Cerebral Creatine Deficiency Syndromes

Overview

Cerebral creatine deficiency syndromes (CCDS) are inborn errors of creatine metabolism which interrupt the formation or transport of creatine. Creatine is necessary to render available the energy of adenosine triphosphate (ATP) to all cells in the body. Creatine is essential to sustain the high energy levels needed for muscle and brain development.

There are three types of CCDS: creatine transporter deficiency (CTD), guanidinoacetate methyltransferase deficiency (GAMT) and arginine: glycine amidinotransferase deficiency (AGAT).

Signs & Symptoms

The severity of CCDS varies from patient to patient. Global developmental delays affect all children with these disorders and may be the first sign, appearing before other symptoms. Speech delay may be particularly severe and is present in all affected children. Intellectual disability of variable severity is typically present in all older children and adults.

Additional symptoms may include seizure disorders, muscle weakness, behavior disorders, autism-like behaviors, movement disorders, gastrointestinal problems, and failure to thrive.

Causes

Creatine transporter defect (CTD)

CTD is caused by a change (mutation or variant)) in the creatine transporter gene, SLC6A8. This variant results in a blockage in the transportation of creatine to the brain and muscle. CTD is the most common CCDS. Affected individuals may demonstrate cerebral creatine deficiency on MR spectroscopy, normal GAA, but high creatine: creatinine ratio in urine. Individuals typically present with intellectual disabilities and severe expressive speech delays, seizures and autistic behaviors. The age of diagnosis ranges from 2 to 66 years of age, indicating that life expectancy can be normal.

The inheritance pattern for CTD is X-linked. X-linked genetic disorders are conditions caused by a non-working gene on the X chromosome and manifest mostly in males. Females that have a non-working gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the non-working gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a non-working gene, he will develop the disease.

Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.

If a male with an X-linked disorder is able to reproduce, he will pass the non-working gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.

Guanidinoacetate methyltransferase deficiency (GAMT)

GAMT deficiency is a caused by a variant in the GAMT gene that codes for the enzyme that transforms guanidinoacetate into creatine, resulting in a shortage of creatine and the accumulation of guanidinoacetate (GAA). 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 have cerebral creatine deficiency on MR spectroscopy and high GAA in plasma. People with GAMT deficiency typically present with severe intellectual disabilities, seizure disorders and autistic behaviors. The onset of symptoms is between ages 3 months and 3 years of age.

Diagnosis

CCDS screening is non-invasive.Testing in both urine and plasma is recommended for all three types of CCDS by measuring the concentration of creatine (Cr), guanidinoacetate (GAA) and creatinine (Crn). Follow up genomic testing for specific genes and brain MRI with spectroscopy may be ordered to confirm a CCDS diagnosis. GAMT deficiency is also part of the recommended uniform newborn screening panel and children can be identified at birth in states that have adopted it.

Treatments

Individuals diagnosed with a CCDS 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 CCDS patient. Oral supplementation is available and effective if initiated early for GAMT and AGAT. To date, this type of therapy has not shown to improve outcomes in individuals with CTD. Additional treatments for CTD are under investigation.

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

What does creatine deficiency syndrome do to the mitochondria?

Creatine deficiency leads to early alteration of mitochondrial proteomic landscape. Proteins involved in the energy metabolism chain and antioxidant enzymes are upregulated in creatine deficient brain. Spine dynamics, inflammatory response and ERK/MAPK pathway are affected by creatine deficiency.

How can I increase creatine in my brain?

Moreover, mental training has been shown to elevate brain creatine levels, hinting to an upregulation of resting energy storage (Valenzuela et al., 2003). Higher resting creatine levels have been proven to enhance performance in cognitive tasks such as recognition memory (Ferrier et al., 2000).

How do you test for creatine deficiency?

Urine is the sample of choice for diagnosing creatine transporter deficiency in males, as plasma creatine concentrations are typically normal in this condition.

Does creatine have neurological effects?

For older individuals, supplementing with creatine for 2 weeks significantly improved memory and recall ability ( 47 ). In older adults, creatine may boost brain function, protect against neurological diseases, and reduce age-related loss of muscle and strength ( 48 ).

What foods contain creatine?

Creatine is also found in foods such as milk, red meat and seafood. In a normal omnivorous /carnivorous diet, you consume one to two grams/day of creatine. Vegetarians may have lower amounts of creatine in their bodies.

Can creatine affect sleep?

Key takeaways. Creatine supplementation increases creatine stores in the brain. By reducing the accumulation of adenosine and adenosine triphosphate in the brain during wakefulness, creatine supplementation seems to reduce sleep depth, duration, and “rebound sleep” after sleep deprivation.

How much creatine does the brain need?

May improve brain function

A review of 6 studies involving 281 healthy people looked at the effects of taking creatine supplements on particular aspects of brain function ( 16 ). It found that taking 5–20 grams daily for a period of 5 days to 6 weeks may improve short-term memory and intelligence or reasoning ( 16 ).

How can I get more creatine naturally?

The bottom line

Creatine is a “carninutrient,” meaning it's only found in animal products. Fish and meats, including beef and pork, and chicken are the best natural food sources of creatine. Supplementing with creatine rather than trying to consume adequate amounts through the diet alone is a more effective strategy.

What blood tests show creatine?

The creatinine blood test measures the level of creatinine in the blood. This test is done to see how well your kidneys are working. Creatinine can also be measured with a urine test. A measurement of the serum creatinine level is often used to evaluate kidney function.