Biomarker-based risk prediction for the onset of neuroinflammation in X-linked adrenoleukodystrophy

Weinhofer, Isabelle; Rommer, Paulus; Gleiss, Andreas; Ponleitner, Markus; Zierfuss, Bettina; Waidhofer-Söllner, Petra; Fourcade, Stéphane; Grabmeier-Pfistershammer, Katharina; Reinert, Marie-Christine; Göpfert, Jens; Heine, Anne; Yska, Hemmo A.F.; Casasnovas, Carlos; Cantarín, Verónica; Bergner, Caroline G.; Mallack, Eric; Forss-Petter, Sonja; Aubourg, Patrick; Bley, Annette; Engelen, Marc; Eichler, Florian; Lund, Troy C.; Pujol, Aurora; Köhler, Wolfgang; Kühl, Jörn-Sven; Berger, Johannes

doi:10.1016/j.ebiom.2023.104781

Cited by 9 publications

(3 citation statements)

References 40 publications

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“…Recently, axonal damage was found to precede myelin breakdown in the prelesional zone [ 52 ].. This is in line with the finding that Neurofilament Light (NfL), a biomarker for axonal damage, is an early marker for the development of cerebral ALD [ 53 ]. Axonal degeneration therefore appears to be an early step in the sequence of pathological events in leukodystrophy lesions (Table 2 ).…”

Section: Introductionsupporting

confidence: 65%

The pathology of X-linked adrenoleukodystrophy: tissue specific changes as a clue to pathophysiology

Yska,

Engelen,

Bugiani

2024

Orphanet J Rare Dis

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Although the pathology of X-linked adrenoleukodystrophy (ALD) is well described, it represents the end-stage of neurodegeneration. It is still unclear what cell types are initially involved and what their role is in the disease process. Revisiting the seminal post-mortem studies from the 1970s can generate new hypotheses on pathophysiology. This review describes (histo)pathological changes of the brain and spinal cord in ALD. It aims at integrating older works with current insights and at providing an overarching theory on the pathophysiology of ALD. The data point to an important role for axons and glia in the pathology of both the myelopathy and leukodystrophy of ALD. In-depth pathological analyses with new techniques could help further unravel the sequence of events behind the pathology of ALD.

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Section: Introductionsupporting

confidence: 65%

The pathology of X-linked adrenoleukodystrophy: tissue specific changes as a clue to pathophysiology

Yska,

Engelen,

Bugiani

2024

Orphanet J Rare Dis

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“…Furthermore, patients with the same variant genotype can have different cerebral phenotypes. Based on reports and pathophysiological characteristics of the disease and of pathology (23)(24)(25), the risk for cerebral ALD appears to be partly from an underlying genetically determined risk and then a secondary second effect. Similarly, for most Mitchell patients, disease onset is after many asymptomatic years of life (5 years in this case) (26).…”

Section: Discussionmentioning

confidence: 99%

Generation and characterization of a zebrafish gain-of-function ACOX1 Mitchell disease model

Raas,

Wood,

Stevenson

et al. 2024

Front. Pediatr.

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BackgroundMitchell syndrome is a rare, neurodegenerative disease caused by an ACOX1 gain-of-function mutation (c.710A>G; p.N237S), with fewer than 20 reported cases. Affected patients present with leukodystrophy, seizures, and hearing loss. ACOX1 serves as the rate-limiting enzyme in peroxisomal beta-oxidation of very long-chain fatty acids. The N237S substitution has been shown to stabilize the active ACOX1 dimer, resulting in dysregulated enzymatic activity, increased oxidative stress, and glial damage. Mitchell syndrome lacks a vertebrate model, limiting insights into the pathophysiology of ACOX1-driven white matter damage and neuroinflammatory insults.MethodsWe report a patient presenting with rapidly progressive white matter damage and neurological decline, who was eventually diagnosed with an ACOX1 N237S mutation through whole genome sequencing. We developed a zebrafish model of Mitchell syndrome using transient ubiquitous overexpression of the human ACOX1 N237S variant tagged with GFP. We assayed zebrafish behavior, oligodendrocyte numbers, expression of white matter and inflammatory transcripts, and analysis of peroxisome counts.ResultsThe patient experienced progressive leukodystrophy and died 2 years after presentation. The transgenic zebrafish showed a decreased swimming ability, which was restored with the reactive microglia-targeted antioxidant dendrimer-N-acetyl-cysteine conjugate. The mutants showed no effect on oligodendrocyte counts but did display activation of the integrated stress response (ISR). Using a novel SKL-targeted mCherry reporter, we found that mutants had reduced density of peroxisomes.ConclusionsWe developed a vertebrate (zebrafish) model of Mitchell syndrome using transient ubiquitous overexpression of the human ACOX1 N237S variant. The transgenic mutants exhibited motor impairment and showed signs of activated ISR, but interestingly, there were no changes in oligodendrocyte counts. However, the mutants exhibited a deficiency in the number of peroxisomes, suggesting a possible shared mechanism with the Zellweger spectrum disorders.

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“…Much less information is available on Nf in pediatric neurological diseases. Recently, however, more pediatric Nf data have emerged, and elevated levels of NfL have been detected in pediatric multiple sclerosis, spinal muscular atrophy, X-linked adrenoleukodystrophy, myelin oligodendrocyte glycoprotein-associated disease (MOGAD), cerebrovascular disease in children with sickle cell anemia, and others [ 7 , 8 , 9 , 10 , 11 , 12 ]. Moreover, elevated NfL levels in cerebrospinal fluid (cNfL) have been described in a cohort with infectious and inflammatory CNS diseases without providing details on subgroups [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Neurofilament Light Chain Concentration in Cerebrospinal Fluid in Children with Acute Nontraumatic Neurological Disorders

Geis,

Gutzeit,

Disse

et al. 2024

Children

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(1) Introduction: This pilot study aimed to analyze neurofilament light chain levels in cerebrospinal fluid (cNfL) in a cohort of children with different acute nontraumatic neurological conditions. (2) Methods: This prospective observational cohort study consisted of 35 children aged 3 months to 17 years and was performed from November 2017 to December 2019. Patients’ clinical data were reviewed, and patients were assigned to the following groups: n = 10 (28.6%) meningitis, 5 (14.3%) Bell’s palsy, 7 (20.0%) febrile non-CNS infection, 3 (8.6%) complex febrile seizure, 4 (11.4%) idiopathic intracranial hypertension, and 6 (17.1%) others. cNfL levels were measured using a sensitive single-molecule array assay. (3) Results: The cNfL levels [median (range)] in children with meningitis were 120.5 pg/mL (58.1–205.4), in Bell’s palsy 88.6 pg/mL (48.8–144.5), in febrile non-CNS infection 103.9 pg/mL (60.1–210.8), in complex febrile seizure 56 pg/mL (53.2–58.3), and in idiopathic intracranial hypertension 97.1 pg/mL (60.1–124.6). Within the meningitis group, children with Lyme neuroborreliosis (LNB) had significantly higher cNfL concentrations (median 147.9 pg/mL; range 87.8–205.4 pg/mL) than children with enterovirus meningitis (72.5 pg/mL; 58.1–95.6 pg/mL; p = 0.048) and non-significantly higher cNfL levels when compared to Bell’s palsy (88.6 pg/mL; 48.8–144.5 pg/mL; p = 0.082). There was no correlation between cNfL levels and age. (4) Conclusions: Although the number of patients in this pilot study cohort is limited, higher cNfL levels in children with LNB compared to those with viral meningitis (significant) and Bell’s palsy (trend) may indicate the potential of cNfL as a biomarker in the differential diagnosis of pediatric meningitis and facial palsy.

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Biomarker-based risk prediction for the onset of neuroinflammation in X-linked adrenoleukodystrophy

Cited by 9 publications

References 40 publications

The pathology of X-linked adrenoleukodystrophy: tissue specific changes as a clue to pathophysiology

The pathology of X-linked adrenoleukodystrophy: tissue specific changes as a clue to pathophysiology

Generation and characterization of a zebrafish gain-of-function ACOX1 Mitchell disease model

Neurofilament Light Chain Concentration in Cerebrospinal Fluid in Children with Acute Nontraumatic Neurological Disorders

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