Congenital Zika syndrome with arthrogryposis: retrospective case series studyBMJ 2016; 354 doi: https://doi.org/10.1136/bmj.i3899 (Published 09 August 2016) Cite this as: BMJ 2016;354:i3899
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We welcome the paper by van der Linden et al published in the August 9th issue reporting an analysis of seven cases of congenital Zika syndrome (CZS) with arthrogryposis in which neurophysiological and neuro-imagery investigations were completed . Based on mounting evidence that Zika virus (ZIKV) infection during the early stages of gestation causes severe brain damage and brainstem dysfunction and convincing observations in agreement, it is fair and safe to propose that ZIKV-associated arthrogryposis disorders may be neurogenic. In line with this pathogenesis, the alleged mechanisms underlying the CZS phenotype would be a direct tropism of the virus to neuronal cells in all stages of maturity (neural stem cells, neural progenitor cells, cortical neurons) [2, 3] or vascular disorders, as it has been proposed for the foetal brain disruption sequence observed in Brazilian cohorts and case reports (whose ZIKV-associated microcephaly is the most eloquent element) . As a result, the multiple joint contractures defining the arthrogryposis syndrome would be primarily the consequence of motor end plate, lower motor neuron or muscle injuries.
We suggest that this latter deduction is too restrictive. First because, as suggested by the authors, “arthrogryposis is not a specific diagnosis, but a clinical finding” and it is a feature of more than 400 aetiologies and variants of more than 220 genes have been associated with these disorders . Second, because when the authors report the occurrence of arthrogryposis in the setting of a new congenital syndrome fated to be revisited, it is based on the universe of notified cases with microcephaly or severe neurological findings referred to hospital rather than in the population of all exposed neonates, which is likely the consequence of a detection bias . In this framework, rather than selecting candidate genes to explain the mechanism of central nervous system malformations, we conducted a non-systematic review of the genes found dysregulated in the four distinct arthrogryposis patterns (amyoplasia or arthrogryposis multiplex congenita, distal arthrogryposis, central nervous system and muscular causes of arthrogryposis) and sought whether they could be also dysregulated in the target cells of two recent in vitro models of ZIKV infection [2, 3]. Of the arthrogryposis-related genes published over the last 5-year period, we found 48 genes (24 upregulated and 24 down-regulated) also dysregulated in ZIKV-infected cells (Supplementary File (C.doc, attached)). With respect to the multitude of manifestations associated with these genes and their multiple related aetiologies and variable host susceptibility, we conceive that ZIKV driven gene dysfunctions may cause a broader clinical phenotype than initially observed. This clinical phenotype would be the sum of all the gene interactions within the host genetic background under the challenge of ZIKV infection reaching a pathological threshold to cause a disease manifestation.
Far beyond the possibility of brain abnormalities in normal sized head babies reported from Brazil , another substantive fact arguing against the exclusive neurological origin of ZIKV-associated arthrogryposis is the report from Panama, Colombia and French West Indies of foetal anaemia, genitourinary, cardiac, digestive, and hepatic system involvement, which enlarges considerably the putative spectrum of CZS with the possibility of other syndromic associations and underlying pathogenic processes to be involved [8, 9]. Accordingly, WHO experts, Wellcome Trust stakeholders and Swiss perinatal researchers have claimed for effective data sharing through different initiatives, including the creation of a registry for women exposed to ZIKV during pregnancy and improvement of pre-existing congenital birth defects registries capacities [10, 11]. The report of arthrogryposis disorders, along with these new findings should request the same attention that paid for ZIKV-associated microcephaly . More than ever, it is time for a global action on the ZIKV epidemic  and a movement from case series and epidemiological correlations to case-control and cohort studies to strengthen our insight and pave the way for mechanistic studies. In this goal, we propose a workflow (Figure) to scrutinize the genes found dysregulated in experimental studies to generate insights that may help maternity clinicians to deal with the “new manifestations” of congenital ZIKV infection. This assimilation effort in daily practice of the most recent translational research advances from the bench of highly skilled laboratories to the bed of nurseries, along with the increased power of observational capacities through data sharing, will allow delineation of the extent of the spectrum of the congenital Zika syndrome.
Patrick Gérardin,1,2,3* Hanitra Randrianaivo,1,4 Bruno Schaub,5 Raymond Césaire,6 Bérénice Doray,4,7 A. Désirée LaBeaud8
1 CHU Réunion, Pôle Femme Mère Enfant, Saint Pierre, Reunion, France, 2 INSERM CIC 1410, Saint Pierre, Reunion, 3 Université de La Réunion, CNRS 9192, INSERM U1187, IRD 249, CHU Réunion, Unité Mixte 134 Processus Infectieux en Milieu Insulaire Tropical (PIMIT), Plateforme Technologique CYROI, Sainte-Clotilde, Reunion, France, 4 Eurocat/JRC-affiliated Registry of Congenital Birth Defects, Saint Pierre, Reunion, France, 5 CHU de Martinique, Centre Pluridisciplinaire de Diagnostic Prénatal, Fort de France, French West Indies, France 6 CHU de Martinique, Laboratoire de Virologie, Fort de France, French West Indies, France 7 CHU Réunion, Service de Génétique, Saint Denis, 8 Stanford School of Medicine, Division of Pediatric Infectious Diseases, Palo Alto, California, USA.
* Correspondence to: Dr Patrick Gérardin, M.D., Ph.D
Service de Néonatologie, Réanimation Néonatale et Pédiatrique,
Groupe Hospitalier Sud Réunion, Centre Hospitalier Universitaire
BP 350, 97448 Saint Pierre Cedex - Reunion
E-mail : firstname.lastname@example.org
1. Vanessa van der Linden, Filho EL, van der Linden A, et al. Congenital Zika syndrome with arthrogryposis: retrospective case series study. BMJ. 2016; 354 doi: http://dx.doi.org/10.1136/bmj.i.38993. [Epub ahead of print].
2. Tang H, Hammack C, Ogden SC, et al. Zika virus infects human cortical neural progenitor cells and attenuates their growth. Cell Stem Cell 2016; 18: 587-90.
3. Dang J, Tiwari SK, Lichinchi G, et al. Zika virus depletes neural progenitors in human cerebral organoïds through the activation of the innate immune receptor TLR3. Cell Stem Cell 2016; 19: 258-65.
4. Culjat M, Darling SE, Nerurkar VR, et al. Clinical and imaging findings in an infant with Zika embryopathy. Clin Infect Dis 2016 May 18 pii: ciw324 [Epub ahead of print].
5. Bayram Y, Karaca E, Coban Akdemir Z, et al. Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin. J Clin Invest 2016; 126: 762-78.
6. Miranda-Filho DdB, Turchi-Martelli CM, Ximenes RAA, et al. Inititial description of the presumed congenital Zika syndrome. Am J Public Health 2016; 106: 598-600.
7. França GV, Schuler-Faccini L, Oliveira WK, et al. Congenital Zika virus syndrome in Brazil: a case series of the first 1501 livebirths with complete investigation. Lancet 2016 Jun 29. pii: S0140-6736(16)30902-3. [Epub ahead of print].
8. Costello A, Dua T, Duran P, et al. Defining the syndrome associated with congenital Zika virus infection. Bull World Health Org 2016; 94: 406-406A.
9. Schaub B, Monthieux A, Najioullah F, Adenet C, Muller F, Césaire R. Zika virus: microcephaly and what? Ultrasound Obstet Gynecol 2016 Aug 3. doi: 10.1002/uog.17210. [Epub ahead of print].
10. The Welcome Trust. Global scientific community commits to sharing data on Zika. Feb 10, 2016. http://www.wellcome.ac.uk/News/Media-office/Press-releases/2016/WTP06016...
11. Panchaud A, Vouga A, Musso D, Baud D. An international registry for women exposed to Zika virus during pregnancy: time for answers. Lancet Infect Dis 2016, in press. doi:10.1016/S1473-3099(16)30255-9. https://epgl.unige.ch/Zika-in-pregnancy-registry/
12. Frank C, Faber C, Stark K. Causal or not: applying the Bradford Hill aspects of evidence to the association between Zika virus and microcephaly. Embo Mol Med 2016; 8: 305-7.
13. Lucey DR. Time for global action on Zika virus epidemic. BMJ 2016; 352: i781. doi 1136/bmj.i781.
Movement from clinical and experimental observations to the new definition of the congenital Zika syndrome.
Competing interests: No competing interests
The authors have thrown a light on the association between Congenital Zika Syndrome & arthrogryposis. The term arthrogryposis is often used as shorthand to describe multiple congenital contractures that affect two or more different areas of the body. Arthrogryposis is not a specific diagnosis, but rather a clinical finding. Arthrogryposis can be classified depending upon whether the child has normal or abnormal neurological function. A normal neurological examination suggests that arthrogryposis is due to amyoplasia, a distal arthrogryposis, a generalized connective tissue disorder, or fetal crowding. In contrast, an abnormal neurological examination indicates that movement in utero was diminished as a result of an abnormality of the central or peripheral nervous system, the motor end plate, or muscle.
Developmental abnormalities affecting the forebrain (e.g., hydranencephaly, microcephaly, or forebrain neuronal migration disorders), whether due to primarily genetic factors or as a consequence of fetal central nervous system infection, are sometimes associated with arthrogryposis. In most such cases, joint contractures are probably due to diminished corticospinal tract activation of spinal cord motor neurons. Thus in the present retrospective case-series study, the authors have studied this association of fetal CNS infection from zika virus1.
Zika virus is an intensely neurotropic virus that particularly targets neural progenitor cells but also to a lesser extent neuronal cells in all stages of maturity. Viral cerebritis can disrupt cerebral embryogenesis and result in microcephaly and other neurological abnormalities.The spatiotemporal association of cases of microcephaly with the Zika virus outbreak and the evidence emerging from case reports and epidemiologic studies have led to a strong scientific consensus that Zika virus is implicated in congenital abnormalities.2
The authors have tried to expand the spectrum of congenital malformations in a short case series that could be associated with intrauterine Zika virus infection, thus broadening the term as congenital zika syndrome rather zika virus infection alone. In order to relate arthrogryposis with solely congenital zika syndrome much more evidence is required so as to rule out arthrogryposis in other similar viral infections caused by Aedes aegypti mosquitoes like dengue and chikungunya.
As the authors rightly pointed out, the sample studied is inadequate for studying neurological abnormalities behind arthrogryposis. Thus, further research is required to study the association of arthrogryposis in solely congenital zika syndrome.
1. Arthrogryposis: A Review and Update. Michael Bamshad, MD; Ann E. Van Heest, MD; David Pleasure, MD,J Bone Joint Surg Am, 2009 Jul 01; 91 (Supplement 4): 40 -46 . http://dx.doi.org/10.2106/JBJS.I.00281
2.Bulletin of the World Health Organization 2016;94:406-406A. doi: http://dx.doi.org/10.2471/BLT.16.176990
1Dr Swati Sharma, Dr L.Satyanarayana2, Dr Smitha Asthna3
1 Associate Professor, Department of Public Health Dentistry, School of Dental Sciences, Sharda University, Greater Noida, UP, India
2 Sr.Scientist G, NICPO, NOIDA
3 Sr.Scientist D, NICPO,NOIDA
Competing interests: No competing interests
Zika virus is a severely pathogenic virus causing many brain malformations, several birth defects and many neurological problems, including microcephaly in neonates. Two mechanisms hav been postulated for the development of central nervous malformations due to zika virus.
Zika virus activates the TLR3 (Toll Like Receptor 3) molecule normally used to defend against invading viruses in human cells.Then this hyper-activated TLR3 turns off genes that stem cells need to specialise into brain cells and turns on genes that trigger cell cell death, leading to various brain malformations. If this mechanism is proved, it will help to develop new therapies like TLR3 inhibitors against zika virus infection associated brain malformations.
The second possible mechanism by which zika viral infection causes brain malformations in the fetuses of zika virus infected women is interference with retinoic acid signaling by introducing its genome sequence repeats (called Retinoic Acid Response Elements or simply RARE consensus repeats) into the developing brain cells of the fetus. Retinoic acid (a metabolite of vitamin A) is one of the earliest factors for regulating the anteroposterior axis of neural tube and positioning of structures in the developing brain through RARE consensus sequence in promoter regions of retinoic acid-dependent genes.
Based on this, it may be helpful to design vaccines and other newer and effective treatments against zika viral infection and its complications in the near future.
Competing interests: No competing interests