AGAT Deficiency Information

Mutations found in the GATM gene result in AGAT Deficiency

A diagram showing AGAT's creatine production

Patients with AGAT Deficiency lack the first enzyme necessary for creating creatine.

Treatment with oral supplementation of creatine monohydrate is effective in replenishing the body’s needed creatine supply and greatly improves outcomes if initiated early for AGAT Deficiency patients. Diet restrictions are not typically recommended for AGAT patients.

Symptoms

AGAT patients typically have less severe symptoms in comparison to GAMT and CTD because they have functioning transporters to utilize creatine found naturally in the diet and they do not have a buildup of GAA.

AGAT deficiency is inherited. As a recessive trait, both parents must be carriers of the disorder to pass it to a child.

AGAT 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 40 versions of the GATM 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.