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Arginine: Glycine Amidinotransferase Deficiency

Arginine: Glycine Amidinotransferase Deficiency



Overview

Arginine: 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 transport of creatine. Creatine is necessary to use properly adenosine triphosphate (ATP), which provides energy to all cells in the body.

Symptoms

The severity of AGAT varies from patient to patient. People with AGAT typically present with mild to moderate intellectual disabilities, delayed speech and may have seizure activity. Some individuals may develop autistic like behaviors. Children with AGAT may not gain weight and grow at the expected rate (failure to thrive) and have delayed development of motor skills such as sitting and walking. Affected individuals may also have weak muscle tone and tend to tire easily.

Causes

AGAT is the first step of creatine production, resulting in the formation of guanidinoacetate, the immediate precursor of creatine. Changes (mutations or pathogenic variants) 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 plasma.

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 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

Fewer than 20 patients with AGAT have reported worldwide.

Disorders with Similar Symptoms

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

Diagnosis

Testing in plasma is recommended by measuring the concentration of creatine (Cr), and guanidinoacetate (GAA). A positive screen for AGAT is based on plasma GAA that is low with creatine being low to normal. Urine GAA is usually low but is difficult to distinguish from normal levels.

Follow up genomic testing for pathogenic variants 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 cultured skin fibroblasts may be helpful when gene sequencing test results are unclear.

Standard Therapies

Treatment

Individual 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 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 AGAT patient. 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, 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 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.

Type of Doctor Department : A Medical Geneticist (or Metabolic Specialist) and a Neurologist

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