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Biomarker for the Early Diagnosis and Monitoring in Tyrosinemia Type 1 (BioTyrosin) (BioTyrosin)

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. Read our disclaimer for details. Identifier: NCT03284658
Recruitment Status : Active, not recruiting
First Posted : September 15, 2017
Last Update Posted : May 18, 2021
Information provided by (Responsible Party):

Tracking Information
First Submitted Date September 13, 2017
First Posted Date September 15, 2017
Last Update Posted Date May 18, 2021
Actual Study Start Date August 20, 2018
Estimated Primary Completion Date June 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: January 22, 2019)
Sequencing of the Tyrosinemia Type 1 disease related gene [ Time Frame: 4 weeks ]
Next-Generation Sequencing (NGS) of the FAH gene will be performed. The mutation will be confirmed by Sanger sequencing.
Original Primary Outcome Measures
 (submitted: September 13, 2017)
The diagnosis of Tyrosinemia type 1 measured by sequencing of Tyrosinemia type 1 [ Time Frame: 36 months ]
Change History
Current Secondary Outcome Measures
 (submitted: January 22, 2019)
The Tyrosinemia type 1 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.
Original Secondary Outcome Measures
 (submitted: September 13, 2017)
Number of correct identified patients with Tyrosinemia type 1 [ Time Frame: 36 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title Biomarker for the Early Diagnosis and Monitoring in Tyrosinemia Type 1 (BioTyrosin)
Official Title BioTyrosin - Biomarker for the Early Diagnosis and Monitoring in Tyrosinemia Type 1 - An International, Multicenter, Epidemiological Protocol
Brief Summary Development of a new MS-based biomarker for the early and sensitive diagnosis of Tyrosinemia type 1 from blood (plasma)
Detailed Description

Hereditary Tyrosinemia type 1 (HT-1) is a rare genetic disorder in which the newborn child lacks the ability to break down the amino acid tyrosine. As a result of this deficiency, toxic sub-stances build up in the blood and can cause liver failure, kidney dysfunction and neurological problems. There are two different forms of the disease - acute and chronic. The acute form is most common.

Worldwide, Tyrosinemia type 1 affects about one newborn child in 100,000, although geo-graphical variation is seen.

Tyrosinemia type 1 is hereditary. The disorder is caused by a defect in the gene coding for the enzyme responsible for breaking down tyrosine. For a child to be affected by the disease, both parents have to carry a defective gene. The risk of being born with Tyrosinemia type 1, i.e. receiving both genes from the parents, is thus 25%.

Children with Tyrosinemia type 1 can display symptoms such as failure to gain weight and grow at the expected rate, diarrhea, vomiting, enlarged liver, liver failure, accumulation of fluid in the peritoneal cavity, kidney failure, softening of the bones (rickets) and liver tumors.

The acute form usually appears in the first few months of life. The child has a slow weight gain plus fever, diarrhea, blood in the feces and vomiting. The liver is enlarged and yellowing of the skin and the whites of the eyes (jaundice) with an increased tendency to bleed (particularly nosebleeds) may be evident. The spleen and abdomen can also be enlarged and the legs swollen. Without treatment, liver failure and clotting problems can arise.

Children with the chronic form of Tyrosinemia type 1 develop symptoms gradually. The child can suffer from enlarged liver, distended abdomen (due to enlarged liver and spleen, acites and excessive fluids), changes in skeleton, and liver and kidney failure. Symptoms such as abdominal pain, damage to the peripheral nerves and high blood pressure appear. In addition, symptoms common in acute intermittent porphyria can also occur. If the child is not treated, it will develop liver failure and liver tumors.

The condition is also referred to as hepatorenal Tyrosinemia, and is the most critical variant of Tyrosinemia. The main function of the FAH gene is to regulate the production of the enzyme fumarylacetoacetase that is required to break down or metabolize amino acid tyrosine. The mutations of FAH gene leads to a deficiency of the enzyme fumarylacetoacetase, which then leads to a failure in breaking down tyrosine.

Tyrosinemia type 1 is suspected on the basis of clinical presentation. Diagnostic investigations include analyses of amino acids, succinylacetone and alpha-fetoprotein.

Today, the condition can be treated by diet, medication and liver transplantation. Liver trans-plantation was once the only treatment, but since a new drug was introduced in 1991, survival has increased significantly. Nevertheless, diet and special protein replacements remain an important part of life-long treatment.

New methods, like mass-spectrometry give a good chance to characterize specific metabolic alterations in the blood (plasma) of affected patients that allow diagnosing in the future the dis-ease 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 plasma of the affected patients helping to benefit other patients by an early diagnose and thereby with an earlier treatment.

Study Type Observational
Study Design Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples With DNA

For the development of the new biomarkers using the technique of Mass-spectrometry, a blood sample of maximal 7,5 ml blood will be taken from the patient via using a dry blood spot filter card. To proof the correct diagnosis a Tyrosinemia type 1, in those patients where up to the enrollment in the study no genetic testing has been done, sequencing of a Tyrosinemia type 1 will be done.

The analyses will be done at:

Centogene AG Am Strande 7 18055 Rostock Germany

Sampling Method Probability Sample
Study Population Patients with a Tyrosinemia type 1 or high-grade suspi-cion for Tyrosinemia type 1
  • Tyrosinosis
  • Hepatorenal Tyrosinemia
  • Fumarylacetoacetase Deficiency
  • Fah Deficiency
  • Metabolic Disorders
Intervention Not Provided
Study Groups/Cohorts Observation
Patients with a Tyrosinemia type 1 or high-grade suspi-cion for Tyrosinemia type 1
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status Active, not recruiting
Estimated Enrollment
 (submitted: August 24, 2018)
Original Estimated Enrollment
 (submitted: September 13, 2017)
Estimated Study Completion Date June 2021
Estimated Primary Completion Date June 2021   (Final data collection date for primary outcome measure)
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 Tyrosinemia type 1 or a high-grade suspicion for Tyrosinemia type 1

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

  • Positive family anamnesis for Tyrosinemia type 1
  • Hepatomegaly
  • Splenomegaly
  • Ascites
  • Coagulopathy

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 Tyrosinemia type 1 or no valid criteria for profound suspicion of Tyrosinemia type 1
Sexes Eligible for Study: All
Ages 2 Months and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts Contact information is only displayed when the study is recruiting subjects
Listed Location Countries Germany,   India,   Sri Lanka
Removed Location Countries Egypt
Administrative Information
NCT Number NCT03284658
Other Study ID Numbers BTY 06-2018
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement
Plan to Share IPD: Undecided
Responsible Party CENTOGENE GmbH Rostock
Study Sponsor CENTOGENE GmbH Rostock
Collaborators Not Provided
Study Chair: Peter Bauer, Prof. Centogene GmbH
PRS Account CENTOGENE GmbH Rostock
Verification Date May 2021