Guanidinoacetate methyltransferase deficiency

Signs and symptoms of guanidinoacetate methyltransferase (GAMT) deficiency typically become noticeable between the age of 3 months to 3 years. These symptoms typically include meeting milestones such as sitting up and walking later than expected (developmental delay), weak muscle tone (hypotonia), recurrent seizures (epilepsy), and problems coordinating movements (ataxia). As an affected individual gets older, other signs such as intellectual disability and behavior problems may become apparent. Behavior problems can include hyperactivity, autistic behaviors, and a tendency to harm oneself (self-mutilation).^[2]

Symptoms of GAMT deficiency may worsen with age if a person is undiagnosed and does not receive the necessary treatment.^[2] 

Guanidinoacetate methyltransferase (GAMT) deficiency is caused by changes (mutations) in the GAMT gene. This gene provides instructions to the body to create a substance called creatine. Creatine helps the body store and use energy properly. When there is a mutation in GAMT, the body does not receive enough creatine to function. This causes body parts that use a lot of energy, such as the brain and the muscles, to not work properly.^[1] In addition, when the body does not have enough GAMT, there is a buildup of a substance called guanidinoacetate. This buildup causes problems in the brain and muscles as well.^[1]

Guanidinoacetate methyltransferase (GAMT) deficiency is inherited in an autosomal recessive manner.^[1] This means that both copies of the GAMT gene must be changed in order for a person to have symptoms of the disease. We inherit one copy of each gene from our mother and the other from our father.

People with only one copy of the GAMT gene that is changed are known as carriers. When two carriers of GAMT deficiency have children together, for each child there is a:

• 25% chance that the child will have GAMT deficiency
• 50% chance that the child will be a carrier of GAMT deficiency like the parents
• 25% chance that the child will have two working copies of GAMT, so the child will not have GAMT deficiency and will not be a carrier.

Guanidinoacetate methyltransferase (GAMT) deficiency can be diagnosed when guanidinoacetate is present in high levels in the urine. Doctors may also be suspicious that this disease is causing symptoms if there is shown to be a deficiency of creatine in the brain based on brain imaging. Genetic testing can then be used to confirm the diagnosis. If genetic testing is inconclusive, doctors may wish to take a sample of skin to see if the enzyme guanidinoacetate methyltransferase is working properly.^[2] 

Guanidinoacetate methyltransferase (GAMT) deficiency is treated by supplementation with oral creatine monohydrate. By taking creatine orally, people with GAMT deficiency are able to supplement the amount of creatine in their systems so that the brain and muscles have more energy.^[2]

People with GAMT deficiency may also be on a diet that restricts their arginine or protein intake. This is necessary so that the body creates less guanidinoacetate, which can result in the symptoms related to the buildup being less severe.^[3] In order to allow the body to get enough nutrients with this diet restriction, people with GAMT deficiency may need to take a formula that has all amino acids except arginine in it.^[2]

Doctors will recommend that people affected by GAMT deficiency be monitored closely to see how treatment is working for them. Treatment for GAMT deficiency can keep the symptoms of the disease from progressing, but treatment has not been shown to improve intellectual disability or developmental delay. ^[4][5] Treatment has been shown to help improve the coordination of movements and behavioral problems associated with GAMT deficiency.^[6]

Other forms of therapy that may help people with GAMT deficiency include speech, occupational, and physical therapy. Behavioral therapy may reduce the behavioral symptoms of the disease as well.^[2] 

There is limited information about the long-term outlook for people affected with guanidinoacetate methyltransferase (GAMT) deficiency. Individuals who are diagnosed early in life and begin treatment before the onset of symptoms will likely have the best outcome. For this reason, newborn siblings of children with GAMT deficiency should begin treatment right away until it can be determined whether or not they have GAMT deficiency as well.^[2] Many researchers are also hoping that GAMT deficiency can be added to newborn screening programs. These programs would test all newborns for the disease so that treatment can be started right away.^{[7][8][9][10]}

When people are diagnosed later in life, treatment cannot reverse symptoms of the disease such as developmental delay or intellectual disability, but it can prevent the symptoms from worsening. In some cases, treatment has been shown to improve issues with movement coordination and behavioral problems.^[6] Although GAMT deficiency has not been shown to reduce a person’s lifespan, it is possible that some of the symptoms of the disorder such as having multiple disabilities or seizures can impact life expectancy.^[6]

There have been some side effects to treatment with oral creatine monohydrate. This treatment can cause kidney malfunction, so doctors need to closely monitor the kidney health of anyone who is taking this medication. Because GAMT deficiency affects the muscles, doctors may also want to monitor the heart function of people with this disease to make sure that it is functioning properly.^[2]