February 28th is Rare Disease Day!
Let's celebrate researchers who continue to passionately spend their time and resources helping advance knowledge of rare diseases! Thank you Dr Judi Miller and team for the March 2019 publication in the Journal of Pediatrics " Early Indicators of Creatine Transporter Deficiency", available for free access online through this shared link until April 12th, 2019. https://authors.elsevier.com/a/1Yb~l55CrsUwF
What Is Creatine Transporter Deficiency (CTD)?
What Are Cerebral Creatine Deficiency Syndromes (CCDS)?
- Creatine transporter deficiency (CTD) is a genetic disease that appears in early childhood and often results in severe intellectual disability.
- Creatine (Cr) is necessary for normal brain development and function, and CTD creates a situation where creatine cannot enter into brain cells.
- CTD mainly affects boys. Boys who inherit the condition are often more severely affected than girls.
- Symptoms of all three disorders (AGAT,GAMT,CTD) develop due to a lack of creatine in the brain.
- GAMT deficiency and AGAT deficiency occur because the body is unable to make creatine on its own and these two disorders affect males and females alike.
- CTD deficiency occurs because the body is unable to transport creatine to brain cells and this disorder affects males more than females.
Most common signs and symptoms of CTD and CCDS
- Global developmental delay, or GDD
(delay in meeting 2 or more developmental milestones, including body movements, large and small; speech and language; ability to think; social and personal skills; and daily life skills). GDD is a term applied to children under 5 years and typically predicts a future diagnosis of intellectual disability.1
- Intellectual disability, or ID
(marked by serious limitations in intellectual functioning and behaviors and skills needed to function in daily life). ID is a term applied to older children whose intelligence can be measured with an IQ test. It appears before age 18 years.1
- Speech/language development delay2
involving muscle stiffening and/or jerking2
- Behavior disorders
such as autism and attention deficit and/or hyperactivity disorders2
- Movement disorders
involving lack of coordination and delays in crawling, sitting, and walking2,3
- Vomiting and Digestive Problems3
- Failure to thrive3
Healthcare professionals who specialize in the diagnosis and/or management of CTD and other creatine disorders may include the following:
- Metabolic Geneticists
- Pediatric Neurologists
- Genetic Counselors
- Developmental-Behavioral Pediatricians
How to Diagnosis the Creatine Deficiencies (CCDS)
If a child is missing early developmental milestones, a healthcare professional may order several tests. When a creatine deficiency is suspected, these tests may be used to confirm (or not) the diagnosis:
- A urine test
- A blood test
- An imaging procedure called magnetic resonance spectroscopy (MRS)
- Genetic testing
Creatine (Cr) and Cerebral Creatine Deficiency Syndromes (CCDS)
Creatine (Cr) is a substance the body needs to store and produce energy. About half of our creatine comes from food, mainly meat and dairy products. The other half is produced in the kidney and the liver. Creatine is then carried in the bloodstream to organs and tissues that use lots of energy, such as muscles and the brain. In the brain, creatine must be able to enter nerve cells to do its job.4
CTD is one of three cerebral creatine deficiency syndromes (CCDS). Symptoms of all three disorders (AGAT,GAMT,CTD) develop due to a lack of creatine in the brain. GAMT deficiency and AGAT deficiency occur because the body is unable to make creatine on its own and these two disorders affect males and females alike. CTD deficiency occurs because the body is unable to transport creatine to brain cells and this disorder affects males more than females.
What Causes CTD?
CTD is caused by a genetic mutation in the SLC6A8 gene. The mutation does not interfere with creatine production, which is normal in people with CTD. But creatine needs a special transporter—the creatine transporter—to get to its destination in the brain. The transporter helps creatine pass into brain cells.
CTD produces a poorly functioning or non-functioning creatine transporter. So creatine cannot enter into brain cells, where it needs to be. The normal production of energy cannot occur, resulting in symptoms of CTD.
CTD is described as the second-most common cause of X-linked intellectual disability.6 The pattern of inheritance is different from that of the other creatine disorders.
Here’s how X-linked disorders are passed from parents to children:2,7
Recall that each person has two sex chromosomes. Females have two X chromosomes and males have an X and a Y. Girls inherit two X chromosomes, one from each parent. Boys inherit an X chromosome from their mothers and a Y chromosome from their fathers. In an X-linked disorder, an affected father can pass the mutation to his daughter (who inherits her father’s X chromosome) but not to his son (who inherits his father’s Y chromosome).
CTD: Genetic testing has shown that most children with CTD have either inherited the mutation from their mother or they are the first person in their family to have it (de novo mutation). Mothers who have the mutation(carrier/affected) may have a mild intellectual disability or a history of learning disabilities. They may also show no signs of CTD at all.
If a mother has the mutation, every one of her children has a 50% chance of inheriting it. Girls who inherit the mutation will become carriers and may or may not experience mild symptoms of CTD. Boys who inherit the mutation will develop CTD.
GAMT deficiency is a rare condition caused by an alteration of the GAMT gene. As of 2015, about 110 people worldwide were reported to have it.
Creatine production occurs in a 2-step process. In people with GAMT deficiency, an alteration in the GAMT (guanidinoacetate methyltransferase) enzyme interferes with the second step of the process. No creatine can be made. This results in a shortage of creatine in the brain and other symptoms of GAMT deficiency.
Early symptoms of GAMT deficiency appear in children aged 3 months to 3 years. Here are the most common symptoms:2
- Intellectual disability, mild to severe
- Language delay
- Epilepsy or seizures ranging from occasional to severe and not responsive to epilepsy drugs
- Movement disorders involving uncontrollable jerking or slowness and delays in crawling, sitting, and walking
- Behavior disorders involving hyperactivity, autism, or self-injury
GAMT deficiency is a treatable condition. Supplementary creatine, supplementary ornithine (an important amino acid), and a protein-restricted diet are often prescribed. Early diagnosis and treatment may prevent development of intellectual disability and other symptoms of GAMT deficiency.2
AGAT deficiency is a very rare disorder caused by an alteration of the GATM gene. As of 2015, fewer than 20 people worldwide were known to have it.
AGAT deficiency involves an alteration in the AGAT (arginine:glycine amidinotransferase) enzyme, which interferes with the first step of the creatine production process. No creatine can be made. This results in a shortage of creatine in the brain and other symptoms of AGAT deficiency.
Here are the two most common symptoms:2
- Intellectual disability, mild to moderate
- Muscle weakness
AGAT deficiency is treatable with supplementary creatine. Early diagnosis and treatment may prevent development of intellectual disability and other symptoms of AGAT deficiency.2
Pattern of Inheritance
Both GAMT deficiency and AGAT deficiency are inherited in an autosomal recessive manner.
Here’s what this means:2,5
- If your child has either GAMT deficiency or AGAT deficiency, both you and your mate are carriers of the genetic alteration that causes the disorder. Carriers do not have symptoms nor do they develop the disorder themselves but they can pass the disorder on to their children.
- If your child has one of these disorders, each sibling has a 25% chance of having the same disorder, a 50% chance of being a carrier without symptoms, and a 25% chance of being unaffected and not a carrier.
- Siblings of a parent whose child has GAMT or AGAT deficiency are at 50% risk of being carriers of the disorder.
- AAP Definitions of ID and GDD accessed from:
Moeschler et al. Comprehensive Evaluation of the Child with Intellectual Disability or Global Developmental Delays. Pediatrics September 2014 http://pediatrics.aappublications.org/content/134/3/e903
- Mercimek-Mahmutoglu S, Salomons GS. Creatine Deficiency Syndromes. GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 1993-2015 Published January 15, 2009. Updated December 10, 2015. Accessed December 19, 2016 https://www.ncbi.nlm.nih.gov/books/NBK3794/.
- Miller JS et al. Red Flags for Creatine Transporter Deficiency, and Potential Outcome Variables for the Severely Impaired. Poster first presented at Society for Developmental Behavioral Pediatrics (SDBP) 2016 Annual Meeting Savannah, GA September 2016.
- Longo N et al Disorders of Creatine Transport and Metabolism American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 2011 Wiley-Liss, Inc
- U.S. National Library of Medicine, Medline Plus. https://medlineplus.gov/ency/article/002052.htm
- Kurosawa Y, DeGrauw TJ, Lindquist DM et al. Cyclocreatine treatment improves cognition in mice with creatine transporter deficiency. J Clin Invest. 2012;122(8):2837-2846. doi:10.1172/JCI59373.
- NIH National Human Genome Research Institute, https://www.genome.gov/glossary/index.cfm?id=209