Clinical Domain Working Groups

Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel


Creatine deficiency syndromes are a group of inherited metabolic disorders of creatine synthesis and transport. There are three disorders including guanidinoacetate N-methyltransferase (GAMT), L-arginine:glycine amidinotransferase (AGAT) and creatine transporter (CRTR) deficiencies. GAMT and AGAT deficiencies are inherited autosomal recessively. CRTR deficiency is inherited X-linked. GAMT is encoded by GAMT (MIM#601240); AGAT is encoded by GATM (MIM#602360) and CRTR is encoded by SLC6A8 (MIM#300036). There are <120 patients with GAMT deficiency, <20 patients with AGAT deficiency and <200 patients with CRTR deficiency reported in the literature. The estimated carrier frequency of GAMT deficiency is 0.123% in the general population. The estimated carrier frequency of AGAT deficiency is 1 in 929 individuals. The estimated carrier frequency of CRTR in females is 1 in 4060. The main clinical features of all three creatine deficiency syndrome include global developmental delay, and intellectual disability. Epilepsy, movement disorder and behavioral problems have been reported in GAMT and CRTR deficiencies. Muscle weakness or myopathy has been reported in AGAT deficiency. Biochemical features include creatine deficiency in brain magnetic resonance spectroscopy in males and females in GAMT and AGAT deficiencies and in males in CRTR deficiency. Elevated guanidinoacetate in GAMT and low guanidinoacetate in AGAT deficiencies in body fluids are characteristic biomarkers. Elevated creatine to creatinine ratio in urine is characteristic biochemical feature in males with CRTR deficiency.

The Expert Panel will examine GAMT, GATM and SLC6A8 variants, associated with GAMT, AGAT and CRTR deficiencies respectively.

Expert Panel Status

Step 1
Step 2
Step 3
Step 4
Define Group
Completed Jan. 2019
Develop Classification Rules
Completed Jun. 2020
Pilot Rules
In progress
Expert Panel Approval

Expert Panel Membership

Membership spans many fields, including genetics, medical, academia, and industry.

Past Members


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