Biomarker for Creatine Deficiency Syndromes. An International, Multicenter, Epidemiological Study.

The Creatine Deficiency Syndromes (CDS) are a group of inborn errors of metabolism which interrupt the biosynthesis or transportation of creatine. Individuals with CDS classically present neurological symptoms (seizures, movement disorders and myopathy), and behavioral manifestations. This group includes two creatine biosynthesis disorders (Guanidinoacetate Methyltransferase Deficiency and L-Arginine: Glycine Amidinotransferase Deficiency), as well as X-linked Creatine Transporter Deficiency.

Guanidinoacetate Methyltransferase Deficiency:

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 this 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. Dietary management via manipulation of critical amino acids may improve clinical outcome. Mutations in the GAMT gene are a relatively rare cause of creatine deficiency syndrome.

L-Arginine: Glycine Amidinotransferase Deficiency:

L-Arginine: Glycine Amidinotransferase Deficiency is a very rare type of CDS 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. This deficiency is caused by mutations in GATM gene, located to chromosome 15q15.1. This gene encodes the enzyme L-Arginine: Glycine Amidinotransferase, which converts arginine and glycine to ornithine and guanidinoacetate in the creatine cycle pathway. This deficiency is transmitted in an autosomal recessive manner.