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

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


Primary Outcome

Sequencing of the Tyrosinemia Type 1 disease related gene

Secondary Outcome

 The Tyrosinemia type 1 specific biomarker candidates finding

Condition

Tyrosinosis


Study Arms / Comparison Groups

 Observation
Description:  Patients with a Tyrosinemia type 1 or high-grade suspi-cion for Tyrosinemia type 1

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information



Estimated Enrollment

1000

Start Date

August 20, 2018

Completion Date

June 2021

Primary Completion Date

June 2021

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
      

Gender

All

Ages

2 Months - N/A

Accepts Healthy Volunteers

No

Contacts

Peter Bauer, Prof., , 

Location Countries

Germany

Location Countries

Germany

Administrative Informations


NCT ID

NCT03284658

Organization ID

BTY 06-2018


Responsible Party

Sponsor

Study Sponsor

CENTOGENE GmbH Rostock


Study Sponsor

Peter Bauer, Prof., Study Chair, Centogene GmbH


Verification Date

May 2021