Natural History and Genotype-Phenotype Correlations in Mitochondrial Leukoencephalopathies: A Multicentric, International Observational Study
| Registry | NCT07868796, acronym Leuko Mito |
|---|---|
| Status | Recruiting |
| Study type | Observational |
| Enrollment | 100 (Estimated) |
| Sponsor | Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta (Other) |
| Conditions | Mitochondrial, Leukoencephalopathies, Leukoencephalopathy |
| Dates | start 2025-09-15, primary completion 2026-12-01 (estimated), completion 2026-12-01 (estimated), first posted 2026-10-09, last updated 2026-10-09 |
| Locations | 1 site in Italy |
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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
Sex: All
Inclusion Criteria: * 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 Exclusion Criteria: * 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
| Facility | City | Country | Status |
|---|---|---|---|
| Fondazione IRCCS Istituto Neurologico Carlo Besta | Milan | Italy | Recruiting |