Diagnosis of X-Linked creatine transporter deficiency in a patient from Northeast China

Background: Creatine transporter (CRTR) deficiency is the most common creatine deficiency syndrome, of which the final diagnosis relies on mutation in the X-linked CRTR gene. To date, more than 90 mutations in the SLC6A8 gene have been reported. This paper discusses a novel mutation detected via the thorough sequencing of all the X-chromosome-specific exons investigated in a four and a half year old boy with an intellectual disability, speech and language delay and motor disturbance. Methods: A brain magnetic resonance imaging (MRI) and a proton magnetic resonance spectroscopy (MRS) were carried out, the creatine and creatinine concentrations in the urine were checked and all exons were sequenced. Results: A detailed clinical investigation revealed a reduction in the cerebral creatine levels in the brain by the MRS, elevated creatine and creatinine concentrations in the urine and signal abnormalities in the left frontal cortex of the brain by the MRI. A novel change was identified in the heterozygosity of the exon 10: c.1395-c.1401 deletion. Conclusion: The use of a combination of powerful new technologies, such as thorough exome-nextgeneration sequencing and a brain MRS, should be considered, in order to determine any neurometabolic diseases, especially when the signal abnormalities in the brain MRI cannot be explained by any other factors. This mutation results most likely in a dysfunction of the creatine transport and synthesis, hence causing central nervous system symptoms. Neurology Asia 2015; 20(2) : 197 – 201 Address correspondence to: Dr. Hua Wang, Department of Pediatric Neurology, Shengjing Hospital, China Medical University, Shenyang, China. E-mail: [email protected] INTRODUCTION Creatine deficiency syndromes are confirmed congenital metabolic diseases of the creatine transport and synthesis, characterised by depleted cerebral creatine levels. The manifestations of the clinical symptoms are related, mainly, to intellectual disability (ID), speech and language retardation, autistic behaviour, epileptic seizures and hypomyotonia. It has been acknowledged that genetic defects play a significant role in these disorders. All these symptoms have been identified by either autosomal recessive, induced by mutations in the genes, encoding arginine glycine amid inotransferase (AGAT) (OMIM#612718) or guanidinoacetate methyltransferase (GAMT) (OMIM #612736), or they are X-linked, induced by mutations in the gene creatine transporter (CRTR) SLC6A8 (OMIM #300036, Gene ID: 6535). Oral creatine has been proved to be beneficial for individuals with AGAT or GAMT deficiency, and especially younger individuals, but not for those who experience CRTR deficiency. CRTR deficiency is the most common cause of X-linked ID in males. The diagnosis of CRTR deficiency depends on the clinical symptoms, biochemical metabolites, brain proton magnetic resonance spectroscopy (MRS) and gene mutation. The elevated creatine/creatinine ratio in the urine is helpful, and depleted cerebral creatine levels detected by the brain MRS are reliable, for a diagnosis, although the final diagnosis relies on the mutation in the X-linked CRTR gene. The SLC6A8 gene consists of 13 coding exons, spanning approximately 8.3kb at Xq28. More than 90 mutations in this gene have been described. To date, approximately 120 patients have been diagnosed with CRTR deficiency. Not only have intragenic duplications involving exons been reported on, but RNA sequencing studies have also been conducted, in order to provide a better understanding of the clinical symptoms of CRTR deficiency. This paper reports on a novel SLC6A8 gene mutation discovered in a family, and which was detected via a deep sequencing of all the X-chromosome-specific exons. Neurology Asia June 2015