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Biomarker for Creatine Deficiency Syndromes (BioCDS) (BioCDS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02934854
Recruitment Status : Recruiting
First Posted : October 17, 2016
Last Update Posted : May 14, 2019
Information provided by (Responsible Party):
Centogene AG Rostock

Brief Summary:
Development of a new mass spectrometry-based biomarker for the ear-ly and sensitive diagnosis of the Creatine Deficiency Syndromes from dry-blood-spot sample

Condition or disease
Intellectual Disability Developmental Delay Movement Disorder Behavioral Disorder Intractable Epilepsy

Detailed Description:

The Creatine Deficiency Syndromes (CDS) are a group of inborn errors of metabolism which interrupt the biosynthesis or transportation of creatine. Individuals with CDS classically present neurological symptoms (seizures, movement disorders and myopathy), and behavioral manifestations. This group includes two creatine biosynthesis disorders (Guanidinoacetate Methyltransferase Deficiency and L-Arginine: Glycine Amidinotransferase Deficiency), as well as X-linked Creatine Transporter Deficiency.

Guanidinoacetate Methyltransferase Deficiency:

Guanidinoacetate Methyltransferase Deficiency is inherited in an autosomal recessive manner and is caused by biallelic mutations in the GAMT gene. This gene maps to 19p13.3 and is involved in the biosynthesis of creatine. Individuals with this deficiency typically present with severe intellectual disabilities and seizure disorders which may be resistant to drug therapy. Behavioral problems, including autistic behaviors and self-mutilation are common, and pyramidal/extrapyramidal symptoms affect about one-half of patients. Dietary management via manipulation of critical amino acids may improve clinical outcome. Mutations in the GAMT gene are a relatively rare cause of creatine deficiency syndrome.

L-Arginine: Glycine Amidinotransferase Deficiency:

L-Arginine: Glycine Amidinotransferase Deficiency is a very rare type of CDS characterized by global developmental delay, appearing in infancy, which can be associated with language impairment and autistic behavior in some, as well as a mild to moderate intellectual disability. Progressive muscle weakness and fatigability have been reported in older patients. Seizures and failure to thrive have also been described. If creatine supplementation is administered early enough, psychomotor delay may be avoided. This deficiency is caused by mutations in GATM gene, located to chromosome 15q15.1. This gene encodes the enzyme L-Arginine: Glycine Amidinotransferase, which converts arginine and glycine to ornithine and guanidinoacetate in the creatine cycle pathway. This deficiency is transmitted in an autosomal recessive manner.

X-linked Creatine Transporter Deficiency:

X-linked Creatine Transporter Deficiency is a creatine deficiency syndrome characterized clinically by global developmental delay, intellectual disability with prominent speech/language delay, autistic behavior and seizures. Affected individuals may present low weight gain, muscular hypotonia, and poor muscle mass. Subtle dysmorphic features such as midface hypoplasia, long face, and prominent chin have been reported in various affected male patients. In adult patients, cardiac and gastrointestinal disorders have been reported. The onset of symptoms occurs during infancy, usually before the age of 2 years. Males are mainly affected, but females can also have various degrees of severity of disease manifestations. This deficiency has been reported in more than 150 individuals worldwide and is mostly due to frameshift and splicing mutations in the creatine transporter gene SLC6A8 (Xp28).

New methods, like mass-spectrometry, give a good chance to characterize specific metabolic alterations in the blood of affected patients, that allow diagnosing in the future the disease earlier, with a higher sensitivity and specificity.

Therefore it is the goal of the study to identify and validate a new biochemical marker from the blood of the affected patients helping to benefit other patients by an early diagnose and thereby with an earlier treatment.

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Study Type : Observational
Estimated Enrollment : 1000 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Biomarker for Creatine Deficiency Syndromes. An International, Multicenter, Epidemiological Study.
Actual Study Start Date : August 20, 2018
Estimated Primary Completion Date : June 2021
Estimated Study Completion Date : June 2021

Patients with the Creatine Deficiency Syndromes or high-grade suspicion for the Creatine Deficiency Syndromes

Primary Outcome Measures :
  1. Sequencing of the Creatine Deficiency Syndromes related genes [ Time Frame: 4 weeks ]
    Next-Generation Sequencing (NGS) of the genes SLC6A8, GAMT, and GATM will be performed. The mutation will be confirmed by Sanger sequencing.

Secondary Outcome Measures :
  1. The Creatine Deficiency Syndromes specific biomarker candidates finding [ Time Frame: 24 months ]
    The quantitative determination of small molecules (molecular weight 150-700 kD, given as ng/μl) within a dried blood spot sample will be validated via liquid chromatography multiple reaction-monitoring mass spectrometry (LC/MRM-MS) and compared with a merged control cohort. The statistically best validated molecule will be considered as a disease specific biomarker.

Biospecimen Retention:   Samples With DNA

For the development of the new biomarkers using the technique of Mass-spectrometry, maximal 7,5 ml of blood will be taken via using a dry blood spot filter card. To proof the correct Creatine Deficiency Syndromes diagnosis in those patients where up to the enrollment in the study no genetic testing has been done, sequencing of Creatine Deficiency Syndromes will be done.

The analyses will be done at:

Centogene AG Am Strande 7 18055 Rostock Germany

Information from the National Library of Medicine

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Ages Eligible for Study:   2 Months and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
Patients with the Creatine Deficiency Syndromes or high-grade suspicion for the Creatine Deficiency Syndromes


  • Informed consent will be obtained from the patient or the parents before any study related procedures.
  • Patients of both genders older than 2 months
  • The patient has a diagnosis of the Creatine Deficiency Syndromes or a high-grade suspicion for the Creatine Deficiency Syndromes

High-grade suspicion is present, if one or more inclusion criteria are valid:

  • Positive family anamnesis for the Creatine Deficiency Syndromes
  • Intellectual disability
  • Seizure disorder of variable severity
  • Developmental delay
  • Speech/language delay
  • Movement disorder
  • Behavioral disorder (autism, hyperactivity, self-injury)
  • Intractable epilepsy


  • No Informed consent from the patient or the parents before any study related procedures.
  • Patients of both gender younger than 2 months
  • No diagnosis of Creatine Deficiency Syndromes or no valid criteria for profound suspicion of the Creatine Deficiency Syndromes

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02934854

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Contact: Arndt Rolfs, Prof +4938180113500 ext 500

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Children Hospital, Faculty of Medicine, Cairo University Recruiting
Cairo, Egypt, 11511
Contact: Laila Selim, Prof.         
Ain Shams University, Medical Genetics Center Recruiting
Cairo, Egypt
Contact: Solaf Elsayed         
Chindren's hospital, Faculty of Medicine, Ain Shams University Recruiting
Cairo, Egypt
Contact: Hoda Tomoum         
Navi Mumbai Institute of Research In Mental And Neurological Handicap (NIRMAN) Recruiting
Mumbai, India, 400705
Contact: Anil Jalan, Dr.         
Sponsors and Collaborators
Centogene AG Rostock
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Principal Investigator: Arndt Rolfs, Prof. Centogene AG Rostock

Additional Information:
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Responsible Party: Centogene AG Rostock Identifier: NCT02934854     History of Changes
Other Study ID Numbers: BCDS 06-2018
First Posted: October 17, 2016    Key Record Dates
Last Update Posted: May 14, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Centogene AG Rostock:
Creatine Transporter Deficiency (CTD)
Guanidinoacetate Methyltransferase Deficiency (GAMT)
Arginine: Glycine Amidinotransferase Deficiency (AGAT)
Additional relevant MeSH terms:
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Movement Disorders
Intellectual Disability
Drug Resistant Epilepsy
Problem Behavior
Pathologic Processes
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neurobehavioral Manifestations
Neurologic Manifestations
Signs and Symptoms
Neurodevelopmental Disorders
Mental Disorders
Behavioral Symptoms