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

BioTyrosin - Biomarker for the Early Diagnosis and Monitoring in Tyrosinemia Type 1 - An International, Multicenter, Epidemiological Protocol

Development of a new MS-based biomarker for the early and sensitive diagnosis of Tyrosinemia type 1 from blood (plasma)

Study Overview

• Status: Withdrawn
• Conditions: Metabolic Disorders; Tyrosinosis; Hepatorenal Tyrosinemia; Fumarylacetoacetase Deficiency; Fah Deficiency

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

Contacts and Locations

Study Locations

• Germany
  • Rostock, Germany, 18055
    • Centogene AG
• India
  • Mumbai, India, 400705
    • NIRMAN Navi Mumbai Institute of Research In Mental And Neurological Handicap/Pediatric Geneticist
• 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 a Tyrosinemia type 1 or high-grade suspi-cion for Tyrosinemia type 1

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 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

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Observation; Patients with a Tyrosinemia type 1 or high-grade suspi-cion for Tyrosinemia type 1

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sequencing of the Tyrosinemia Type 1 disease related gene	Next-Generation Sequencing (NGS) of the FAH gene will be performed. The mutation will be confirmed by Sanger sequencing.	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Tyrosinemia type 1 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 13, 2017
• First Submitted That Met QC Criteria: September 13, 2017
• First Posted (ACTUAL): September 15, 2017

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; Tyrosinemia Type 1
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Amino Acid Metabolism, Inborn Errors; Metabolic Diseases; Tyrosinemias
• Other Study ID Numbers: BTY 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