Neurodegeneration With Brain Iron Accumulation (NBIA)NBIA MITONCT05615571
Testing of NBIA Genes: Analysis of Genetic Heterogeneity and Validation of Mitochondrial Markers for Assessing Causality of Sequence Variants.
An observational study of Neurodegeneration With Brain Iron Accumulation (NBIA), run by University Hospital, Bordeaux at 1 site in France.
Trial summary
Neurodegeneration with brain iron accumulation (NBIA) represent a group of rare neurodevelopmental diseases, genetically as well as phenotypically heterogeneous. The diagnosis is based on brain MRI. It is also based on genetic testing. Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Neurodegeneration With Brain Iron Accumulation (NBIA)
- What is being tested?
- Establishment of mitochondrial markers and Sequencing tests
- How many people
- 70 participants
- Where
- 1 siteFrance
- Study dates
- 4 Jan 2018to 30 Nov 2020
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- Child, Adult, Older adult
Study population: Patients with NBIA
Who may be able to join
- NBIA Patients diagnosed with a pathogenic variation or any variation that could impact gene function (class 4 or 5 according to ACMG criteria) in the following genes: C19ORF12, PANK2, PLA2G6, DCAF17, FA2H, WDR45, FTL, CP and ATP13A2 and whose fibroblasts have been collected at Bordeaux University Hospital for functional analysis during the diagnosis procedure
- NBIA patients without conclusive testing in none of these nine genes and whose DNA has been collected during the diagnosis procedure at Bordeaux University Hospital
Who cannot join
- Patients without imaging (MRI or scan) signs of NBIA
- Patients without french healthcare insurance
Trial locations and contacts
1 site in 1 country.
About this study
Neurodegeneration with brain iron accumulation (NBIA) represent a group of rare neurodevelopmental diseases, genetically as well as phenotypically heterogeneous.
The diagnosis is based on brain MRI. It is also based on genetic testing. However overlaps exist between the different clinical presentations and the molecular diagnosis may be misinterpreted.
Two main purposes must be addressed to get a better molecular diagnosis: on one hand reaching enough exhaustivity which may be performed with a larger gene panel and next generation sequencing; on the other hand, it is now necessary to validate or infirm the deleterious consequences of variants with the help of functional studies.
Read the detailed description
Neurodegeneration with brain iron accumulation (NBIA) represent a group of rare neurodevelopmental diseases, genetically as well as phenotypically heterogeneous.
The diagnosis is based on brain MRI. It shows abnormal deposit of iron in the basal ganglia, especially in the globus pallidus and the substance nigra. It is also based on genetic testing. Ten individualized forms are now described. However overlaps exist between the different clinical presentations and the molecular diagnosis may be misinterpreted because of variants, named as variants of unknown signification, whom the pathogenic role is not proven. Approximately half of the clinically relevant cases with iron deposits on brain MRI remain without any molecular deleterious alteration.
Two main purposes must be addressed to get a better molecular diagnosis: on one hand reaching enough exhaustivity which may be performed with a larger gene panel and next generation sequencing; this panel will include new genes and could be enlarged as more genes are identified. On the other hand, it is now necessary to validate or infirm the deleterious consequences of variants with the help of functional studies.
Four major pathways are involved in the pathophysiology of NBIA: iron and lipids metabolisms, mitochondrial metabolism and autophagy.
Considering that biochemical mechanisms inside the mitochodrion are involved in these four pathways, the investigators performed a first test starting from patient's fibroblasts and analyzed the literature in order to define the parameters that could be pertinent as biological markers of NBIA.
Two different groups will be studied :
- A group of NBIA patients without found mutation after sequencing of the gene panel currently used at the university hospital of Bordeaux. Genetic testing will be performed with the help of an alternative method of target enrichment applied to 16 NBIA genes.
- A group of patients with 2 frequent forms of NBIA with identified variants will be analysed to assess the best mitochondrial markers from fibroblasts.
The investigators plan to transfer these new genetic and biochemical strategies to the diagnostic procedures with the support of the french rare disease network in charge of neurodegenerations and the "CARAMMEL" network involved in the diagnosis of mitochondrial diseases.
- Being tested
- Establishment of mitochondrial markers, Sequencing tests
- Medical subject headings
- Pantothenate Kinase-Associated Neurodegeneration
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Establishment of mitochondrial markersGenetic
Establishment of mitochondrial markers from fibroblasts in culture, obtained from a skin biopsy. Establishment of yeast models to show biochemical mitochondrial alterations: introduction of missense variants in the pantothenate kinase yeast gene Cab1 whose deletion is lethal, followed by growth of mutant strains on fermentation and respiratory media.
Sequencing testsGenetic
sequencing tests of a panel of 22 genes (9 already known and 13 new genes) using a dedicated custom capture and a medium throughput sequencing protocol.
| Study group | Role | What they receive |
|---|---|---|
| Patients with NBIA who remain without molecular diagnosis | A group of 40 patients with NBIA, who remain without molecular diagnosis Receives: Genetic: Sequencing tests | |
| Patients with NBIA with identified mutations in genes | A group of patients with 2 frequent forms of NBIA, carrying mutations in genes (already studied in the CHU molecular diagnostic laboratory) Receives: Genetic: Establishment of mitochondrial markers |
What is being measured
The primary outcome is the main question the study is designed to answer.
Sequencing tests of a panel of 22 genes using a dedicated custom capture and a medium throughput sequencing protocol.
Records of coverage (% of designed regions)
Measured: through study completion, an average of 2 years
Sequencing tests of a panel of 22 genes using a dedicated custom capture and a medium throughput sequencing protocol.
Records of depth of sequencing (reads number)
Measured: through study completion, an average of 4 years
Secondary outcomes (2)
Identification of the dominant form using biochemical analysis in patient's fibroblasts
Counting of mitochondria with Voltage-dependent anion channel (VDAC) labeling
Measured: through study completion, an average of 2 years
Identification of the dominant form using biochemical analysis in patient's fibroblasts
Measurements of iron and ferritin cellular levels after iron deprivation and iron loading
Measured: through study completion, an average of 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Nov 2022
- Study start4 Jan 2018
- Primary completion30 Nov 2020
- Study completion30 Nov 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Neurodegeneration With Brain Iron Accumulation (NBIA)Studies of the same condition, open and under way.
- More trials run by University Hospital, BordeauxThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Retrospective
- Enrolment
- 70 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Hospital, Bordeaux
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Patricia FERGELOT MAURIN, Principal investigator, University Hospital, Bordeaux
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05615571
- Sponsor's protocol ID
- CHUBX 2017/38
- Acronym
- NBIA MITO
- Status last verified
- Sep 2022
- First submitted
- 1 Jul 2021
- Last updated
- 14 Nov 2022
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Angelini C, Durand CM, Fergelot P, Deforges J, Vital A, Menegon P, Sarrazin E, Bellance R, Mathis S, Gonzalez V, Renaud M, Frismand S, Schmitt E, Rouanet M, Burglen L, Chabrol B, Desnous B, Arveiler B, Stevanin G, Coupry I, Goizet C. Autosomal Dominant MPAN: Mosaicism Expands the Clinical Spectrum to Atypical Late-Onset Phenotypes. Mov Disord. 2023 Nov;38(11):2103-2115. doi: 10.1002/mds.29576. Epub 2023 Aug 21.
PubMed 37605305
Study at a glance
From the registry record, last updated by the sponsor on 14 Nov 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Testing of NBIA Genes: Analysis of Genetic Heterogeneity and Validation of Mitochondrial Markers for Assessing Causality of Sequence Variants.
- ClinicalTrials.gov ID
- NCT05615571
- Acronym / sponsor ID
- NBIA MITO / CHUBX 2017/38
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 70 participants (actual)
- Lead sponsor
- University Hospital, BordeauxUniversity, hospital or other
- Collaborators
- Institut National de la Santé Et de la Recherche Médicale, France
- Study start
- 4 Jan 2018 (actual)
- Primary completion
- 30 Nov 2020 (actual)
- Study completion
- 30 Nov 2020 (actual)
- First posted
- 14 Nov 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Neurodegeneration with brain iron accumulation (NBIA) represent a group of rare neurodevelopmental diseases, genetically as well as phenotypically heterogeneous.
The diagnosis is based on brain MRI. It is also based on genetic testing. However overlaps exist between the different clinical presentations and the molecular diagnosis may be misinterpreted.
Two main purposes must be addressed to get a better molecular diagnosis: on one hand reaching enough exhaustivity which may be performed with a larger gene panel and next generation sequencing; on the other hand, it is now necessary to validate or infirm the deleterious consequences of variants with the help of functional studies.
Detailed description
Neurodegeneration with brain iron accumulation (NBIA) represent a group of rare neurodevelopmental diseases, genetically as well as phenotypically heterogeneous.
The diagnosis is based on brain MRI. It shows abnormal deposit of iron in the basal ganglia, especially in the globus pallidus and the substance nigra. It is also based on genetic testing. Ten individualized forms are now described. However overlaps exist between the different clinical presentations and the molecular diagnosis may be misinterpreted because of variants, named as variants of unknown signification, whom the pathogenic role is not proven. Approximately half of the clinically relevant cases with iron deposits on brain MRI remain without any molecular deleterious alteration.
Two main purposes must be addressed to get a better molecular diagnosis: on one hand reaching enough exhaustivity which may be performed with a larger gene panel and next generation sequencing; this panel will include new genes and could be enlarged as more genes are identified. On the other hand, it is now necessary to validate or infirm the deleterious consequences of variants with the help of functional studies.
Four major pathways are involved in the pathophysiology of NBIA: iron and lipids metabolisms, mitochondrial metabolism and autophagy.
Considering that biochemical mechanisms inside the mitochodrion are involved in these four pathways, the investigators performed a first test starting from patient's fibroblasts and analyzed the literature in order to define the parameters that could be pertinent as biological markers of NBIA.
Two different groups will be studied :
- A group of NBIA patients without found mutation after sequencing of the gene panel currently used at the university hospital of Bordeaux. Genetic testing will be performed with the help of an alternative method of target enrichment applied to 16 NBIA genes.
- A group of patients with 2 frequent forms of NBIA with identified variants will be analysed to assess the best mitochondrial markers from fibroblasts.
The investigators plan to transfer these new genetic and biochemical strategies to the diagnostic procedures with the support of the french rare disease network in charge of neurodegenerations and the "CARAMMEL" network involved in the diagnosis of mitochondrial diseases.
Study design
- Observational model
- Cohort
- Time perspective
- Retrospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Patients with NBIA who remain without molecular diagnosis | – | Genetic: Sequencing testsA group of 40 patients with NBIA, who remain without molecular diagnosis |
| Patients with NBIA with identified mutations in genes | – | Genetic: Establishment of mitochondrial markersA group of patients with 2 frequent forms of NBIA, carrying mutations in genes (already studied in the CHU molecular diagnostic laboratory) |
Who may qualify
- Sex
- All
- Age groups
- Child, Adult, Older adult
- Study population
- Patients with NBIA
Key inclusion criteria (2 listed)
- NBIA Patients diagnosed with a pathogenic variation or any variation that could impact gene function (class 4 or 5 according to ACMG criteria) in the following genes: C19ORF12, PANK2, PLA2G6, DCAF17, FA2H, WDR45, FTL, CP and ATP13A2 and whose fibroblasts have been collected at Bordeaux University Hospital for functional analysis during the diagnosis procedure
- NBIA patients without conclusive testing in none of these nine genes and whose DNA has been collected during the diagnosis procedure at Bordeaux University Hospital
Key exclusion criteria (2 listed)
- Patients without imaging (MRI or scan) signs of NBIA
- Patients without french healthcare insurance
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Establishment of mitochondrial markersEstablishment of mitochondrial markers from fibroblasts in culture, obtained from a skin biopsy. Establishment of yeast models to show biochemical mitochondrial alterations: introduction of missense variants in the pantothenate kinase yeast gene Cab1 whose deletion is lethal, followed by growth of mutant strains on fermentation and respiratory media. | Genetic | Patients with NBIA with identified mutations in genes |
| Sequencing testssequencing tests of a panel of 22 genes (9 already known and 13 new genes) using a dedicated custom capture and a medium throughput sequencing protocol. | Genetic | Patients with NBIA who remain without molecular diagnosis |
Primary outcome
Sequencing tests of a panel of 22 genes using a dedicated custom capture and a medium throughput sequencing protocol.
Time frame: through study completion, an average of 2 years
Records of coverage (% of designed regions)
Sequencing tests of a panel of 22 genes using a dedicated custom capture and a medium throughput sequencing protocol.
Time frame: through study completion, an average of 4 years
Records of depth of sequencing (reads number)
2 secondary outcomes
Identification of the dominant form using biochemical analysis in patient's fibroblasts
Time frame: through study completion, an average of 2 years
Identification of the dominant form using biochemical analysis in patient's fibroblasts
Time frame: through study completion, an average of 2 years
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Nov 2022.
- Derived from this study: PubMed 37605305Angelini C, Durand CM, Fergelot P, Deforges J, Vital A, Menegon P, Sarrazin E, Bellance R, Mathis S, Gonzalez V, Renaud M, Frismand S, Schmitt E, Rouanet M, Burglen L, Chabrol B, Desnous B, Arveiler B, Stevanin G, Coupry I, Goizet C. Autosomal Dominant MPAN: Mosaicism Expands the Clinical Spectrum to Atypical Late-Onset Phenotypes. Mov Disord. 2023 Nov;38(11):2103-2115. doi: 10.1002/mds.29576. Epub 2023 Aug 21.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Patricia FERGELOT MAURIN principal investigator
University Hospital, Bordeaux
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Neurodegeneration With Brain Iron Accumulation (NBIA), run by University Hospital, Bordeaux at 1 site in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 14 Nov 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Sequencing tests of a panel of 22 genes using a dedicated custom capture and a medium throughput sequencing protocol. (time frame: through study completion, an average of 2 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05615571, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Nov 2022; AzTrials last refreshed its copy on 8 Nov 2026.