Whole exome sequencing in a child with acute disseminated encephalomyelitis, optic neuritis, and periodic fever syndrome: a case report

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Abstract

Background

Acute disseminated encephalomyelitis is generally preceded by an infection, and it is usually self-limiting and non-recurrent. However, when there are multiple attacks of acute disseminated encephalomyelitis followed by optic neuritis, it is defined as acute disseminated encephalomyelitis-optic neuritis. To the best of our knowledge, there are no previous reports of acute disseminated encephalomyelitis and optic neuritis preceded by autoinflammation, triggered by periodic fever syndrome.

Case summary

We report on a case of acute disseminated encephalomyelitis with optic neuritis and periodic fever syndrome in a 12-year-old Ecuadorian Hispanic boy with several relapses over the past 10 years, always preceded by autoinflammatory manifestations and without evidence of infectious processes. Whole exome sequencing was performed, and although the results were not conclusive, we found variants in genes associated with both autoinflammatory ( NLRP12) and neurological ( POLR3A) phenotypes that could be related to the disease pathogenesis having a polygenic rather than monogenic trait.

Conclusion

We propose that an autoinflammatory basis should be pursued in patients diagnosed as having acute disseminated encephalomyelitis and no record of infections. Also, we show that our patient had a good response after 1 year of treatment with low doses of intravenous immunoglobulin and colchicine.

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Most cited references 19

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Mutations in NALP12 cause hereditary periodic fever syndromes.

P Duquesnoy, E Grimprel, S Amselem … (2008)

NALP proteins, also known as NLRPs, belong to the CATERPILLER protein family involved, like Toll-like receptors, in the recognition of microbial molecules and the subsequent activation of inflammatory and immune responses. Current advances in the function of NALPs support the recently proposed model of a disease continuum bridging autoimmune and autoinflammatory disorders. Among these diseases, hereditary periodic fevers (HPFs) are Mendelian disorders associated with sequence variations in very few genes; these variations are mostly missense mutations whose deleterious effect, which is particularly difficult to assess, is often questionable. The growing number of identified sporadic cases of periodic fever syndrome, together with the lack of discriminatory clinical criteria, has greatly hampered the identification of new disease-causing genes, a step that is, however, essential for appropriate management of these disorders. Using a candidate gene approach, we identified nonambiguous mutations in NALP12 (i.e., nonsense and splice site) in two families with periodic fever syndromes. As shown by means of functional studies, these two NALP12 mutations have a deleterious effect on NF-kappaB signaling. Overall, these data identify a group of HPFs defined by molecular defects in NALP12, opening up new ways to manage these disorders. The identification of these first NALP12 mutations in patients with autoinflammatory disorder also clearly demonstrates the crucial role of NALP12 in inflammatory signaling pathways, thereby assigning a precise function to this particular member of an emerging family of proteins whose putative biological properties are currently inferred essentially through in vitro means.

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Clinical spectrum of 4H leukodystrophy caused by POLR3A and POLR3B mutations.

Nicole I Wolf, Adeline Vanderver, Rosalina M L van Spaendonk … (2014)

To study the clinical and radiologic spectrum and genotype-phenotype correlation of 4H (hypomyelination, hypodontia, hypogonadotropic hypogonadism) leukodystrophy caused by mutations in POLR3A or POLR3B. We performed a multinational cross-sectional observational study of the clinical, radiologic, and molecular characteristics of 105 mutation-proven cases. The majority of patients presented before 6 years with gross motor delay or regression. Ten percent had an onset beyond 10 years. The disease course was milder in patients with POLR3B than in patients with POLR3A mutations. Other than the typical neurologic, dental, and endocrine features, myopia was seen in almost all and short stature in 50%. Dental and hormonal findings were not invariably present. Mutations in POLR3A and POLR3B were distributed throughout the genes. Except for French Canadian patients, patients from European backgrounds were more likely to have POLR3B mutations than other populations. Most patients carried the common c.1568T>A POLR3B mutation on one allele, homozygosity for which causes a mild phenotype. Systematic MRI review revealed that the combination of hypomyelination with relative T2 hypointensity of the ventrolateral thalamus, optic radiation, globus pallidus, and dentate nucleus, cerebellar atrophy, and thinning of the corpus callosum suggests the diagnosis. 4H is a well-recognizable clinical entity if all features are present. Mutations in POLR3A are associated with a more severe clinical course. MRI characteristics are helpful in addressing the diagnosis, especially if patients lack the cardinal non-neurologic features. © 2014 American Academy of Neurology.

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Clinical Presentation and Pathogenesis of Cold-Induced Autoinflammatory Disease in a Family With Recurrence of an NLRP12 Mutation

S Borghini, S Tassi, S Chiesa … (2011)

Objective NLRP12 mutations have been described in patients affected with peculiar autoinflammatory symptoms. This study was undertaken to characterize NLRP12 mutations in patients with autoinflammatory syndromes, particularly a novel missense mutation, p.D294E, affecting a protein sequence crucial for ATP binding, which was identified in a Caucasian family with familial cold-induced autoinflammatory syndrome in some family members. Methods Fifty patients were tested for NLRP12 mutations. A Caucasian family with the p.D294E missense mutation of NLRP12 in some family members was clinically characterized. In vitro analysis of the effects of the mutation on NF-κB activity was performed in HEK 293 cells after cotransfection of the cells with a luciferase NF-κB–responsive element and mutant or wild-type (WT) NLRP12 expression plasmids. NF-κB activity was also evaluated 24 hours after stimulation with tumor necrosis factor α in monocytes from individual family members carrying the mutation. Furthermore, secretion of interleukin-1β (IL-1β), production of reactive oxygen species (ROS), and activation of antioxidant systems in patient and healthy donor monocytes, under resting conditions and after stimulation with pathogen-associated molecular patterns (PAMPs), were also assessed. Results In the family assessed, the p.D294E mutation segregated in association with a particular sensitivity to cold exposure (especially arthralgias and myalgia), but not always with an inflammatory phenotype (e.g., urticarial rash or fever). In vitro, the mutant protein maintained the same inhibitory activity as that shown by WT NLRP12. Consistently, NLRP12-mutated monocytes showed neither increased levels of p65-induced NF-κB activity nor higher secretion of IL-1β. However, the kinetics of PAMP-induced IL-1β secretion were significantly accelerated, and high production of ROS and up-regulation of antioxidant systems were demonstrated. Conclusion Even with a variable range of associated manifestations, the extreme sensitivity to cold represents the main clinical hallmark in an individual carrying the p.D294E mutation of the NLRP12 gene. Although regulation of NF-κB activity is not affected in patients, redox alterations and accelerated secretion of IL-1β are associated with this mild autoinflammatory phenotype.

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Author and article information

Contributors

Pablo A. Ledesma: pledesma@mgh.harvard.edu

Juan Carlos Guerra: juancarlosguerra100@gmail.com

Manuel Burbano: m_burbanososa@hotmail.com

Patricio Procel: patricioprocel@gmail.com

Luis Alberto Pedroza: lpedroza@usfq.edu.ec

Journal

Journal ID (nlm-ta): J Med Case Rep

Journal ID (iso-abbrev): J Med Case Rep

Title: Journal of Medical Case Reports

Publisher: BioMed Central (London )

ISSN (Electronic): 1752-1947

Publication date (Electronic): 14 December 2019

Publication date PMC-release: 14 December 2019

Publication date Collection: 2019

Volume: 13

Electronic Location Identifier: 368

Affiliations

[1 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Massachusetts General Hospital, ; 55 Fruit St, Boston, MA 02114 USA

[2 ]ISNI 000000041936754X, GRID grid.38142.3c, Harvard Medical School, ; 25 Shattuck St, Boston, MA 02115 USA

[3 ]ISNI 0000 0000 9008 4711, GRID grid.412251.1, Universidad San Francisco de Quito, Escuela de Medicina, ; Diego de Robles, Cumbaya, 170901 Quito, Ecuador

[4 ]Hospital de los Valles, Av. Interoceanica km 12.5 y Av. Florencia, Quito, Ecuador

[5 ]ISNI 0000 0001 2160 926X, GRID grid.39382.33, Baylor College of Medicine, ; 1 Baylor Plaza, Houston, TX 77030 USA

Article

Publisher ID: 2305

DOI: 10.1186/s13256-019-2305-3

PMC ID: 6911267

PubMed ID: 31836009

SO-VID: a675a63d-da68-473d-85e5-e7dcaa8cb371

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 14 November 2018

Date accepted : 28 October 2019

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ScienceOpen disciplines: Medicine

Keywords: case report,whole exome sequencing,acute disseminated encephalomyelitis,adem,adem-on,optic neuritis,nlrp12,periodic fever syndrome,familial cold autoinflammatory syndrome,fcas2

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ScienceOpen disciplines: Medicine

Keywords: case report, whole exome sequencing, acute disseminated encephalomyelitis, adem, adem-on, optic neuritis, nlrp12, periodic fever syndrome, familial cold autoinflammatory syndrome, fcas2

Whole exome sequencing in a child with acute disseminated encephalomyelitis, optic neuritis, and periodic fever syndrome: a case report

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Abstract

Background

Case summary

Conclusion

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European Journal of Medical Case Reports (EJMCR)

Most cited references 19

Mutations in NALP12 cause hereditary periodic fever syndromes.

Clinical spectrum of 4H leukodystrophy caused by POLR3A and POLR3B mutations.

Clinical Presentation and Pathogenesis of Cold-Induced Autoinflammatory Disease in a Family With Recurrence of an NLRP12 Mutation

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