Nodding syndrome (NS) is a devastating and enigmatic childhood epilepsy. NS is accompanied by multiple neurological impairments and neuroinflammation, and associated with the parasite Onchocerca volvulus (Ov) and other environmental factors. Moreover, NS seems to be an 'Autoimmune Epilepsy' since: 1.~50% of NS patients have neurotoxic cross-reactive Ov/Leimodin-I autoimmune antibodies. 2. Our recently published findings: Most (~86%) of NS patients have glutamate-receptor AMPA-GluR3B peptide autoimmune antibodies that bind, induce Reactive Oxygen Species, and kill both neural cells and T cells. Furthermore, NS patient's IgG induce seizures, brain multiple damage alike occurring in brains of NS patients, and elevation of T cells and activated microglia and astrocytes, in brains of normal mice. Human Leukocyte antigen (HLA) class I and II molecules are critical for initiating effective beneficial immunity against foreign microorganisms and contributing to proper brain function, but also predispose to detrimental autoimmunity against self-peptides. We analyzed seven HLA loci, either by next-generation-sequencing or Sequence-Specific-Oligonucleotide-Probe, in 48 NS patients and 51 healthy controls from South Sudan. We discovered that NS associates significantly with both protective HLA haplotype: HLA-B*42:01, C*17:01, DRB1*03:02, DQB1*04:02 and DQA1*04:01, and susceptible motif: Ala24, Glu63 and Phe67, in the HLA-B peptide-binding groove. These amino acids create a hydrophobic and sterically closed peptide-binding HLA pocket, favoring proline residue. Our findings suggest that immunogenetic fingerprints in HLA peptide-binding grooves tentatively associate with protection or susceptibility to NS. Accordingly, different HLA molecules may explain why under similar environmental factors, only some children, within the same families, tribes and districts, develop NS, while others do not.

A 30-year-old woman was referred to our medical center for amniocentesis in her first pregnancy due to sex discordance in monochorionic twins. The pregnancy was spontaneous, and a first-trimester ultrasound demonstrated monochorionic diamniotic twins (Supp. Fig. S1). Nuchal translucency was normal for both fetuses (1.1 and 1.3 mm). An anomaly scan at the 17th gestational week revealed both female and male fetuses without malformations (Fig. 1A). At this point, a double amniocentesis was performed for single nucleotide polymorphism (SNP) array (Affymetrix, Santa Clara, CA, USA) that revealed dizygotic twins, female and male with normal karyotypes. Short tandem repeat analysis supported dizygosity (Supp . Table S1). However, human leukocyte antigen (HLA) typing was similar for both twins (Supp . Table S2). At the 34th week of gestation, an emergency cesarean delivery was performed due to twin anemia polycythemia syndrome. A girl and a boy were delivered, weighing 2150 g and 2130 g with hemoglobin 21.8 g/dL and 10.2 g/dL respectively. External genitalia were defined as normal by an experienced pediatric endocrinologist, and an ultrasound of the female pelvis demonstrated a uterus. Cord blood revealed chimerism in both twins, as the karyotype of the male contained five cells with 46,XX out of 30 analyzed (17%). However, buccal smear fluorescence in situ hybridization (FISH) analysis did not reveal chimerism. Karyotype analysis of the female's blood demonstrated 27% chimerism (8/30 cells), whereas buccal smear FISH revealed 1% chimerism (5/405). Gross and microscopic examination of the placenta revealed a monochorionic diamniotic structure (Fig. 1B).Two-year follow-up eventually proved persistent chimerism in both twins. The male had 3% chimerism for 46,XX cells (7/200) and the female had 5% chimerism for 46,XY cells (7/139) from buccal smear.The present study describes non-confined blood chimerism in monochorionic dizygotic twin (MCDZ) twins with an excellent outcome in the first two years. The rare phenomenon of MCDZ twins and blood chimerism has been described both in cattle and humans. 1 Few reports have demonstrated fusion-susceptibility following artificial reproductive techniques, 2 but spontaneous MCDZ pregnancies like the one seen in this study have also rarely been described. Uncertainties accompany such pregnancies, because placental anastomoses might expose the female fetus to blood products of the male such as anti-Müllerian hormone and androgens that might masculinize Müllerian derivatives (freemartin effect), such as has been described in cattle. Details regarding human female development under such circumstances are distinctly lacking. There is one case reporting freemartinism in a female with trisomy 21, 3 but all other 30 cases are of a twin female with normal inner and outer genitalia. 4 The present case is another example of good outcome for both twins following meticulous pregnancy follow-up, without freemartinism despite chimerism. Follow-up through puberty and even throughout the life course is ...

Nodding syndrome (NS) is a catastrophic and enigmatic childhood epilepsy, accompanied by multiple neurological impairments and neuroinflammation. Of all the infectious, environmental and psychological factors associated with NS, the major culprit is Onchocerca Volvulus (Ov)–a parasitic worm transmitted to human by blackflies. NS seems to be an ’Autoimmune Epilepsy’ in light of the recent findings of deleterious autoimmune antibodies to Glutamate receptors and to Leiomodin-I in NS patients. Moreover, we recently found immunogenetic fingerprints in HLA peptide-binding grooves associate with protection or susceptibility to NS. Macrophage migration inhibitory factor (MIF) is an immune-regulatory cytokine playing a central role in modulating innate and adaptive immunity. MIF is also involved in various pathologies: infectious, autoimmune and neurodegenerative diseases, epilepsy and others. Herein, two functional polymorphisms in the MIF gene, a −794 CATT5–8 microsatellite repeat and a −173 G/C single-nucleotide polymorphism, were assessed in 49 NS patients and 51 healthy controls from South Sudan. We also measured MIF plasma levels in established NS patients and healthy controls. We discovered that the frequency of the high-expression MIF -173C containing genotype was significantly lower in NS patients compared to healthy controls. Interestingly however, MIF plasma levels were significantly elevated in NS patients than in healthy controls. We further demonstrated that the HLA protective and susceptibility associations are dominant over the MIF association with NS.Our findings suggest that MIF might have a dual role in NS. Genetically controlled high-expression MIF genotype is associated with disease protection. However, elevated MIF in the plasma may contribute to the detrimental autoimmunity, neuroinflammation and epilepsy.

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