by PCDD patients. These disorders drastically affect brain function inducing, in patients, intellectual disability, autistic behavior and other neurological signs (delays in speech and language, epilepsy, ataxia, dystonia and choreoathetosis), being a common feature the drop in brain creatine content. For this reason, screening of PCDD patients has been repeatedly carried out in populations with neurological signs. This report is aimed at providing reference laboratory values and related age ranges found for a large scale population of patients with neurological signs (more than 6 thousand patients) previously serving as a background population for screening French patients with PCDD. These reference laboratory values and age ranges compare rather favorably with literature values for healthy populations. Some differences are also observed, and female participants are discriminated from male participants as regards to urine but not blood values including creatine on creatinine ratio and guanidinoacetate on creatinine ratio values. Such gender differences were previously observed in healthy populations; they might be explained by literature differential effects of testosterone and estrogen in adolescents and adults, and by estrogen effects in prepubertal age on SLC6A8 function. Finally, though they were acquired on a population with neurological signs, the present data might reasonably serve as reference laboratory values in any future medical study exploring abnormalities of creatine metabolism and transport.

Introduction

The isolation of creatine is historically attributed to the French chemist Eugène Chevreul [1]. This physiological compound is supplied through body biosynthesis and the diet [2], [3], [4], and its role in muscle physiology has been largely claimed [5], [6], [7], [8]. A creatine/creatine phosphate cycle involving creatine kinases enables the reversible exchange of the high energy phosphate bond of ATP [3]. A role of brain creatine in neurotransmission has been recently proposed ([9], [10], [11], [12], and references therein).

Primary creatine deficiency disorders (PCDD) are inborn errors of metabolism affecting proteins which catalyze creatine biosynthesis (AGAT and GAMT) or transport (SLC6A8) [10], [11], [12], [13], [14], [15], [16], [17]. This group of disorders has rapidly focused the attention of the physicians because, relatively unexpected, neurological dysfunctions (intellectual disability, speech delay, autistic behaviors, epilepsy) predominate sometimes over muscle signs [10], [11], [12], [13], [14], [15], [16], [17]. Interestingly, these disorders share in common a fall in brain creatine detectable by ¹H-MRS [16]. This gives a basis for the neurological expression of these disorders and also explains why in many studies PCDD patients are screened by exploring populations of patients with neurological symptoms [18], [19], [20], [21], [22], [23], [24], [25], [26]. For these studies, reference values of a normal healthy population are often employed without knowing whether the population targeted by the screening and the normal population providing reference values differ or not in their body fluid contents in creatine and metabolites. We previously conducted a screening of primary creatine deficiencies in French patients with unexplained neurological symptoms [27]. In this cohort, laboratory data were collected in patients without PCDD (more than 6 thousand). This great number of data, here, has been used to calculate through adapted statistical tool new reference laboratory values and age intervals related to the large neurological population. Values and age intervals, obtained in this neurological population, are further compared with literature reference data given by different studies.