Patients and Methods: The controls cohort included 6417 subjects without CDS recruited in 6 French public hospitals during 28 months. Creatine and GAA were measured in plasma and urine and data were exploited by different statistical tools. Clinical, biological and genetic data from patients affected with CDS since 2003 were collected. Results: Analyses of control data highlighted new age reference range for plasma and urine GAA and creatine and a sex distinction for urine values. 51 patients affected with CDS (14 with GAMT deficiency and 37 with CRTR deficiency) were described. Conclusion: These new references values as a function of sex and age should improve the diagnosis of CDS, in particular to reduce the false positive rate. To conclude, we propose a diagnostic algorithm including biochemical investigations, gene studies and brain 1H-MRS, to improve the screening and the follow-up of the CDS patients. Elevated urinary excretion of creatine (CRE) is an important marker of creatine transporter (SLC6A8) deficiency. In addition to the alimentary sources of creatine (e.g. meat) the endogenous production comes from methylation of guanidinoacetate (GUA). The level of a biological component may be dependent upon its nearest metabolic precursor or other closely related substance, as has been shown for many other analytes where two dimensional reference areas do not have a quadratic form. Lg(U-creatinine) is fairly proportional to lg(age) in the interval 1-18 years of age, but deviates from that outside this interval. To investigate the functional relationship between the variables we performed a linear regression analysis from our laboratory production during the last 3 years, excluding 4 patients with documented SLC6A8 deficiency, one with muscular dystrophy and one with creatine supplementation. The model lg (U-CRE/creatinine)i=a+b.sexi+c.lg(age)i+d.lg(creatinine)i+e.lg(GUA)i+ fi where fi represents a residual, gave the following significant estimates: a**=1.11; c**=−0.548 ; d*=− 0.220 ; e**=1.009. (n=1255; **P<10-30; *P=7.10-8). Thus there is a one-to-one relationship between CRE and GUA, which requires the use of multidimensional reference ranges. Objetive: To present a sensitive and robust method for routine measurement of urinary Cr and GAA, combining solid-phase extraction (SPE), hydrophilic interaction liquid chromatography (HILIC) separation, and detection by tandem mass spectrometry. Methods: Sample preparation: addition of deuterated internal standards, phosphate buffer and water in 96-well plates. Extraction: in-house assembled 96-well SPE using a strong cation-exchange resin. Separation of analytes was obtained on a Luna Silic column. Detection was done by positive-mode electrospray ionization using selected reaction monitoring with a Waters Quattro Micro TMS. Clinical validation was performed with NCCLS approved guidelines. Results and conclusion: Combination of cation exchange SPE with HILIC provided an efficient and specific method for simultaneous detection of Cr and GAAwithout derivatization, in less than 4 minutes. Achieved linearity was up to 10.4 mmol/L for Cr and 13.0 mmol/L for GAA. Total assay imprecision was bellow 16%. Limit of quantification were 5.9 μmol/L for Cr and 12.6 μmol/L for GAA. No ion suppression or enhancement was observed. The phospholipase C beta 1 (PLCbeta1) enzyme is essential for neurotransmitter-mediated signal transduction. Following receptor occupancy, PLCbeta1 catalyzes the production of myo-inositol 1,4,5-trisphosphate (IP3) and diacylglycerol from phosphatidylinositol 4,5-bisphosphate (PIP2). PLCbeta1 gene defects may disrupt CNS development and function. One male infant with early-onset epileptic encephalopathy and a homozygous loss-of-function 0.5 Mb deletion in the PLCbeta1 gene has been reported (Kurian et al, Brain 2010). We report a second male with malignant migrating epilepsy of infancy, and a homozygous deletion of the 5' non-coding region and exons 1-3 of PLCbeta1. Seizures began at 6 months, occurred 50-60/day, and were refractory to antiepileptic drugs and ketogenic diet. Baseline MRI showed diffuse parenchymal volume loss. Mega-dose of myo-inositol (Ins) was administered gradually in an attempt to raise Ins in neurons and PIP2 levels at receptor sites and elicit a recruitment of other PLC isoforms. After 10 days of 500 mg Ins/kg/day, electroencephalographic seizures decreased to 5/day, and meaningful movements and alertness increased. TE MRS revealed a 2-4-fold Ins increase in the left basal ganglia and parietooccipital white matter regions.