Biomarker for Creatine Deficiency Syndromes (BioCDS) (BioCDS)

Biomarker for Creatine Deficiency Syndromes. An International, Multicenter, Epidemiological Study.

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

Study Overview

• Status: Withdrawn
• Conditions: Intellectual Disability; Developmental Delay; Intractable Epilepsy; Movement Disorder; Behavioral Disorder

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.

• Study Type: Observational

Contacts and Locations

Study Locations

• Egypt
  • Cairo, Egypt
    • Ain Shams University, Medical Genetics Center
  • Cairo, Egypt
    • Chindren's hospital, Faculty of Medicine, Ain Shams University
• India
  • Mumbai, India, 400705
    • Navi Mumbai Institute of Research In Mental And Neurological Handicap (NIRMAN)
• Sri Lanka
  • Colombo 8, Sri Lanka, 00800c
    • Lady Ridgeway Hospital for Children

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 months and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

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

Description

INCLUSION CRITERIA:

• 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

EXCLUSION CRITERIA:

• 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

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Observation; Patients with the Creatine Deficiency Syndromes or high-grade suspicion for the Creatine Deficiency Syndromes

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Creatine Deficiency Syndromes specific biomarker candidates finding	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.	24 months

Collaborators and Investigators

• Sponsor: CENTOGENE GmbH Rostock

Publications and helpful links

Helpful Links

• Centogene is one of the leading laboratories focusing on genetic testing for rare hereditary disorders. We now offer more than 2200 routine genetic and biochemical tests.

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 20, 2018
• Primary Completion (ACTUAL): February 28, 2021
• Study Completion (ACTUAL): February 28, 2021

Study Registration Dates

• First Submitted: September 19, 2016
• First Submitted That Met QC Criteria: October 14, 2016
• First Posted (ESTIMATE): October 17, 2016

Study Record Updates

• Last Update Posted (ACTUAL): February 13, 2023
• Last Update Submitted That Met QC Criteria: February 9, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Biomarker; Creatine Transporter Deficiency (CTD); Guanidinoacetate Methyltransferase Deficiency (GAMT); Arginine: Glycine Amidinotransferase Deficiency (AGAT)
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Neurodevelopmental Disorders; Epilepsy; Disease; Movement Disorders; Intellectual Disability; Drug Resistant Epilepsy
• Other Study ID Numbers: BCDS 06-2018

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No