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Guanidinoacetate Methyltransferase Deficiency

Guanidinoacetate Methyltransferase Deficiency



 OVERVIEW

Guanidinoacetate methyltransferase deficiency (GAMT) is one of the three cerebral creatine deficiency syndromes (CCDS). These conditions are inborn errors of creatine metabolism which interrupt the formation or transport of creatine. Creatine is necessary to use energy derived from adenosine triphosphate (ATP), which provides energy to all cells in the body. Creatine is essential to sustain the high energy levels needed for muscle and brain development. The onset of GAMT symptoms occurs between ages 3 months and 3 years of age.

SYMPTOMS

The severity of GAMT varies from patient to patient. Global developmental delays affect all individuals with this disorder and may be the first sign, appearing before other symptoms. Most individuals with GAMT deficiency have intellectual disabilities, seizure disorders, muscle weakness, behavior disorders and movement disorders. People with GAMT may have weak muscle tone and delayed development of motor skills such as sitting or walking. Severely affected patients may lose previously acquired skills such as the ability to support their head or to sit unsupported.

CAUSES

GAMT deficiency is a caused by changes (called variants or mutations) in the GAMT gene that makes the enzyme that creates creatine, resulting in a shortage of creatine. It is the most severe of the three CCDS due to the elevation of guanidinoacetate (which is neurotoxic) in addition to creatine deficiency. Affected individuals may demonstrate cerebral creatine deficiency on MR spectroscopy and high GAA in plasma.

The inheritance pattern for GAMT 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 for 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.

AFFECTED POPULATIONS

The prevalence of GAMT deficiency has been estimated to be from 1 out of 250,000 to 1 out of 550,000 patients being diagnosed. As of 2015, there have only been 110 individuals with GAMT deficiency diagnosed worldwide.

DISORDERS WITH SIMILAR SYMPTOMS

GAMT deficiency patients are frequently misdiagnosed with cerebral palsy as infants and toddlers. Children are often misdiagnosed with autism or global developmental delays.


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 GAMT is based on plasma GAA that is elevated with creatine being low and urine GAA that is elevated and creatine being low to normal. Urine testing might be normal in young children, for which plasma testing is recommended.

Follow up genomic testing for mutations in the GAMT gene may be ordered along with brain MRI with spectroscopy to confirm GAMT diagnosis. MRI with spectroscopy is useful for measuring creatine levels in the brain.

Generally not required for diagnosis, but cultured skin fibroblasts for enzyme assay may be helpful when gene sequencing test results are unclear.

GAMT deficiency was recommended for inclusion in the Recommended Uniform Screening Panel (RUSP) for newborns in 2022. As of January 2023, the RUSP recommends that state newborn screening programs include GAMT deficiency.


STANDARD THERAPIES

Treatment

Individuals diagnosed with GAMT may require the coordinated efforts of a team of specialists. A pediatrician or an adult primary care physician, neurologist, geneticist, dietician and a 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 GAMT patient. Oral supplementation is available and effective if initiated early in life.

Oral creatine monohydrate is given to replenish creatine levels in the brain and other tissues in individuals with GAMT. A low arginine/protein diet, L-ornithine supplementation, and sodium benzoate are used to reduce toxic levels of guanidinoacetate in individuals with GAMT deficiency. For GAMT patients being treated with creatine monohydrate, a routine measurement of renal function should be considered to detect possible creatine-associated kidney disease (nephropathy).


Prevention of Primary Symptoms

Early treatment at the first sign of symptoms in patients with GAMT is effective in improving patient’s quality of life. The treatment in newborn siblings of individuals with GAMT has been shown to prevent disease manifestation.

Types Of Doctor Department : Genetics specialist

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