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Creatine Transporter Deficiency (CTD)

Article in development. For more information, visit the Genetics Home Reference page, a service of the U.S. National Library of Medicine: http://ghr.nlm.nih.gov/condition/x-linked-creatine-deficiency


CTD is an X-linked inherited disorder that primarily affects the brain. People with this disorder have intellectual disability, which can range from mild to severe, and delayed speech development. Some affected individuals develop behavioral disorders such as attention deficit hyperactivity disorder or autistic behaviors that affect communication and social interaction. They may also experience seizures. Children with CTD may experience slow growth and exhibit delayed development of motor skills such as sitting and walking. Affected individuals tend to tire easily.

Description/ Symptoms

The primary clinical manifestations of CTD include moderate to severe developmental disability, expressive speech and language delay, global developmental delay, epilepsy and behaviors associated with autism. A neurological profile obtained from a sub-set of Dutch boys demonstrated both attention deficit hyperactivity disorder and a semantic pragmatic language disorder with verbal dyspraxia. Various types of epilepsy affect a large proportion of males with CTD, which is typically controlled with anti-epileptic drugs (AEDs). Females heterozygous for the mutation in SLC6A8 can exhibit varying levels of global developmental delay, behavioral problems, and intractable epilepsy.


The prevalence of CTD is unknown. More than 150 affected individuals have been identified. The disorder has been estimated to account for between 1 and 2 percent of males with intellectual disability. The exact incidence is not clear, due to under-diagnosis.

It is hypothesized that CTD is responsible for a significant number of males with mental retardation of otherwise unknown causes. It is likely that CTD is the second most-common cause of X-linked mental retardation behind Fragile X.


Mutations in the SLC6A8 gene on the X chromosome cause CTD. The SLC6A8 gene provides instructions for making a protein that transports the compound creatine into cells. Creatine is needed for the body to store and use energy properly.

SLC6A8 gene mutations impair the ability of the transporter protein to bring creatine into cells, resulting in a creatine shortage (deficiency). The effects of creatine deficiency are most severe in organs and tissues that require large amounts of energy, especially the brain.

This condition is inherited in an X-linked pattern. The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. In females (who have two X chromosomes), a mutation in one of the two copies of the gene in each cell may or may not cause the disorder. In males (who have only one X chromosome), a mutation in the only copy of the gene in each cell causes the disorder. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

In most cases of X-linked inheritance, males experience more severe symptoms of the disorder than females. About half of females with one mutated copy of the SLC6A8 gene in each cell have intellectual disability, learning difficulties, or behavioral problems. Other females with one mutated copy of the SLC6A8 gene in each cell have no noticeable neurological problems.

Additional Concerns/Complications

A small number of people with CTD have additional signs and symptoms including abnormal heart rhythms, an unusually small head (microcephaly), or distinctive facial features such as a broad forehead and a flat or sunken appearance of the middle of the face (midface hypoplasia). Growth retardation has also been reported.

Laboratory Investigations

Males that present with intellectual disability and delays in expressive speech and language are usually screened initially with a  creatine:creatinine ratio in a urine sample. If this is abnormally elevated, further confirmation can be made based on the absence of creatine in the brain using a special MRI scan known as H-MRS, however this typically requires sedation of the patient and availability of suitable equipment to detect brain levels. The final diagnosis is made with genetic analysis of the SLC6A8 gene. Currently, males are diagnosed on average at age 4 (range is 2-5 yrs of age), but can be as late as the seventh decade.

Heterozygous females are typically diagnosed much later and are identified because they are relatives of symptomatic males. The pediatric neurology community believes that CTD is currently under-diagnosed or misdiagnosed, as these patients are generally classified as having either autism spectrum disorder, or mental retardation of unknown etiology.

Diagnostic Standards

The ultimate diagnosis is made with genetic analysis of the SLC6A8 gene. For novel (new) mutations which have not been previously described, reduced creatine in cultured fibroblasts obtained by a skin biopsy can also be used as a confirmatory diagnosis.

Therapeutic Intervention

Because patients with CTD lack a creatine transporter, creatine supplementation alone does not improve clinical outcome and does not result in increased cerebral creatine levels. High-dose L-arginine and L-glycine supplementation did not improve clinical or biochemical outcome. One female with intractable epilepsy responded to high-dose L-arginine and L-glycine supplementation with cessation of seizures.


Creatine Transporter Deficiency (CTD) has no currently accepted standard of care. Patients with epilepsy are treated with AEDs and other medications may be employed to treat behavioral problems.


Family Stories

Reid’s Story: The Road to a Diagnosis: A Mother’s Intuition and How One Family Never Gave Up

Reid CTDParents have a sixth sense about their children. Call it a hunch, a gut feeling or a Mother’s/Father’s intuition, but it is real. I think as parents we feel like we have a responsibility to society to be logical and methodical. We don’t like making assumptions based on a mere feeling, but instead want evidence to show proof and validation. After all, that’s what we’ve been taught. It is a terrifying thing to come to the realization that there might be something wrong with your child, but it’s even worse not being able to prove it.

It’s that gut feeling that pushed me to keep searching for a diagnosis for my then-2-year-old son, Reid. For me, and for so many others out there like me, the road to a diagnosis can be a long journey. It is tiring and it’s easy to run out of gas. I found myself searching for something I KNEW was there, but without direction I was forced to pave my own way. I took wrongs turns, but I stayed the course because I couldn’t give up. On my quest to uncover Reid’s diagnosis, I heard it all. We were told our son was delayed, to put him in therapy and that he might grow out of “this.” We heard words like cerebral palsy, autism and failure to thrive. It was that feeling inside that urged me forward. If Reid was all of those things, then I wanted to know why.Reid Strauss CTD

After visits with over 20 specialists and years of dead ends, we felt like we had exhausted our resources in the Austin area. I was determined to find a specialist who was progressive and who wouldn’t just stick a label on Reid and wish him well. I wanted someone who would see Reid as a whole and not just treat his symptoms. I packed Reid in the car and we drove to Houston hoping that Texas Children’s Hospital would have the answers. On that drive along Interstate-10 from Austin to Houston I wondered if I’d ever find a team who would champion this child. Three days later, on my drive back home to Austin, I was confident that Dr. Michelle Holick and Texas Children’s Hospital were the champions I had been looking for.

After more than two years, Dr. Michelle Holick at Texas Children’s Hospital diagnosed Reid with X-linked (SLC-6A8) Creatine Transporter Deficiency. While I listened to her tell me how our lives would never be the same, I felt relief that the road to a diagnosis had finally come to an end.  If I could tell parents one thing, I’d tell them to persevere. Listen to your intuition and follow that for as long as it takes. Just because it hasn’t been found, doesn’t mean it isn’t there to find.

Today, Reid is four-years-old. He battles daily with muscular and movement disorders, global developmental delay, expressive language delay, mental retardation, autistic behaviors and seizures. Thanks to Dr. Holick, I know for certain that he will not grow out of “this”. Reid will live a life of constant care. But, he will smile and play and love. He will infect us with his energy and bring us joy. He will meet milestones at his own pace and I’ll continue to be there every step of the way.

The Parker Family: Submitted by Melissa Parker, In Loving Honor of her Son, Will Parker

Will Parker-CTD“There have been angels in my life….” This was written to me on a thank you note by the wife of a friend who passed away suddenly. For some reason, that quote always stuck with me. It meant even more to me when Will was little and his babysitter took me aside one day to tell me “something wasn’t right”. That was angel number 2. She was 73 at the time and had kept practically every child in our hometown. Everyone knew her and everyone trusted her. I was no exception. We trotted straight to the doctor, then to another doctor, then to another. Cerebral Palsy was the diagnosis. “Put him in physical therapy, occupational therapy and speech therapy,” the doctor said. Have a nice life Parker family. He didn’t say it, but I felt it. He was NOT angel number 3, and Will did NOT have CP. We switched doctors and over the next few years both she and I decided he had Will Parker Syndrome. Why not name it after him? She had no idea what was wrong. She became angel number 3.

Will Parker Syndrome was adequate for a while. We just dealt with the lack of speech, the way behind motor skills, the tantrums and the reflux – which almost changed his diagnosis to Will Parker Demonic Syndrome. How could that much come out of one little body?! Then a friend of mine suggested we investigate the possibility that he had some type of mitochondrial disorder. Was this out of the blue? No. Her child died from MCAD (Medium chain acyl CoA dehydrogenase deficiency) and her fight to have this condition become part of the newborn screening required in Mississippi became Ben’s Law. Angel number 4.

That conversation took us on a journey that brought us to Mayo Clinic and Dr. Jerry Vockley. His team tested, and scanned, and interviewed, and tested again, and measured and well, you get the picture. Things were starting to fall into place. By the end of the visit and subsequent visits after that, we determined that Will probably had a mitochondrial disorder, but they could not definitively tell us which one. So our diagnosis became Will Parker Probably Metabolic Disorder Syndrome, this was much longer and more impressive to the medical community. Mayo Clinic became angel number 5.

Will turned 12 and then came the seizures. Oh yaaay! This was a new manifestation of this illusive condition. There is nothing like a grand mal seizure at home to enlighten you on how you and your husband respond to an emergency. I think we forgot the number to 9-1-1 and as I recall, all my shouting from Will’s room prompted a sprint down the hall by my husband, Tony – a hall recently dust-mopped with Pledge. He can’t skate so you can imagine how that turned out.

Angel number 3 (the doctor) suggested we visit with a new geneticist at the University of Mississippi Medical Center, which is close to our home. “He is young, aggressive and excited,” she told us. “I think a new pair of eyes is what we need.” I guess by that time I was ready to ditch the Will Parker Probably Metabolic Disorder Syndrome. It was making me tired saying it, and I thought there is no way I can be more tired than right now.

Will was on enough medicine to open a pharmacy in my kitchen and his behavior was enough to put me in a nut house. It was like Mayo Clinic: The Sequel, but we answered the geneticist’s questions and he simply said, “I think I know what is wrong with him.” Huh? Are you kidding me? He must have been in my medicine cabinet. I thought he was young and aggressive alright…and as nutty as me! He ordered some tests and after a week or so we had our answer – Creatine Transporter Deficiency (CTD) Syndrome. He explained that he felt there were many more kids like Will whose parents are roaming around in the developmentally delayed, mental retardation, seizure disorder world. He wasn’t nuts after all. He was angel number 6.

So our journey continues with Will. He just turned 18. We decided a few years back that I was never going to open that pharmacy in my kitchen, so we took him off everything except seizure meds and a small dose of clonidine. The seizures have stopped, he’s talking more and when I look at him, he’s in there.

Today, I’m finding more people just like us, more angels to add to the list. I know they have been placed in my life for a reason. I’ve connected with another CTD parent to talk to, that seems to have gone through the exact same timeline of life that I’ve had with Will. We are able to laugh together in our “CTD journey” and it helps me appreciate the many blessings that I have. You see now that I can really count, Will is my angel number 1. He wakes up happy. He loves his family. He especially loves his Daddy (who still cannot skate but is also on my list of angels). He does not meet a stranger, and I cannot tell you the times I’ve met people because they have met Will out and about. Tony and I used to think about what it would be like if “Will were normal”. What we’re finding is that Will is perfectly normal. He has taught us so much about what it truly means to love a child, what it means to be married and how to open your heart no matter what the consequence.

I have often wondered what in the world God was doing thinking we could handle this. Did He not know how hard this was? Then someone said to me, “God must have thought a lot of you and Tony to give you Will.” So I guess He did.

Trenton’s Story

Trenton-CTDWhen Trenton was born in New York, he weighed 7 lbs 2 ounces. Before we left the hospital, he dropped to 6 lbs 12 ounces, by our first appointment 6 lbs 9 ounces and stayed there. He was bottle fed and projectile vomited often. I took him to the pediatrician and they just kept informing me that baby spit up is normal. No matter how much I argued with them it was not just spit up, they didn’t begin to do anything until he finally projectile vomited on them. We were in and out of the doctors at least 2 times a week for approximately seven months. They just kept switching his formula. He got a GI scan and that came back normal. No one knew what to do but he was finally gaining weight so they just dropped it.

Trenton didn’t sit up until he was nine months, did not crawl until after age one, and did not walk until almost two.

We moved to Colorado when he was 11 months. Every time I would take him to his new pediatrician, I was told he was healthy. I would bring up his developmental delays and I was informed that he was fine. A month after he turned two, Trenton would get upset about little things and hold his breath until he passed out. He would get up right after and be back to normal. One day while we were at my parents’ house, he was on the porch with my husband and my dad while I was in the house with my mom. My husband came running in the house carrying Trenton who was not breathing and having convulsions. We could not get him breathing, called 911, and my brother had to give him chest compressions to get him breathing again. That was the absolute worst day of my life. We almost lost him that day, and that was the most painful thing I have ever felt. He got a CT scan which came back normal. We went to his pediatrician and she referred him for an EEG. That came back normal as well. I brought up my concerns again with her about the breath holding spells, developmental delays and speech delays. I once again was told he was fine and as far as the breath holding spells, he would grow out of them. Those were not good enough answers so I started searching for a new pediatrician.

When I started taking him to his new pediatrician, I instantly liked her. His first visit with her, she told us there were some concerns. She referred us to get him evaluated for autism and be genetically tested. I called to set him up for appointments, and talk about waiting lists! Finally after about a year and a half of waiting for answers, he was diagnosed with X linked creatine transporter deficiency. He was also diagnosed with ADHD, and mild autism, but the autism diagnosis is only because of his lack of speech.

Trenton2-CTDTrenton is now 5 years old and in his second year of preschool. It has been a battle with the school due to his behavior. He is extremely hyper all the time, and puts himself in danger quite often. He does not have seizures. His speech is still limited. He says a few words and can sign 2 words. I will always remember the moment he said his first word, mama. It was like music to my ears. Trenton has a way to make you want to pull your hair out one second and then melt your heart the next. He is so full of life and loves everyone. He says “hi” to almost every person in the store, as long as he’s not in one of his moods. His smile can light up a room. He learns a lot from his little sister, which amazes me every day.

I took his diagnosis hard when we first found out. To me, the unknowns in this diagnosis are the scariest. Even though it’s been a hard road to travel, we will never give up on this little boy. He has opened my eyes to so many things. With my family and I and my husband and his family, Trenton has a great support group. When he was first born, I kept looking at him and saying how perfect he was, that has not changed, he will always be perfect in our eyes and wouldn’t trade him for the world.


*Important: The information contained in the resources sections of the Disorder Directory is provided for informational purposes only. There is no implied endorsement by Child Neurology Foundation. Child Neurology Foundation does not promote or endorse participation in any specific organization. The information is subject to change without notice. Every effort is made to ensure that the details and links are as current as possible.

Association for Creatine Deficiencies Website: www.creatineinfo.org

Association for Creatine Deficiencies Community Facebook Page: www.facebook.com/creatineinfo

The Association for Creatine Deficiencies (ACD) is the only patient advocacy group that is devoted to Cerebral Creatine Deficiency Syndromes (CCDS).  We are committed to meet our goals, which are “to provide patient, family and public education; to advocate for early intervention through newborn screening, and to promote and fund medical research for treatments and cures for Cerebral Creatine Deficiency Syndromes.”

The ACD sets these goals to bring the CCDS Community together as one strong voice, to be united in our efforts, to urge allied medical professions to test, and to treat and promote scientific research.  It is through our mission that our vision for the future is clear: to eliminate the challenges of Cerebral Creatine Deficiency Syndromes.


Baby’s First Test Website: www.babysfirsttest.org

Baby’s First Test houses the nation’s newborn screening clearinghouse. The clearinghouse provides current educational and family support and services information, materials, and resources about newborn screening at the local, state, and national levels and serves as the Clearinghouse for newborn screening information.


Orphanet Website: www.orpha.net

Orphanet is the reference portal for information on rare diseases and orphan drugs, for all audiences. Orphanet’s aim is to help improve the diagnosis, care and treatment of patients with rare diseases.


Global Genes Website: globalgenes.org/

Global Genes Rare Disease Toolkits Website: globalgenes.org/toolkits/

Global Genes™  is one of the leading rare disease patient advocacy organizations in the world. The non-profit organization promotes the needs of the rare disease community under a unifying symbol of hope – the Blue Denim Genes Ribbon™. What began as a grassroots movement in 2009 , with just a few rare disease parent advocates and foundations , has since grown to over 500 global organizations.


Lumos Pharma Website: lumos-pharma.com

Lumos Pharma, based in Austin, Texas, is focused on developing novel therapies for patients with unmet medical needs in rare and neglected diseases. Lumos Pharma is a proud awardee of the National Institutes of Health’s (NIH) Therapeutics for Rare and Neglected Diseases (TRND) program. The TRND program collaborates with biotechnology companies in the development of early stage technologies that show promise for the treatment of rare diseases. The TRND program provides in-kind scientific and financial support for the preclinical program to allow for the commencement of clinical trials in human subjects. Lumos Pharma’s lead compound, LUM001, is a novel treatment for the rare disease, Creatine Transporter Deficiency (CTD). LUM001 has been granted orphan status in the US and is in preclinical development in partnership with scientists at the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health, through its Therapeutic for Rare and Neglected Diseases program. This NCATS collaboration has helped advance the lead molecule LUM001 as a clinical candidate by generating the data needed to file an investigational new drug application with the Food and Drug Administration. Additionally, Lumos Pharma has partnered with Key Opinion Leaders in the field in conducting a preclinical and clinical development program to evaluate the safety and efficacy of its promising drug candidate for the treatment of CTD.