Biochemical diagnostic criteria for CCDS may need to be adjusted depending on the patient’s age at time of diagnosis

Abstract: Creatine deficiency syndrome is a metabolic disorder affecting creatine biosynthesis or transport. There are three genetic defects associated with creatine deficiency syndrome include the two creatine biosynthesis disorders, guanidinoacetate methyltransferase deficiency and L-arginine:glycine amidinotransferase deficiency, and the creatine transporter deficiency. Guanidinoacetate (GAA) and creatine are reliable biochemical markers for creatine metabolic defects. The main aim of this study was to establish age adjusted reference interval for urinary GAA/ creatinine ratio and creatine/ creatinine ratio in a cohort of Egyptian children using gas chromatography-Mass spectrometry (GC-MS). The study was conducted on 150 subjects partitioned by age into two groups: less than 4 years old and from 4 to 15 years old. Metabolic profiling of urine samples was performed using GC-MS. The reference interval was calculated as values between 2.5th and 97.5th percentiles. The reference interval for GAA/ creatinine ratio was set as (20.3 – 223.3 μmol/mmol) and (15.3 – 209.8 μmol/mmol) for age groups (0 – 4 years) and (4 – 15 years) respectively; Regarding creatine/creatinine ratio, the reference interval was (0.047 – 1.45 mmol/mmol) for children aging less than 4 years old and (0.013 – 1.36 mmol/mmol) for age group (4 – 15 years). Both GAA and creatine decreased significantly with age (p= 0.039 and 0.001 respectively) denoting the importance of interpreting both biomarkers’ results considering age group for proper diagnosis of creatine metabolic defects.

ACD Summary: Mustafa et al. analyzed levels of guanidinoacetic acid (GAA), creatine, and creatinine in urine in neurotypical children ages 0- to 15-years-old in Egypt. Specifically, the authors looked at the ratio of GAA to creatinine (GAA:creatinine) and the ratio of creatine to creatinine (creatine:creatinine). Typically, GAA:creatinine levels in urine are low in patients with AGAT deficiency, elevated in patients with GAMT deficiency, and normal in patients with CTD. In contrast, creatine:creatinine levels in urine are normal in patients with AGAT or GAMT deficiency and may be elevated in patients with CTD. These ratios are used by physicians to help with diagnosing CCDS. Accordingly, Mustafa et al. wanted to determine how these ratio levels change with age, so they could begin to establish an age-specific reference level for these diagnostic criteria. The authors collected data on 160 children but removed 10 children from analysis because of positive screening for a CCDS. For the remaining 150 neurotypical children, there was a steady decline in GAA:creatinine and creatine:creatinine levels with age, with there being a large difference in these average levels when comparing children less than 4 years old to children between 4 and 15 years old. Accordingly, the reference criteria for diagnosing CCDS may change with age at time of diagnosis, which may be contributing to the underdiagnosis of CCDS.

Parent Summary: Mustafa et al. analyzed levels of guanidinoacetic acid (GAA), creatine, and creatinine in urine in children ages 0- to 15-years-old in Egypt. Specifically, the authors looked at the ratio of GAA to creatinine (GAA:creatinine) and the ratio of creatine to creatinine (creatine:creatinine). Typically, GAA:creatinine levels in urine are low in patients with AGAT deficiency, elevated in patients with GAMT deficiency, and normal in patients with CTD. In contrast, creatine:creatinine levels in urine are normal in patients with AGAT or GAMT deficiency and may be elevated in patients with CTD. These ratios are used by physicians to help with diagnosing CCDS. Accordingly, Mustafa et al. wanted to determine how these ratio levels change with age, so they could begin to establish an age-specific reference level for these diagnostic criteria. The authors collected data on 160 children but removed 10 children from analysis because of positive screening for a CCDS. For the remaining 150 children, there was a steady decline in GAA:creatinine and creatine:creatinine levels with age, with there being a large difference in these average levels when comparing children less than 4 years old to children between 4 and 15 years old. Accordingly, the reference criteria for diagnosing CCDS may change with age at time of diagnosis, which may be contributing to the underdiagnosis of CCDS.

Link to free article: Age Adjusted Reference Interval for Creatine Deficiency Syndrome Biomarkers by Gas chromatography-Mass Spectrometry

Authors: Naira M. Mustafa, Amal Abdo, Doaa M. Abdou, & Nevine E. Elaba

Key Terms: Multiple CCDS, diagnostic, clinical study, pediatric patient