GAMT Deficiency Information
Mutations in the GAMT gene cause GAMT Deficiency.
Due to a lack of the GAMT enzyme, patients with GAMT are unable to break down the GAA formed in the first step of creatine synthesis. This results in a buildup of guanidinoacetate (GAA) which is believed to be toxic to the brain at high levels.
Treatment is aimed at reducing GAA production and supplying the creatine that is not produced by the body. Patients are typically prescribed oral supplements of creatine monohydrate and l-ornithine. Some physicians also recommend diet restrictions and sodium benzoate supplementation to further minimize GAA accumulation.
Symptoms
GAMT severity differs among patients, with global developmental delays being an early and common sign. Most individuals experience intellectual disabilities, seizures, muscle weakness, behavioral issues, and movement disorders. Delayed motor skill development, such as sitting or walking, is common, and severely affected patients may lose previously learned abilities like head control or sitting independently.
GAMT deficiency is inherited. As a recessive trait, both parents must be carriers of the disorder to pass it to a child.
GAMT deficiency is an autosomal recessive disorder (Mercimek-Andrews et al. 2022), which means two copies of the defective gene must be inherited to have symptoms – both parents must be carriers of the disorder. A carrier is someone who has one defective copy of the gene and one working copy of the gene. They do not have symptoms of the disorder. Any additional children of two carrier parents have a 25% chance of inheriting the disorder, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Over 70 versions of the GAMT gene have been reported (Goldstein et al., 2023), and work is currently ongoing to understand how different mutations lead to different clinical outcomes.
Additional Information
CCDS Symptoms
The most common CCDS symptoms are listed below.
- Speech delay may be particularly severe and appears to be present in all untreated children. Some individuals develop no speech or speak only in single words.
- Global Developmental Delay affects young children with these disorders. It may be the first sign, appearing before other symptoms.
- Intellectual Disability of variable severity is typically present in all older children and adults.
- Seizure disorders have a variable age of onset and severity and are not always present.
- Hypotonia, muscle weakness, and muscle hypotrophy are common.
- Behavior disorders including autism-like behaviors and hyperactivity often occur.
- Movement disorder including dystonia and dyskinesia (sometimes labeled as cerebral palsy) may be present.
- Gastrointestinal problems such as chronic constipation and vomiting are common, especially in children with CTD.
- Failure to thrive is a term often used to describe CCDS patients.
Initial Diagnoses
It is often many years before the CCDS patient is diagnosed due to the non-specific symptoms of the disorders and the lack of clear dysmorphic features. CCDS patients are often first diagnosed with other disorders, including:
- Developmental Delay/Disability
- Failure to Thrive
- Cerebral Palsy
- Unknown Mitochondrial Disorder
- Movement Disorders
- Gastrointestinal Disorders
- Epilepsy
- Autism
View Clinician Screening recommendations.
CCDS Prevalence
The exact prevalence of Cerebral Creatine Deficiency Syndromes is unknown. Yet, sources estimate that approximately 1% of individuals with intellectual disabilities of unknown origin may have a Cerebral Creatine Deficiency Syndrome. It is also estimated that Creatine Transporter Deficiency (CTD) represents the second largest cause of x-linked mental disability behind Fragile X syndrome. There are more than 100 documented cases of GAMT Deficiency. AGAT is the rarest of the CCDS with only a few dozen known cases.
