Biomarker for Creatine Deficiency Syndromes (BioCDS)

NCT ID: NCT02934854

Last Updated: 2023-02-13

Basic Information

• Recruitment Status: WITHDRAWN
• Study Classification: OBSERVATIONAL
• Study Start Date: 2018-08-20
• Study Completion Date: 2021-02-28

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

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.

Conditions

Intellectual Disability; Developmental Delay; Movement Disorder; Behavioral Disorder; Intractable Epilepsy

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

Observation

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

No interventions assigned to this group

Eligibility Criteria

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

• 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

• Minimum Eligible Age: 2 Months
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

CENTOGENE GmbH Rostock

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Peter Bauer, Prof.

Role: STUDY_CHAIR

Centogene GmbH

Locations

Ain Shams University, Medical Genetics Center

Cairo, , Egypt

Chindren's hospital, Faculty of Medicine, Ain Shams University

Cairo, , Egypt

Navi Mumbai Institute of Research In Mental And Neurological Handicap (NIRMAN)

Mumbai, , India

Lady Ridgeway Hospital for Children

Colombo, , Sri Lanka

Countries

Egypt; India; Sri Lanka

Other Identifiers

BCDS 06-2018

Identifier Type: -

Identifier Source: org_study_id