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
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
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
Patient with a confirmed genetic diagnosis of mitochondrial leukoencephalopathy
Cohort
Retrospective
Not listed
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
The comprehensive characterization of disease progression in MLs, assessed through the collection and analysis of longitudinal clinical, instrumental and genetic data: NMDAS
Disease progression in adults assessed by the Newcastle Mitochondrial Disease Adult Scale (NMDAS) Disease severity and progression in adult participants will be assessed using the Newcastle Mitochondrial Disease Adult Scale (NMDAS). Unit of Measure: NMDAS total score.
The comprehensive characterization of disease progression in MLs, assessed through the collection and analysis of longitudinal clinical, instrumental and genetic data: Serum lactate levels
Serum lactate levels will be collected and analyzed, when available, to characterize biochemical abnormalities and their changes over time Unit of Measure: nmol/h/mg.
The comprehensive characterization of disease progression in MLs, assessed through the collection and analysis of longitudinal clinical, instrumental and genetic data. : Serum pyruvate levels
Serum pyruvate levels will be collected and analyzed, when available, to characterize biochemical abnormalities and their changes over time Unit of Measure: nmol/h/mg.
Change in disease severity in treated adult participants assessed by NMDAS
In adult participants receiving disease-specific therapeutic interventions as part of their clinical care, changes in disease severity will be assessed using the Newcastle Mitochondrial Disease Adult Scale (NMDAS), when available. Unit of Measure: NMDAS total score
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