Autoantibodies against Folate Receptors in Women with a Pregnancy Complicated by a Neural-Tube Defect

Rothenberg, Sheldon P.; Costa, Maria Pia; Sequeira, Jeffrey M.; Cracco, Joan B.; Roberts, Jaclyn L.; Weedon, Jeremy; Quadros, Edward V.

doi:10.1056/nejmoa031145

Cited by 205 publications

(159 citation statements)

References 27 publications

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“…This suggested that if the AuAbs to the FR in women with NTD pregnancy are contributing to the fetal abnormalities, these could be rescued by folinic acid treatment. Subsequent analysis of human serum samples demonstrated the presence of FR α AuAbs in women with a history of an NTD pregnancy [ 8 ]. The properties of these antibodies were confirmed by the high-affinity binding to FR α ( K a = 10 9 -10 10 L/mol) and by their ability to block folate uptake in FR α -expressing KB cells in culture [ 8 ].…”

Section: Discovery Of Fr α Auabsmentioning

confidence: 96%

“…The benefits of folate supplementation in the absence of systemic folate deficiency or genetic abnormalities of folate pathways have not been adequately explained. The identification of FR autoantibodies (AuAbs) in women with a history of NTD pregnancy provides a mechanism by which the developing embryo could be deprived of folate [ 8 ]. Although the cause of this autoimmune disorder in mothers remains unknown, the AuAb directed against the FR α could disrupt folate transport to the fetus.…”

Section: Introductionmentioning

confidence: 99%

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The diagnostic utility of folate receptor autoantibodies in blood

Sequeira

Ramaekers

Quadros

2013

Clinical Chemistry and Laboratory Medicine

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Folate supplementation reduces the risk of neural tube defect (NTD) pregnancy, and folinic acid has been used to correct cerebral folate deficiency (CFD) in children with developmental disorders. In the absence of systemic folate deficiency, the discovery of autoantibodies (AuAbs) to folate receptor α (FR α ) that block the uptake of folate offers one mechanism to explain the response to folate in these disorders. The association of FR α AuAbs with pregnancy-related complications, CFD syndrome, and autism spectrum disorders and response to folate therapy is highly suggestive of the involvement of these AuAbs in the disruption of brain development and function via folate pathways. The two types of antibodies identified in the serum of patients are blocking antibody and binding antibody. The two antibo dies can be measured by the specific assays described and exert their pathological effects either by functional blocking of folate transport as previously shown or hypothetically by disrupting the FR by an antigen-antibody-mediated inflammatory response. We have identified both IgG and IgM AuAbs in these conditions. The predominant antibodies in women with NTD pregnancy belong to the IgG1 and IgG2 isotype and in CFD children, the IgG1 and IgG4 isotype. This review describes the methods used to measure these AuAbs, their binding characteristics, affinity, cross-reactivity, and potential mechanisms by which folate therapy could work. Because these AuAbs are associated with various pathologies during fetal and neonatal development, early detection and intervention could prevent or reverse the consequences of exposure to these AuAbs.

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Section: Discovery Of Fr α Auabsmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

The diagnostic utility of folate receptor autoantibodies in blood

Sequeira

Ramaekers

Quadros

2013

Clinical Chemistry and Laboratory Medicine

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“…187 This suggests that folate transfer to the fetus during pregnancy may be blocked, which may increase risk of neural tube defects. 188 Because these elevated autoantibodies were also present in at least one parent of children with autism, parental antibodies may contribute to autism etiology. 189 Two cohort studies and a case-control study found an association between maternal or family history of autoimmune diseases and ASD 124,190 or autistic regression, 191 whereas another case-control study found no association.…”

Section: Autoimmune Diseasesmentioning

confidence: 99%

Environmental factors associated with autism spectrum disorder: a scoping review for the years 2003–2013

Montigny

Ofner

et al. 2017

Health Promot Chronic Dis Prev Can

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Introduction: The number of children diagnosed with autism spectrum disorder (ASD) has been rapidly rising in the past decade. The etiology of this disorder, however, is largely unknown, although the environmental relative to the genetic contribution is substantial. We conducted a scoping review to comprehensively assess the current state of knowledge of the environmental factors present from preconception to early life associated with ASD, and to identify research gaps.

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“…Recently, Rothenberg et al 22 reported the presence of auto-antibodies to the folate receptor in 75% of mothers who had given birth to NTD-affected infants, but in only 10% of mothers of non-malformed infants. This discrepancy in frequency correlated with a greater than 25-fold increase in the risk of NTDs in the infants of mothers that carried these antibodies.…”

Section: Folic Acid Prevents Neural Tube Defectsmentioning

confidence: 99%

Neural tube defects and folate: case far from closed

Shaw²,

et al. 2006

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Neural tube closure takes place during early embryogenesis and requires interactions between genetic and environmental factors. Failure of neural tube closure is a common congenital malformation that results in morbidity and mortality. A major clinical achievement has been the use of periconceptional folic acid supplements, which prevents ~50-75% of cases of neural tube defects. However, the mechanism underlying the beneficial effects of folic acid is far from clear. Biochemical, genetic and epidemiological observations have led to the development of the methylation hypothesis, which suggests that folic acid prevents neural tube defects by stimulating cellular methylation reactions. Exploring the methylation hypothesis could direct us towards additional strategies to prevent neural tube defects.Neural tube defects (NTDs) are complex congenital malformations of the CNS. Anencephaly and spina bifida are the most common and severe forms of NTD, with a prevalence of about 1 in 1,000 births, although this varies throughout the world 1 . Infants with anencephaly are stillborn or die shortly after birth, whereas infants with spina bifida can survive but are likely to have severe lifelong disabilities and are at risk of psychosocial maladjustment. The estimated lifetime medical costs are high; for example, in California, USA, the costs for children born with spina bifida exceed US$81 million per year 2 .It has been known for more than 20 years that women can reduce their risk of having an NTDaffected pregnancy by taking folic acid supplements. However, the underlying mechanisms byCorrespondence to H.J.B. H.Blom@cukz.umcn.nl. Competing interests statementThe authors declare no competing financial interests. DATABASES NIH Public Access Author ManuscriptNat Rev Neurosci. Author manuscript; available in PMC 2010 November 2. Neurulation and neural tube defectsNeurulation has long fascinated scientists, as evidenced by a devoted literature that extends back hundreds of years. The process of neurulation occurs during early embryogenesis, starting with the formation of the neural plate from specialized ectodermal cells and culminating in the closure of the neural tube (FIG. 1), the precursor of both the CNS and most of the PNS. Considered most simply, the neural plate develops bilateral neural folds, which elevate and fuse at the midline to create the neural tube. Subsequent development, together with vesiculation within the tube, gives rise to the brain and spinal cord. Further details of this complex process are beyond the scope of this review (for reviews, see REFS 4,5 ).Neurulation seems to be highly complex and tightly regulated. The development and closure of the neural tube is usually completed by 28 days post-conception. This means that by the time a woman finds out that she is pregnant, the neural tube is almost completely closed. For the neural tube to close properly, genes that regulate various morphogenetic activities must function cooperatively. These activities include programmed cell death, neural crest...

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Autoantibodies against Folate Receptors in Women with a Pregnancy Complicated by a Neural-Tube Defect

Cited by 205 publications

References 27 publications

The diagnostic utility of folate receptor autoantibodies in blood

The diagnostic utility of folate receptor autoantibodies in blood

Environmental factors associated with autism spectrum disorder: a scoping review for the years 2003–2013

Neural tube defects and folate: case far from closed

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