Biomarker for Farber Disease (BioFarber) (BioFarber)

Biomarker for Farber Disease - An International, Multicenter, Epidemiological Protocol

Development of a new mass spectrometry-based biomarker for the early and sensitive diagnosis of Farber disease from the blood

Study Overview

• Status: Withdrawn
• Conditions: Splenomegaly; Hepatomegaly; Ceramidase Deficiency; Farber's Lipogranulomatosis

Detailed Description

Farber disease (FD), also known as Farber's lipogranulomatosis, is an autosomal recessive lysosomal storage disease marked by a deficiency in enzyme ceramidase which causes a progressive accumulation of fatty material lipids leading to abnormalities in the joints, liver, throat, tissues and central nervous system.

FD is an extremely rare disorder, with a prevalence of less than 1/1000000. Currently only about 80 cases are reported worldwide. Disease onset is typically in early infancy but may occur later in life.

FD is caused by a mutation in the ASAH1 gene, situated on the short arm of chromosome 8. This gene codes for acid ceramidase, a lysosomal heterodimeric enzyme that hydrolyzes ceramide into sphingosine and fatty acid. To date, less than 25 distinct mutations have been identified in Farber patients, but no large deletions have yet been reported. It is inherited with an autosomal recessive pattern.

The clinical presentation of FD is characterized by the appearance of subcutaneous skin nodules, ordinarily near the joints, most often interphalangeal, wrist, elbow and ankle joints, or over points of mechanical pressure. These manifestations are very painful and lead to progressive joint stiffness, limitation of motion by contractures and finally to immobilization and deformation of joints. Also, a characteristic sign of FD is the development of a progressive hoarseness due to laryngeal involvement.

Beside these major manifestations seven phenotypes have been described which differ in severity and additional organ involvement, like the lungs, nervous system, heart and lymph nodes. Dependent on residual lysosomal ceramidase turnover, patients have a variable degree of central nervous system disease, leading to progressive neurologic deterioration. In most cases the neuronal dysfunction rather than the general physical dystrophy seems to limit the duration of FD. As well, patients with FD may die due to pulmonary disease with interstitial pneumonia.

First symptoms usually appear between the newborn period and the first birthday. Milder forms of type 3 were described with onset at 20 months of age. Clinical manifestation in type 5 of FD, dominated by neurologic deterioration, begins at 1 to 2 1/2 years of life. Patients mainly die within the first years of life, but prolonged courses in patients without severe nervous disease may also be observed.

Type 1 is the most common or classical form of this condition and is associated with the classic signs of voice, skin, and joint problems that begin a few months after birth. Developmental delay and lung disease also commonly occur. Infants born with type 1 FD usually survive only into early childhood.

Types 2 and 3 generally have less severe signs and symptoms than the other types. Affected individuals have the three classic signs and usually do not have developmental delay. Children with these types of FD typically live into mid- to late childhood.

Types 4 and 5 are associated with severe neurological problems. Type 4 usually causes life-threatening health problems beginning in infancy due to massive lipid deposits in the liver, spleen, lungs, and immune system tissues. Children with this type typically do not survive past their first year of life. Type 5 is characterized by progressive decline in brain and spinal cord (central nervous system) function, which causes paralysis of the arms and legs (quadriplegia), seizures, loss of speech, involuntary muscle jerks (myoclonus), and developmental delay. Children with type 5 FD survive into early childhood.

Types 6 and 7 are very rare, and affected individuals have other associated disorders in addition to FD.

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, 11511
    • Children Hospital, Faculty of Medicine, Cairo University
• Germany
  • Rostock, Germany, 18055
    • Centogene AG
• India
  • Mumbai, India, 400705
    • Navi Mumbai Institute of Research In Mental And Neurological Handicap (NIRMAN)

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 Farber disease or high-grade suspicion for Farber disease

Description

INCLUSION CRITERIA

• Informed consent will be obtained from the parents before any study related procedures.
• Patients of both gender older than 2 months
• The patient has a diagnosis of Farber disease or a high-grade suspicion for Farber disease

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

  1. - Positive family anamnesis for Farber disease
  2. - Hoarse cry due to laryngeal involvement
  3. - Dysostosis multiplex
  4. - Painful swollen joints,
  5. - Arthritis
  6. - Hepatomegaly
  7. - Splenomegaly
  8. - Elevated urine ceramide levels
  9. - Histiocytic infiltration of liver, spleen, and lungs
  10. - Ceramidase deficiency

EXCLUSION CRITERIA

• No Informed consent from the parents before any study related procedures.
• Patients of both gender younger than 2 months
• No diagnosis of Farber disease or no valid criteria for profound suspicion of Farber disease

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 Farber disease or high-grade suspicion for Farber disease

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sequencing of the Farber disease related gene	Next-Generation Sequencing (NGS) of the ASAH1 gene will be performed. The mutation will be confirmed by Sanger sequencing.	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Farber disease 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

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: October 23, 2014
• First Submitted That Met QC Criteria: November 19, 2014
• First Posted (ESTIMATE): November 24, 2014

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; Lysosomal Storage Diseases; Lipogranulomatosis; Farber disease
• Additional Relevant MeSH Terms: Digestive System Diseases; Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Lymphatic Diseases; Liver Diseases; Genetic Diseases, Inborn; Pathological Conditions, Anatomical; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Lipid Metabolism Disorders; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Lipidoses; Lipid Metabolism, Inborn Errors; Histiocytosis, Non-Langerhans-Cell; Histiocytosis; Hypertrophy; Erdheim-Chester Disease; Splenomegaly; Hepatomegaly; Farber Lipogranulomatosis
• Other Study ID Numbers: BFD 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