No Evidence for the Involvement of Leiomodin-1 Antibodies in the Pathogenesis of Onchocerciasis-Associated Epilepsy

Hotterbeekx, An; Vieri, Melissa Krizia; Ramberger, Melanie; Jozefzoon-Aghai, Ashraf; Mandro, Michel; Tepage, Floribert; Dusabimana, Alfred; Kumar‐Singh, Samir; Titulaer, Maarten J.; Colebunders, Robert

doi:10.3390/pathogens10070845

Cited by 23 publications

(20 citation statements)

References 24 publications

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“… 7 However, a subsequent study did not support the pathogenic role for leiomodin-1 autoantibodies in NS. 38 Our neuropathologic findings do not indicate how onchocerciasis could cause NS. But, serological studies of antibodies to Onchocerca volvulus were not available for our cases.…”

Section: Discussionmentioning

confidence: 57%

The spectrum of disease and tau pathology of nodding syndrome in Uganda

Pollanen

Onzivua

McKeever

et al. 2022

Brain

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Nodding syndrome is an enigmatic recurrent epidemic neurologic disease that affects children in East Africa. The illness begins with vertical nodding of the head and can progress to grand mal seizures and death after several years. The most recent outbreak of nodding syndrome occurred in northern Uganda. We now describe the clinicopathologic spectrum of nodding syndrome in northern Uganda. The neuropathologic findings of 16 children or young adults with fatal nodding syndrome were correlated with the onset, duration and progression of their neurological illness. The affected individuals ranged in age from 14 to 25 years at the time of death with a duration of illness ranging from 6–15 years. All 16 cases had chronic seizures. In ten cases, detailed clinical histories were available and showed that three individuals had a clinical course that was predominantly characterized by epilepsy whereas the other seven individuals had progressive cognitive, behavioural and motor decline, in addition to epilepsy. The main neuropathologic findings included: tau pathology (16/16 cases), cerebellar degeneration (11/16 cases), and white matter degeneration (7/16 cases). The tau pathology was characterized by filamentous tau-positive deposits in the form of neurofibrillary tangles, pre-tangles, and dot-like grains and threads in the neuropil. All cases showed some degree of tau pathology in the neocortex and in the locus coeruleus with frequent involvement of the substantia nigra and tegmental nuclei and lesser involvement of other grey matter sites, but there was a lack of glial tau pathology. The tau pathology in the neocortex showed a multifocal superficial laminar pattern. We conclude that nodding syndrome is a clinicopathological entity associated consistently with tau pathology, but our observations did not establish the cause of the disease, or an explanation for the tau pathology.

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Section: Discussionmentioning

confidence: 57%

The spectrum of disease and tau pathology of nodding syndrome in Uganda

Pollanen

Onzivua

McKeever

et al. 2022

Brain

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“…Ov-associated antibodies (Hu-leiomodin-1 and Ov-16 IgG) were present in both participants with NS and OAE, with no statistically significant association between the level of antibodies and the degree of brain atrophy in either of the 2 groups. Although Hu-leiomodin-1 antibody is proposed to be a pathogenic immune mediator in NS by Johnson et al, 11,12 this association was not confirmed by Hotterbeekx et al 10 in a study with participants with OAE from DR Congo. There were significant differences in the methodology of these studies that could explain the difference in the findings.…”

Section: Discussionmentioning

confidence: 89%

“…[3][4][5] The parasite is also associated with other forms of epilepsy, known as onchocerciasisassociated epilepsy (OAE). [6][7][8][9] Although the results have been inconsistent, 10 parasite-driven antibody responses cross-reacting with human leiomodin-1 protein or other proteins have been proposed to underly the epileptogenesis in NS. 11 Leiomodin-1 protein is a member of the tropomodulin family and functions as an actin nucleating protein in smooth muscle cells, 12 but it is also expressed in the mouse hippocampus, cerebellar Purkinje cells, and cortical neurons and on the membranes of newly formed neurons and astrocytes.…”

mentioning

confidence: 99%

Comparison of Structural Changes in Nodding Syndrome and Other Epilepsies Associated With Onchocerca volvulus

Mazumder

Lubowa

Salamon

et al. 2023

Neurol Neuroimmunol Neuroinflamm

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Background and ObjectiveNodding syndrome (NS) is a unique childhood-onset epileptic disorder that occurs predominantly in several regions of sub-Saharan Africa. The disease has been associated withOnchocerca volvulus (Ov)–induced immune responses and possible cross-reactivity with host proteins. The aim of this study was to compare structural changes in the brain on MRI between NS and other forms of onchocerciasis-associated epilepsies (OAEs) and to relate structural changes to the Ov-induced immune responses and level of disability.MethodsThirty-nine children with NS and 14 age-matched participants with other forms of OAE from an endemic region in Uganda underwent detailed clinical examination, serologic evaluation (including Ov-associated antibodies to Ov-16 and Hu-leiomodin-1) and quantitative volumetric analysis of brain MRIs (1.5 T scanner) using Neuroreader, a cloud-based software.ResultsCerebral and cerebellar atrophy were the predominant features in both NS and OAE. On quantitative volumetric analysis, participants with NS had larger ventricular volumes compared with participants with OAE, indicative of increased global cortical atrophy (pcorr= 0.036). Among children with NS, severe disability correlated with higher degree of atrophy in the gray matter volume (pcorr= 0.009) and cerebellar volume (pcorr= 0.009). NS cases had lower anti-Ov-16 IgG signal-to-noise ratios than the OAE cases (p< 0.01), but no difference in the levels of the Hu-leiomodin-1 antibodies (p= 0.64). The levels of Ov-associated antibodies did not relate to the degree of cerebral or cerebellar atrophy in either NS or OAE cases.DiscussionThis is the first study to show that cerebral and cerebellar atrophy correlated with the severity of NS disability, providing an imaging marker for these endemic epileptic disorders that until now have remained poorly characterized. Both NS and OAE have cerebral and cerebellar atrophy, and the levels of Ov-associated antibodies do not seem to be related to the structural changes on MRI.

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“…While the etiology of NS is unknown, the disease has affected infants and children of impoverished populations in which nematode infestation and food stress are significant factors, and in whom vitamin B6 levels are low. An autoimmune disorder is posited, but studies of cross-reactivity of OV and neuroproteins have yielded contradictory results [ 14 , 15 , 81 ], and OV antibody-negative NS cases are reported [ 82 ]. Displaced and food-insecure families used wild plants and mushrooms as emergency food.…”

Section: Discussionmentioning

confidence: 99%