|Topic:||Creatine Deficiency Syndromes .|
|Details:|| Creatine deficiency syndromes (CDS) represent a group of disorders that result from defects in the synthesis and transport of creatine. These disorders are also referred to as primary metabolism disorders of creatine. As discussed in the previous section, there are two enzymes of creatine synthesis, glycine amidinotransferase (encoded by the GATM gene ) and guanidinoacetate N-methyltransferase (encoded by the GAMT gene), and one major creatine transporter encoded by the SLC6A8 gene. The first disorder in creatine metabolism to be characterized involved mutations in the GAMT gene. The initial GAMT deficient patient experienced severe psychomotor retardation, refractory epilepsy, and movement disorder. The patient exhibited no cerebral creatine along with high GAA concentrations in the brain and body fluids. Treatment of this patient was effected by oral administration of creatine monohydrate. Following this initial patient characterization, mutations in the GATM gene and the SLC6A8 gene were found in patient exhibiting similar pathology. The GATM and GAMT mutation-associated disorders are inherited as autosomal recessive diseases. The SLC6A8 gene is located on the X chromosome and, therefore, creatine transporter deficiencies are inherited in an X-linked recessive manner. Few GATM deficient patients have been identified, 40 GAMT deficient patients have been identified, and around 150 SLC6A8 deficient patients have been identified to date.
Although skeletal muscle creatine synthesis will be impaired in individuals with GATM and GAMT mutations, impaired muscle function is not the major symptom in creatine deficiency syndrome patients. All of these disorders exert dramatic effects on central nervous system function and, therefore, neurological symptoms are the main clinical complications in these patients. The clinical features in creatine deficiency syndromes include intellectual disability, speech and language delay, epilepsy and autism spectrum disorder. Due to the different levels of enzyme defect with various mutations and the different genes there is wide variability in the severity of the clinical symptoms. Patients with GATM deficiencies have milder clinical manifestations which are generally limited to moderate intellectual disability and language disorder. Patients with GAMT deficiencies have high concentrations of GAA in body fluids and manifest with refractory epilepsy and severe movement disorders. Patients with SLC6A8 deficiencies exhibit mental retardation, epilepsy, autism spectrum disorder, and severe language delay.
Treatment of both GATM and GAMT deficient patients can be carried out with oral creatine monohydrate. However, this therapy does not lower the levels of the intermediate metabolite, GAA, seen with GAMT deficiency. In these latter patients the addition of ornithine supplementation and dietary restriction in arginine help to reduce the production of GAA. The reductions in GAA provide better control of the refractory epilepsy that is common in GAMT deficiency. Currently there is no effective treatment for patients with SLC6A8 deficiency
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