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BioCDS – Biomarker for Creatine Deficiency Syndromes

Clinical trial started on October 01, 2016


The creatine deficiency syndromes (CDS) are a group of inborn errors of metabolism which interrupt the biosynthesis or transportation of creatine. Individuals with creatine deficiency syndromes classically present with intellectual disabilities and seizure disorders and may present with pyramidal/extrapyramidal neurologic findings and behavioral problems as well.

Background information

There are three cerebral creatine ceficiency syndromes:

Creatine Transporter Deficiency (CTD) - gene SLC6A8

Guanidinoacetate Methyltransferase Deficiency (GAMT) - gene GAMT

Arginine: Glycine Amidinotransferase Deficiency (AGAT) - gene GATM

X-linked Creatine Transporter Deficiency (CTD, SLC6A8 Deficiency, CRTR):

X-linked creatine transporter deficiency (CRTR-D) is a creatine deficiency syndrome (see this term) characterized clinically by global developmental delay / intellectual disability (DD/ID) with prominent speech/language delay, autistic behavior and seizures.

CRTR-D has been reported in more than 150 individuals worldwide. The onset of symptoms occurs during infancy, usually before the age of 2 years. Males are mainly affected, but females can also have various combinations and severities of disease manifestations. CRTR-D is consistently characterized by mild to severe intellectual deficit, and expressive speech and language delay. Behavioral disorders (mainly autism and hyperactivity) are present in all affected individuals. Affected individuals often experience seizures and may present low weight gain, muscular hypotonia, and poor muscle mass. Subtle dysmorphic features such as midface hypoplasia, long face, and prominent chin have been reported in various affected male patients. Epilepsy and extrapyramidal symptoms may also occur occasionally. In adult patients, cardiac and gastrointestinal disorders have been reported. Carrier females are typically asymptomatic, but learning disabilities have been described in some. CRTR-D is not a life threatening disease, however live expectancy is limited, particularly in those who have severe seizures and associated physical disabilities.

Guanidinoacetate Methyltransferase Deficiency (GAMT)

Mutations in the GAMT gene are a relatively rare cause of creatine deficiency syndrome. Affected individuals may demonstrate cerebral creatine deficiency on MR spectroscopy and high GAA in urine. Guanidinoacetate methyltransferase deficiency is inherited in an autosomal recessive manner and is caused by biallelic mutations in the GAMT gene. This gene maps to 19p13.3 and is involved in the biosynthesis of creatine. Individuals with GAMT deficiency typically present with severe intellectual disabilities and seizure disorders which may be resistant to drug therapy. Behavioral problems, including autistic behaviors and self-mutilation are common, and pyramidal/extrapyramidal symptoms affect about one-half of patients with GAMT deficiency. Dietary management of GAMT deficiency via manipulation of critical amino acids may improve clinical outcome.

Arginine: Glycine Amidinotransferase (AGAT):

L-Arginine:glycine amidinotransferase (AGAT) deficiency is a very rare type of creatine deficiency syndrome characterized by global developmental delay, intellectual disability, and myopathy. AGAT deficiency is characterized by global developmental delay, appearing in infancy, which can be associated with language impairment and autistic behavior in some, as well as a mild to moderate intellectual disability. Progressive muscle weakness and fatigability have been reported in older patients. Seizures and failure to thrive have also been described. If creatine supplementation is administered early enough, psychomotor delay may be avoided. AGAT deficiency is caused by mutations in the L-arginine:glycine amidinotransferase gene (GATM) located to chromosome 15q15.1. This gene encodes AGAT, which converts arginine and glycine to ornithine and guanidino-acetate in the creatine cycle pathway. AGAT deficiency is transmitted in an autosomal recessive manner and genetic counseling is possible.