Natural History and Genotype-Phenotype Correlations in Mitochondrial Leukoencephalopathies

NCT07868796 | Recruiting

• 1 other identifier: Leuko Mito
• Study Type: observational
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

Mitochondrial disorders (MDs) are among the most common inherited metabolic diseases, caused by genetic defects in mitochondrial or nuclear DNA that impair cellular energy production. The central nervous system (CNS) is frequently affected, due to its high energy demands. Within the broad clinical spectrum of MDs, mitochondrial leukoencephalopathies (MLs) have emerged as a distinct subgroup characterized by CNS white matter involvement. MLs are clinically and genetically heterogeneous, with onset ranging from infancy to adulthood. Patients may experience episodes of neurological regression, often triggered by stressors such as febrile illnesses, alongside variable motor, cognitive, and occasionally extraneurological involvement. Neuroimaging typically reveals diffuse or focal white matter abnormalities, including cavitation and rarefaction, with additional involvement of deep gray matter structures. Certain ML subtypes exhibit characteristic MRI patterns that may aid in diagnosis. Despite recent advancements in the genetic and neuroradiological characterization of MLs, significant knowledge gaps persist. Although the number of disease-causing genes has increased over the last decades, a comprehensive understanding of genotype-phenotype correlations is still lacking. Additionally, knowledge on the natural history of these disorders is limited. Existing data often focus on imaging findings with insufficient integration of clinical, biochemical, and molecular features, limiting the understanding of disease mechanisms, progression, and therapeutic responses. In light of these gaps, this multicenter, observational, retrospective study aims to systematically collect and analyze clinical, biochemical, neuroradiological, and genetic data from individuals with MLs, assessed at international reference centers for MDs. The study seeks to better elucidate the phenotypic variability and genotype-phenotype correlations of MLs. This work is expected to enhance diagnostic accuracy, inform management strategies, support prognostic counseling, and ultimately contribute to the better overall management of affected individuals

Conditions

Mitochondrial; Leukoencephalopathies; Leukoencephalopathy

Keywords

Mitochondrial disorder; leukoencephalopathy; leukodystrophy; mitochondrial leukoencephalopathy

Outcome Measures

Primary Outcomes (1)

• Comprehensive characterization of genotype-phenotype correlations in MLs.

  The primary endpoint for evaluating the principal objective of this study is the comprehensive characterization of genotype-phenotype correlations in MLs. This will be assessed through the collection and analysis of retrospective longitudinal clinical, neuroradiological and genetic data. Clinical phenotypes will then be stratified based on specific underlying genetic defects, assessing their impact on disease onset and progression to establish robust genotype-phenotype correlations. Data collection will include: * Family history, including inheritance patterns and consanguinity when applicable. * Age at symptom onset * Initial clinical presentation, documenting key symptoms and signs at disease onset. * Progression of disease manifestations, capturing the evolution of neurological and extraneurological features over time. * Neuroradiological findings, assessed through MRI scans to evaluate white matter abnormalities, other signal abnormalities or specific MRI findings

  12 months

Secondary Outcomes (8)

• The comprehensive characterization of disease progression in MLs, assessed through the collection and analysis of longitudinal clinical, instrumental and genetic data: NMDAS

  12 months

• The comprehensive characterization of disease progression in MLs, assessed through the collection and analysis of longitudinal clinical, instrumental and genetic data: Serum lactate levels

  12 months

• The comprehensive characterization of disease progression in MLs, assessed through the collection and analysis of longitudinal clinical, instrumental and genetic data. : Serum pyruvate levels

  12 months

• Change in disease severity in treated adult participants assessed by NMDAS

  12 months

• Change in disease severity in treated pediatric participants assessed by NPMDS

  12 months

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Patient with a confirmed genetic diagnosis of mitochondrial leukoencephalopathy

You may qualify if:

• Confirmed diagnosis of ML, confirmed by:
• Neuroradiological evidence of a MRI pattern of white matter alterations compatible with leukoencephalopathy
• Genetic evidence of pathogenic variants in nuclear or mitochondrial genes
• Availability of clinical data, including medical records detailing symptom onset, disease progression, neuroimaging findings, and clinical management.
• Written informed consent obtained from the patient or their legal guardian (for minors or individuals with cognitive impairment). If the patient is deceased, consent for the use of medical records in this study will be obtained from the legally authorized representative or next of kin

You may not qualify if:

• Unconfirmed diagnosis of mitochondrial leukoencephalopathy , including cases where:
• MRI findings do not demonstrate a white matter alteration pattern compatible with leukoencephalopathy
• There is neither genetic confirmation of a pathogenic variant in nuclear or mitochondrial genes
• Insufficient clinical data, including cases where medical records lack essential information on symptom onset, disease progression, neuroimaging findings, or clinical management, preventing a meaningful contribution to the study's objectives.
• Concomitant diagnosis of another genetic disorder that may independently contribute to white matter abnormalities or neurological symptoms, confounding the assessment of ML progression and clinical outcomes
• Unavailability of written informed consent

Sponsors & Collaborators

• Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta: lead

Study Sites (1)

Fondazione IRCCS Istituto Neurologico Carlo Besta

Milan, Italy

RECRUITING

Related Publications (5)

• Roosendaal SD, van de Brug T, Alves CAPF, Blaser S, Vanderver A, Wolf NI, van der Knaap MS. Imaging Patterns Characterizing Mitochondrial Leukodystrophies. AJNR Am J Neuroradiol. 2021 Jul;42(7):1334-1340. doi: 10.3174/ajnr.A7097. Epub 2021 Apr 1.

  PMID: 34255734 BACKGROUND

• Kevelam SH, Steenweg ME, Srivastava S, Helman G, Naidu S, Schiffmann R, Blaser S, Vanderver A, Wolf NI, van der Knaap MS. Update on Leukodystrophies: A Historical Perspective and Adapted Definition. Neuropediatrics. 2016 Dec;47(6):349-354. doi: 10.1055/s-0036-1588020. Epub 2016 Aug 26.

  PMID: 27564080 BACKGROUND

• Hosseinpour S, Razmara E, Heidari M, Rezaei Z, Ashrafi MR, Dehnavi AZ, Kameli R, Bereshneh AH, Vahidnezhad H, Azizimalamiri R, Zamani Z, Pak N, Rasulinezhad M, Mohammadi B, Ghabeli H, Ghafouri M, Mohammadi M, Zamani GR, Badv RS, Saket S, Rabbani B, Mahdieh N, Ahani A, Garshasbi M, Tavasoli AR. A comprehensive study of mutation and phenotypic heterogeneity of childhood mitochondrial leukodystrophies. Brain Dev. 2024 Apr;46(4):167-179. doi: 10.1016/j.braindev.2023.12.003. Epub 2023 Dec 21.

  PMID: 38129218 BACKGROUND

• Finsterer J, Zarrouk Mahjoub S. Leukoencephalopathies in mitochondrial disorders: clinical and MRI findings. J Neuroimaging. 2012 Jul;22(3):e1-11. doi: 10.1111/j.1552-6569.2011.00693.x. Epub 2012 Feb 3.

  PMID: 22303997 BACKGROUND

• Bindu PS, Sonam K, Chiplunkar S, Govindaraj P, Nagappa M, Vekhande CC, Aravinda HR, Ponmalar JJ, Mahadevan A, Gayathri N, Bharath MS, Sinha S, Taly AB. Mitochondrial leukoencephalopathies: A border zone between acquired and inherited white matter disorders in children? Mult Scler Relat Disord. 2018 Feb;20:84-92. doi: 10.1016/j.msard.2018.01.003. Epub 2018 Jan 6.

  PMID: 29353736 BACKGROUND

MeSH Terms

Conditions

Leukoencephalopathies; Mitochondrial Diseases

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• Anna Ardissone, MD

  Fondazione IRCCS Istituto Neurologico Carlo Besta

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Anna Ardissone, MD

CONTACT

+ 39 02.2394; anna.ardissone@istituto-besta.it

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 17, 2026
• First Posted: October 9, 2026
• Study Start: September 15, 2025
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026
• Last Updated: October 9, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)