Fourteen cases of cerebral creatine deficiency syndrome in children: a cohort study in China

Weihua Sun; Yi Wang; Mengyuan Wu; Hongjiang Wu; Xiaomin Peng; Yingyan Shi; Feifan Xiao; Bingbing Wu; Wenhao Zhou; Wei Lu

doi:10.21037/tp-23-164

Fourteen cases of cerebral creatine deficiency syndrome in children: a cohort study in China

Transl Pediatr. 2023 May 30;12(5):927-937. doi: 10.21037/tp-23-164. Epub 2023 May 11.

Authors

Weihua Sun¹, Yi Wang², Mengyuan Wu¹, Hongjiang Wu¹, Xiaomin Peng¹, Yingyan Shi³, Feifan Xiao¹, Bingbing Wu^{1

4}, Wenhao Zhou^{1

4}, Wei Lu⁵

Affiliations

¹ Pediatric Research Institute, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
² Department of Neurology, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
³ Department of Radiology, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
⁴ Center for Molecular Medicine, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
⁵ Department of Endocrinology and Inherited Metabolic Diseases, National Children's Medical Center, Children's Hospital of Fudan University, Shanghai, China.

Abstract

Background: This study sought to analyze the clinical characteristics, biochemical metabolic indications, treatment results, and genetic spectrum of cerebral creatine deficiency syndrome (CCDS), estimate the prevalence of CCDS in Chinese children and provide a reference to guide clinical practice.

Methods: We performed a retrospective cohort study of 3,568 children with developmental delay at Children's Hospital of Fudan University over a 6-year period (January 2017-December 2022). Metabolites in the blood/urine were detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and genetic testing was performed by next-generation sequencing (NGS). The patients with suspected CCDS were ultimately diagnosed by magnetic resonance spectroscopy (MRS). The patients were then treated and followed up. All the reported cases of CCDS, their gene mutations, and treatment results in China were summarized.

Results: Ultimately, 14 patients were diagnosed with CCDS. The age of onset was between 1-2 years. All the patients had developmental delay, 9 had epilepsy, and 8 had movement or behavioral disorders. A total of 17 genetic variants were identified, including 6 novel variants. c.403G>A, c.491dupG of the guanidinoacetate methyltransferase (GAMT) gene had a relatively high frequency. After treatment, patients with GAMT deficiency showed obvious improvements, and brain creatine (Cr) levels recovered to 50-80% of normal, 1 patient achieved normal neurodevelopment, and 3 patients became epilepsy free; however, 6 male patients with X-linked creatine transporter gene (SLC6A8) variants received Cr for 3-6 months with no effect, and 2 patients received combined therapy with few improvements.

Conclusions: The prevalence of CCDS is ~0.39% in Chinese children with developmental delay. A low-protein diet, Cr and, ornithine were useful for patients with GAMT deficiency. Male patients with SLC6A8 deficiency showed only limited improvement on combined therapy.

Keywords: Cerebral creatine deficiency syndrome (CCDS); creatine (Cr); liquid chromatography-tandem mass spectrometry (LC-MS/MS); magnetic resonance spectroscopy (MRS).