When multiple sclerosis and X-linked adrenoleukodystrophy are tangled

Paiva, Anderson Rodrigues Brandão de; Filho, Carlos Rory Pucci; Porto, Alan Monteiro; Feltrin, Fabrício Stewan; Kok, Fernando; Camargo, Carlos Henrique Ferreira

doi:10.1212/cpj.0000000000000431

Cited by 5 publications

(6 citation statements)

References 7 publications

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“…The clinical presentation of ALD is complex; involving adrenal insufficiency and myelopathy (de Beer et al, 2014;Kemp et al, 2016). Approximately 60% of male patients develop rapidly progressive inflammatory cerebral demyelination (Moser et al, 1992), which clinically coincides with a progressive neurological decline similar to MS (Ferrer et al, 2010;Brandao de Paiva et al, 2018). However, the complex mechanisms on how this metabolic disease is transitioned to a fatal neuroinflammatory disease remains elusive.…”

Section: Additional "Inside-out" Modelsmentioning

confidence: 99%

Pre-clinical and Clinical Implications of “Inside-Out” vs. “Outside-In” Paradigms in Multiple Sclerosis Etiopathogenesis

Titus

Chen

Podojil

et al. 2020

Front. Cell. Neurosci.

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Multiple Sclerosis (MS) is an immune-mediated neurological disorder, characterized by central nervous system (CNS) inflammation, oligodendrocyte loss, demyelination, and axonal degeneration. Although autoimmunity, inflammatory demyelination and neurodegeneration underlie MS, the initiating event has yet to be clarified. Effective disease modifying therapies need to both regulate the immune system and promote restoration of neuronal function, including remyelination. The challenge in developing an effective long-lived therapy for MS requires that three disease-associated targets be addressed: (1) self-tolerance must be re-established to specifically inhibit the underlying myelin-directed autoimmune pathogenic mechanisms; (2) neurons must be protected from inflammatory injury and degeneration; (3) myelin repair must be engendered by stimulating oligodendrocyte progenitors to remyelinate CNS neuronal axons. The combined use of chronic and relapsing remitting experimental autoimmune encephalomyelitis (C-EAE, R-EAE) ("outside-in") as well as progressive diphtheria toxin A chain (DTA) and cuprizone autoimmune encephalitis (CAE) ("inside-out") mouse models allow for the investigation and specific targeting of all three of these MSassociated disease parameters. The "outside-in" EAE models initiated by myelin-specific autoreactive CD4 + T cells allow for the evaluation of both myelin-specific tolerance in the absence or presence of neuroprotective and/or remyelinating agents. The "inside-out" mouse models of secondary inflammatory demyelination are triggered by toxin-induced oligodendrocyte loss or subtle myelin damage, which allows evaluation of novel therapeutics that could promote remyelination and neuroprotection in the CNS. Overall, utilizing these complementary pre-clinical MS models will open new avenues for developing therapeutic interventions, tackling MS from the "outside-in" and/or "inside-out".

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Section: Additional "Inside-out" Modelsmentioning

confidence: 99%

Pre-clinical and Clinical Implications of “Inside-Out” vs. “Outside-In” Paradigms in Multiple Sclerosis Etiopathogenesis

Titus

Chen

Podojil

et al. 2020

Front. Cell. Neurosci.

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“…In rare heterozygous adult females with cerALD, neuroimaging may resemble that of patients with MS, with multifocal lesions disseminated in the periventricular, juxtacortical (involving U-fibers), and infratentorial compartments and gadoliniumenhancement of the acute lesions. 9 The molecular mechanisms responsible for the conversion of dysmyelination into inflammatory demyelination in cerALD are poorly understood. 33 Circulating VLCFA levels fail to correlate with either the development of disease or the timing of disease onset.…”

Section: Discussionmentioning

confidence: 99%

“…49,50 Inflammation in ALD may be associated with autoantibodies. Increased CSF IgG synthesis and a CSF oligoclonal banding pattern are found in most adult patients with inflammatory cerALD, [8][9][10]32,51 but the prevalence of these findings in childhood cerALD appears low. 52 In our patient, brain MRI showed bilateral parieto-occipital, confluent, and symmetrical demyelination with ring enhancement at the periphery.…”

Section: Discussionmentioning

confidence: 99%

“…CSF markers of B cell autoimmunity have been previously shown to be present in several adults with cerALD who responded to immunomodulation therapy. 9,10 Factors predictive of worse outcome of HSCT in childhood cerALD include clinical presentation before 8 years of age, rapidly progressive disease, EDSS !2 and AL-DRS !2, 15 Loes's score !10, 60 and GIS !2. 14 The only therapy that improves Loes's score is HSCT, as it can decrease dysmyelination after normalizing plasma VLCFA.…”

Section: Discussionmentioning

confidence: 99%

“…7 CerALD in some patients is associated with CSF oligoclonal bands. [8][9][10] In adult patients, demyelinating features can be similar to those seen in MS. 11,12 CerALD and MS are inflammatory leukoencephalopathies, but only MS is considered autoimmune.…”

Section: Introductionmentioning

confidence: 97%

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Untitled

2021

Journal of Pediatric Neurology

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X-linked adrenoleukodystrophy (ALD) is a leukodystrophy characterized not only by progressive loss of myelin in the central nervous system due to dysmyelination, but also by acute, subacute, or chronic inflammatory demyelination. This results in the phenotypic variability of cerebral ALD (cerALD), which is independent of the genotype. In this article, we reported a fulminant presentation with fluctuating encephalopathy and visual loss in a patient with childhood onset cerALD. Brain MRI showed symmetric confluent occipito-temporal demyelination with severe disruption of the blood-brain barrier and prechiasmal optic neuropathy. The patient's cerebral spinal fluid (CSF) demonstrated an elevated IgG index, myelin basic proteins, and oligoclonal bands. Within 48 hours of receiving immunomodulating therapy, the patient's symptoms of psychomotor slowing, visual impairment, and areflexia partially resolved. High plasma C26:0 levels and high ratios of C24/22 and C26/22 were diagnostic of ALD. It has been shown that environmental factors play an important role in the inflammatory demyelination responsible for the severe phenotypes of cerALD.

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Fulminating Autoimmune Demyelination with Optic Neuropathy in a Case of Pediatric Cerebral Adrenoleukodystrophy: Case Report and Review of the Literature

Singhapakdi

Sharma

Maertens

2021

Journal of Pediatric Neurology

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X-linked adrenoleukodystrophy (ALD) is a leukodystrophy characterized not only by progressive loss of myelin in the central nervous system due to dysmyelination, but also by acute, subacute, or chronic inflammatory demyelination. This results in the phenotypic variability of cerebral ALD (cerALD), which is independent of the genotype. In this manuscript, we report a fulminant presentation with fluctuating encephalopathy and visual loss in a patient with childhood onset cerALD. Brain MRI showed symmetric confluent occipito-temporal demyelination with severe disruption of the blood–brain barrier and prechiasmal optic neuropathy. The patient's cerebral spinal fluid (CSF) demonstrated an elevated IgG index, myelin basic proteins, and oligoclonal bands. Within 48 hours of receiving immunomodulating therapy, the patient's symptoms of psychomotor slowing, visual impairment, and areflexia partially resolved. High plasma C26:0 levels and high ratios of C24/22 and C26/22 were diagnostic of ALD. It has been shown that environmental factors play an important role in the inflammatory demyelination responsible for the severe phenotypes of cerALD.

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When multiple sclerosis and X-linked adrenoleukodystrophy are tangled

Abstract: Practical Implications Neurology ® Clinical Practice is committed to providing clinical insights helpful to neurologists in everyday practice. Each Full Case includes a "Practical Implications" statement, a pearl of wisdom for the practicing clinician.

Cited by 5 publications

References 7 publications

Pre-clinical and Clinical Implications of “Inside-Out” vs. “Outside-In” Paradigms in Multiple Sclerosis Etiopathogenesis

Pre-clinical and Clinical Implications of “Inside-Out” vs. “Outside-In” Paradigms in Multiple Sclerosis Etiopathogenesis

Untitled

Fulminating Autoimmune Demyelination with Optic Neuropathy in a Case of Pediatric Cerebral Adrenoleukodystrophy: Case Report and Review of the Literature

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