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Neurodegenerative Disease, HereditaryNCT04594590

Natural History Study of SLC25A46 Mutation-related Mitochondriopathy

An observational study of Neurodegenerative Disease, Hereditary and Mitochondrial Diseases, run by State University of New York at Buffalo at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

The purpose of the study is to systematically characterize the clinical course of the progressive neuropathy and optic atrophy observe in pediatric and adult patients with biallelic mutations in the solute carrier family 25 member 46 (SLC25A46) gene. Read more about this study

Who is it for?
Ages 0 to 65 years
What is being tested?
Mutation analysis
How many people
9 participants
Where
1 siteUnited States
Study dates
3 Nov 2020to 17 Aug 2023
How long will I take part?
3 Years
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 0 to 65 years
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Study population: Primary care clinic

Who may be able to join

  • Patients who are clinically diagnosed with biallelic mutations in the SLC25A46 gene
  • Male and female patients from 2 to 65 years of age
  • Patients who have consented to the study
  • In the case of a deceased patient whose parent(s) and/or legal guardian(s) have provided informed consent for study participation, the investigators will review the patient's medical records to determine study eligibility.

Who cannot join

  • Significant postnatal complications or congenital anomalies that are not known to be associated with SLC25A46 dysfunction
  • Patient has received any experimental treatment for SLC25A46 dysfunction within the 6 months prior to enrollment, or is expected to receive any such therapy during the study period

Trial locations and contacts

1 site in 1 country.

United States1 site
  • UBMD Pediatrics

    Buffalo, New York, 14203

Other trials in United States

About this study

Official title: A Natural History Study of Neurodegeneration and Optic Atrophy Caused by SLC25A46 Mutations in Pediatric and Adult Patients

The purpose of the study is to systematically characterize the clinical course of the progressive neuropathy and optic atrophy observe in pediatric and adult patients with biallelic mutations in the solute carrier family 25 member 46 (SLC25A46) gene.

Read the detailed description

The number of mitochondria in the cell is dynamic and is regulated by two opposite processes, namely fission and fusion. Proteins in both the inner mitochondrial membrane (IMM) and the outer mitochondrial membrane (OMM) are involved in mediating these two processes, including OPA1, MFN2 and SLC25A46. Recent work by the investigators as well as other research groups has shown that mutations in SLC25A46 cause abnormal mitochondrial fusion, leading to optic nerve atrophy, axonal peripheral neuropathy and cerebellar degeneration by interfering with mitochondrial fission. Recently, the investigators have used CRISPR genome editing to generate a global Slc25a46 KO mouse model with complete loss of SLC25A46 in all tissues (PMID: 28934388). Similar to patients with biallelic mutations in SLC25A46, these mice exhibit severe ataxia, optic atrophy, peripheral neuropathy related to axonal degeneration, and demyelination due to mitochondrial hyperfusion and defective energy production. In these mice, histological staining revealed a hypotrophic cerebellum with a severe loss of Purkinje cells (PCs) and/or stunted PC dendrites while electron microscopy revealed enlarged mitochondria with swollen cristae and other abnormal morphologies in PC dendrites and sciatic nerves. Furthermore, in primary culture, PCs from these mice exhibited abnormal mitochondrial distribution and movement.

These findings provide compelling evidence indicating that SLC25A46 plays an important role in the regulation of mitochondrial dynamics-including fusion/fission, distribution, and movement, as well as the maintenance of cristae architecture-and that loss of SLC25A46 function has a particularly severe effect on a distinct subset of neuron types with long axonal processes. More recently, the investigators have shown that AAV-based gene therapy can produce dramatic improvements in their Slc25a46 mutant mouse model (PMID: 31943007). These studies in the Slc25a46 mouse model provide the foundation for uncovering the mechanism whereby these this gene causes disease in humans, as well as lay the groundwork for the possible use of gene therapy to ameliorate the disease phenotype in patients.

However, despite this progress, there remains only a handful of studies published on Slc25a46 and the consequences of loss of Slc25a46 function in humans. Given that human SLC25A46-associated phenotypes overlap substantially with DOA and CMT2A, further study of this rare condition presents an opportunity not only to better understand and treat SLC25A46-related disease, but also to elucidate the broader mechanistic link between neurodegeneration and abnormal mitochondrial dynamics. Thus, in order to better understand the clinical manifestations of SLC25A46-related disease and to help lay the groundwork for eventual clinical trials of gene therapy or drug-based treatments, the investigators propose this natural history study of pediatric as well as adult patients with biallelic mutations in the SLC25A46 gene.

Being tested
Mutation analysis
Keywords
Neurodegeneration, Mitochondrial disease, Optic atrophy, SLC25A46, Mitochondrial fission
Medical subject headings
Heredodegenerative Disorders, Nervous System, Mitochondrial Diseases, Optic Atrophy, Nerve Degeneration

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Mutation analysisGenetic

    The investigators will sequence DNA samples from the patients or their families.

Study groups in NCT04594590
Study groupRoleWhat they receive
Patients with SLC25A46 deficiencyMale and female patients from age 2 to age 65 with clinically confirmed SLC25A46 mutations. Both living and deceased patients will be included, if eligible. For deceased patients, the patient's medical history records will be reviewed, and an interview of the parent(s) or caregiver(s) will be performed.
Receives: Genetic: Mutation analysis

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Custom Medical History Questionnaire for Patients with SLC25A46 Mutation-related Mitochondriopathy

    In addition to a standard medical history, patients or their legal guardians will be asked to complete a custom medical history questionnaire tailored toward conditions commonly observed in patients with biallelic SLC25A46 mutations. The items that will be asked about in this questionnaire are as follows:

    1. Known mutations in SLC25A46
    2. Any family history of illness
    3. Complications of pregnancy
    4. Premature birth
    5. Complications with birth
    6. Developmental delay
    7. Developmental regression
    8. Abnormal size of brain
    9. Movement disorders (ataxia, dystonia, etc.)
    10. Seizures
    11. Optic atrophy in eye exam
    12. Vision loss
    13. Other vision problems (color, eye movement)
    14. Hypotonia (muscle weakness or lack of tone)
    15. Electromyogram (EMG)
    16. Muscle biopsy
    17. Spasticity (muscle stiffness or tightness)
    18. Brain MRI performed?
    19. Electroencephalogram (EEG)

    Measured: 3 years

  2. Retrospective examination of the medical records of patients with SLC25A46 Mutation-related Mitochondriopathy

    With the informed consent of the patients or their parent(s) and/or legal guardian(s), the investigators will perform a retrospective examination of the medical records of both living and deceased patients with confirmed biallelic SLC25A46 mutations.

    Measured: 3 years

  3. Eye assessments to evaluate ocular health

    Visual acuity examination will be performed to determine the patient's clarity or sharpness of vision.

    Measured: 3 years

  4. Growth and development (height)

    World Health Organization (WHO) growth charts will be used to document height in centimeters (cm) for patients ranging from ages 5 to 19 years old. Routine methods will be used to document height for all other age groups.

    Measured: 3 years

  5. Growth and development (weight)

    World Health Organization (WHO) growth charts will be used to document weight in kilograms (kg) for pediatric patients age 5 to 10 years old. Routine methods will be used to document weight for all other age groups.

    Measured: 3 years

  6. Growth and development (BMI)

    World Health Organization (WHO) growth charts will be used to document Body Mass Index (BMI) in kilograms per meter square for patients age 5 to 19 years old. Routine methods will be used to document BMI for all other age groups.

    Measured: 3 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted20 Oct 2020
  2. Study start3 Nov 2020
  3. Primary completion17 Aug 2023
  4. Study completion17 Aug 2023

Resources

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
Case only
Time perspective
Other
Enrolment
9 participants (actual)
Target duration
3 Years
IDs, dates and publications
ClinicalTrials.gov ID
NCT04594590
Sponsor's protocol ID
STUDY00004513-SLC
Status last verified
Mar 2024
First submitted
13 Oct 2020
Last updated
8 Mar 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Abrams AJ, Hufnagel RB, Rebelo A, Zanna C, Patel N, Gonzalez MA, Campeanu IJ, Griffin LB, Groenewald S, Strickland AV, Tao F, Speziani F, Abreu L, Schule R, Caporali L, La Morgia C, Maresca A, Liguori R, Lodi R, Ahmed ZM, Sund KL, Wang X, Krueger LA, Peng Y, Prada CE, Prows CA, Schorry EK, Antonellis A, Zimmerman HH, Abdul-Rahman OA, Yang Y, Downes SM, Prince J, Fontanesi F, Barrientos A, Nemeth AH, Carelli V, Huang T, Zuchner S, Dallman JE. Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder. Nat Genet. 2015 Aug;47(8):926-32. doi: 10.1038/ng.3354. Epub 2015 Jul 13.

    PubMed 26168012
  • Li Z, Peng Y, Hufnagel RB, Hu YC, Zhao C, Queme LF, Khuchua Z, Driver AM, Dong F, Lu QR, Lindquist DM, Jankowski MP, Stottmann RW, Kao WWY, Huang T. Loss of SLC25A46 causes neurodegeneration by affecting mitochondrial dynamics and energy production in mice. Hum Mol Genet. 2017 Oct 1;26(19):3776-3791. doi: 10.1093/hmg/ddx262.

    PubMed 28934388
  • Yang L, Slone J, Li Z, Lou X, Hu YC, Queme LF, Jankowski MP, Huang T. Systemic administration of AAV-Slc25a46 mitigates mitochondrial neuropathy in Slc25a46-/- mice. Hum Mol Genet. 2020 Mar 13;29(4):649-661. doi: 10.1093/hmg/ddz277.

    PubMed 31943007
  • Qiu K, Zou W, Fang H, Hao M, Mehta K, Tian Z, Guan JL, Zhang K, Huang T, Diao J. Light-activated mitochondrial fission through optogenetic control of mitochondria-lysosome contacts. Nat Commun. 2022 Jul 25;13(1):4303. doi: 10.1038/s41467-022-31970-5.

    PubMed 35879298
  • Zou W, Chen Q, Slone J, Yang L, Lou X, Diao J, Huang T. Nanoscopic quantification of sub-mitochondrial morphology, mitophagy and mitochondrial dynamics in living cells derived from patients with mitochondrial diseases. J Nanobiotechnology. 2021 May 13;19(1):136. doi: 10.1186/s12951-021-00882-9.

    PubMed 33985528

Questions about this trial

What is this clinical trial studying?

An observational study of Neurodegenerative Disease, Hereditary and Mitochondrial Diseases, run by State University of New York at Buffalo at 1 site in United States.

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 4 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 8 Mar 2024. 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 United States. 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?

Custom Medical History Questionnaire for Patients with SLC25A46 Mutation-related Mitochondriopathy (time frame: 3 years). The study lists 6 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 NCT04594590, which also lists 5 linked publications.

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 8 Mar 2024.

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