Glycine amidinotransferase deficiency (AGAT) is one of the three cerebral creatine deficiency syndromes (CCDS). These conditions are inborn errors of creatine metabolism which interrupt the formation or transportation of creatine. Creatine is necessary to increase adenosine triphosphate (ATP), which provides energy to all cells in the body.
Arginine: glycine amidinotransferase deficiency is an inherited disorder that primarily affects the brain. People with this disorder have mild to moderate intellectual disability and delayed speech development. Some affected individuals develop autistic behaviors that affect communication and social interaction. They may experience seizures, especially when they have a fever.
Causes
Mutations in the GATM gene cause arginine: glycine amidinotransferase deficiency. The GATM gene provides instructions for making the enzyme arginine: glycine amidinotransferase. This enzyme participates in the two-step production (synthesis) of the compound creatine from the protein building blocks (amino acids) glycine, arginine, and methionine. Specifically, arginine: glycine amidinotransferase controls the first step of the process. In this step, a compound called guanidino acetic acid is produced by transferring a cluster of nitrogen and hydrogen atoms called a guanidino group from arginine to glycine. Guanidinoacetic acid is converted to creatine in the second step of the process. Creatine is needed for the body to store and use energy properly.
GATM gene mutations impair the ability of the arginine: glycine amidinotransferase enzyme to participate in creatine synthesis, resulting in a shortage of creatine. The effects of arginine: glycine amidinotransferase deficiency are most severe in organs and tissues that require large amounts of energy, especially the brain.
AGAT is the first step of creatine production, resulting in the formation of guanidinoacetate, the immediate precursor of creatine. Mutations found in the GATM gene impair the body’s production of creatine. Out of the three CCDS, AGAT is the least reported. Affected individuals may demonstrate cerebral creatine deficiency on MR spectroscopy and low GAA in urine and plasma. People with AGAT typically present with mild to moderate intellectual disabilities.
The inheritance pattern for AGAT is autosomal recessive. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier of the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
Diagnosis
Testing in both urine and plasma is recommended by measuring the concentration of creatine (Cr), guanidinoacetate (GAA), and creatinine (Crn). A positive screen for AGAT is based on plasma GAA that is low with creatine being low to normal and low urine GAA and creatine being low to normal.
AGAT deficiency can be suspected from clinical findings, although there is significant phenotypic overlap with the most common presenting symptoms of intellectual disability and muscle weakness. Laboratory testing of plasma and urine will show decreased levels of creatine and guanidinoacetate. Non-specific elevations of metabolites on urine testing that are normalized to creatinine may appear falsely elevated.[rx] Magnetic resonance spectroscopy (MRS) of the brain will also show an absence of creatine, which is normally present. This finding is not specific to AGAT deficiency, it can be observed in all three cerebral creatine deficiencies. The combination of biochemical testing and MRS findings can be strongly suggestive of AGAT deficiency. Confirmation would most often be done with molecular testing of GATM. Identification of biallelic pathogenic variants in GATM would be confirmation of a diagnosis of AGAT deficiency.[rx] Uncertain findings on molecular testing may be able to be confirmed by enzyme assays, or by measuring creatine uptake in fibroblasts.[rx][rx] Prenatal testing for AGAT deficiency can be performed on chorionic villi samples if the causative pathogenic variants in the family are known.[rx]
Follow-up genomic testing for mutations in the GATM gene may be ordered along with brain MRI with spectroscopy to confirm an AGAT diagnosis. MRI with spectroscopy is useful for measuring creatine levels in the brain.
Generally not required for diagnosis, but a cultured skin fibroblast may be helpful when gene sequencing test results are unclear.
Treatment
Individuals diagnosed with AGAT may require the coordinated efforts of a team of specialists. A pediatrician or an adult primary care physician, neurologist, geneticist, dietician, and doctor who is familiar with metabolic disorders may need to work together to ensure a comprehensive approach to treatment. Occupational, speech and physical therapists may be necessary to treat developmental disabilities and behavior therapy to address behavior problems.
Treatments vary with each AGAT patient. Oral supplementation is available and effective if initiated early for AGAT.
Oral creatine monohydrate is given to replenish creatine levels in the brain and other tissues in individuals with AGAT. For AGAT patients being treated with creatine monohydrate, routine measurement of renal function should be considered to detect possible creatine-associated kidney disease (nephropathy).
The main focus of treatment for AGAT deficiency is supplementation of creatine, to replenish cerebral creatine to normal levels. This is done with oral creatine supplementation. Treatment is most effective if it is started early in life before symptoms are apparent. Treatment in affected individuals does not reverse intellectual disability or improve cognitive function. For treatment at any age, even if the intellectual disability was present, all individuals showed improvement in muscle weakness.[rx] In an asymptomatic sibling, who was started on treatment due to the earlier diagnosis of an affected sibling, early intervention with creatine supplementation resulted in improved outcomes when compared to their untreated siblings at the same age.[rx] In addition to clinical findings, the effectiveness of treatment can be monitored by following creatine levels in blood and urine as well as the creatine signal by MRS. As creatine is rapidly converted and excreted as creatinine, treatment must be lifelong to continue to benefit the patient. Treatment during the early years of brain development is most important for preserving brain function
Prevention of Primary Symptoms
Early treatment at the first sign of symptoms in patients with AGAT is effective in improving a patient’s quality of life. The treatment in newborn siblings of individuals with AGAT deficiency can prevent disease manifestation.
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