Modeling Macrophages Activation Pattern in X-linked Adrenoleukodystrophy, Metachromatic Leukodystrophy and Adult Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia

Study Overview
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Brief Summary
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This study is a national, non-randomized, open-label, multi-site with minimal risk study in adult with adrenomyeloneuropathy (AMN), childhood and adult subjects with cerebral ALD (cALD), juvenile/adult metachromatic leukodystrophy (MLD) and adults with leukoencephalopathy and axonal spheroids and pigmented glia (ALSP). 49 subjects will be enrolled with one blood sample collection during one of their medical follow-up visit. This trial will evaluate the role of innate immunity to influence disease progression in X-ALD, MLD and ALSP, and if the mutations related to these leukodystrophies result in a specific immune response leading to the pathogenesis.

Detailed Description
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X-linked Adrenoleukodystrophy (X-ALD), Metachromatic Leukodystrophy (MLD) and Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) are among the most frequent inherited leukodystrophies. X-ALD and MLD can affect both children and adults, while it is thought that ALSP onset exclusively during adulthood. These three diseases are characterized by phenotypic variability and poor genotype-phenotype correlation. In childhood forms of MLD and childhood cerebral ALD (C-CALD) a devastating cerebral demyelination and neuronal degeneration lead to a rapid neurologic degradation and premature death. Patients with the adult form of X-ALD (adrenomyeloneuropathy (AMN), 60% of males) display a progressive spastic paraplegia without brain involvement. However, 20% of AMN patients will also develop cerebral ALD. Patients diagnosed with the juvenile/adult (JA-) MLD form are affected by a progressive decline of their cognitive function, followed later by that of the motor abilities. ALSP patients present a rapidly progressive neurodegenerative disorder that impairs behavioural, cognitive and motor functions. Several arguments support the contribution of the immune response and neuroinflammation in these three leukodystrophies. In X-ALD, activation of microglia (macrophages of the CNS) plays an essential role in the acute demyelination phase, where a severe inflammatory process occurs. In ALSP, the dysfunctional protein (CSF1R) is almost exclusively expressed in microglia. Even if MLD is not considered as a neuroinflammatory disease per se, microglia activation and increased inflammatory cytokines are observed in the brain of MLD patients and mice. Even if the most commonly accepted hypothesis is that neuroinflammation is caused by secondary activation of microglia following phagocytosis of myelin debris full of undegraded material, a primitive role of the inflammation due to macrophages (MAC) dysfunction has emerged in recent years. MATRIX proposes to explore how disease-related mutations affect key components of MAC activation responses and how it reflects on their functionality.

Official Title
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MATRIX - Modeling Macrophages Activation Pattern in X-linked Adrenoleukodystrophy, Metachromatic Leukodystrophy and Adult Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia

Conditions
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Adrenoleukodystrophy, Adrenomyeloneuropathy, Metachromatic Leukodystrophy, Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia

Intervention / Treatment
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* Diagnostic Test: Blood sample collection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Boys or girls aged between 15 months and 18 years (inclusive) diagnosed with MLD (low ARSA activity and accumulation of sulfatides in urine) Adult males or females diagnosed with MLD (low ARSA activity and accumulation of sulfatides in urine) Adult males diagnosed with AMN (elevated VLCFA and clinical symptoms of AMN without leukodystrophy at brain MRI) Adult male diagnosed with CALD (elevated VLCFA with leukodystrophy at brain MRI) Adult male or female diagnosed with ALSP (genetic confirmation with leukodystrophy at brain MRI) Children (15 months-18 years) without neurologic disease (no obvious neurological symptoms, normal neurologic examination) Informed consent obtained : from the parents or guardian for children patients and children controls ; from subject himself for adult patients. Exclusion Criteria: Participation to a therapeutic clinical trial Treatment likely to modify the immune system Unable to have a blood collection (i.e. low hemoglobin level at the investigator's judgment) Any other reason, to the discretion of the investigator Children or adults without health insurance or social security

Ages Eligible for Study
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Minimum Age: 15 Months
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| affected subjects<br>adult patients with adrenomyeloneuropathy/adrenoleukodystrophy children with adrenoleukodystrophy children with metachromatic leukodystrophy | Diagnostic Test: Blood sample collection<br>* blood sample collection<br>|
| control subjects<br>-healthy children | Diagnostic Test: Blood sample collection<br>* blood sample collection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Macrophages functionality - distribution of monocytes | distribution of monocytes in the CD14-/+/++ and CD16-/+ classification using flow cytometry (% of CD14++/16-; CD14++/16+; CD14+/16+; CD14-/16-) | 2 years after blood collection | 
| Macrophages functionality - myelin phagocytosis capacity | percentage of myelin high, myelin low and myelin negative cells using flow cytometry | 2 years after blood collection | 
| Macrophages functionality - HLA levels | maximum fluorescence intensity for HLA markers using flow cytometry | 2 years after blood collection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Macrophages metabolic profiling | Macrophages metabolic profiling (>2000 metabolites) using liquid chromatography coupled to high resolution mass spectrometry | 2 years after blood collection | 
| Macrophages transcriptomic profiling | Macrophages transcriptomic profiling (>1200 coding and non coding genes) : RNA sequencing using NextSeq 500 Illumina (60 million single-end, 150 base reads ) and analysis (using FastQC, Picard-Tools, Samtools and rseqc softwares | 2 years after blood collection | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Leukodystrophy, Central Nervous System Diseases, Nervous System Diseases, Immune system, Neuroinflammation