CASPR2 autoantibodies are raised during pregnancy in mothers of children with mental retardation and disorders of psychological development but not autism

Abstract

Background, methods and objectives: Maternal autoantibodies to neuronal proteins may be one cause of neurodevelopmental disorders. This exploratory study used the Danish archived midgestational sera and their nationwide registers to search for antibodies to the N-methyl-D-aspartate receptor (NMDAR) and contactin-associated protein-like 2 (CASPR2) in maternal sera, and to relate them to subsequent psychiatric diagnoses in the woman or her child.

Results: In a sample of 192 women, there was no association between antibody status and subsequent psychosis in the mothers. However, NMDAR antibodies (n=4) or CASPR2 antibodies (n=1) were identified in 5/11 (45.5%) women whose children were given a diagnosis of mild or unspecified mental retardation or disorders of psychological and motor development (collectively abbreviated as mental retardation and/or disorders of psychological development (MR/DPD)) compared with 9/176 (5.1%) of the remaining mother (p<0.001). These findings were followed up in a specifically selected cohort, in which CASPR2 antibodies were detected in 7/171 (4.1%) mothers of MR/DPD progeny, compared with only 1/171 (0.6%) control mother (p=0.067). The combined sample showed a significantly higher frequency of CASPR2 antibodies in mothers of MD/DPD children (p=0.01). These autoantibodies were not increased in mothers of children with autistic spectrum disorder.

Conclusions: These findings complement the known roles of CASPR2 in brain development, and warrant further epidemiological and experimental studies to clarify the role of CASPR2 and possibly other antibodies in neurodevelopmental disorders.

Keywords: CASPR2; antibodies; autism; intellectual disability.

Figure 1

(A) Representative photomicrographs of the cell binding of a CASPR2-positive and a CASPR2-negative sample in the live cell-based assay (serum dilution 1:100; score 1.5). Scale bar: 20 µm. (B) CASPR2 antibody binding scores (0–4; negative <1) in mothers of children with MR/DPD and control mothers (combined results of cohorts A and B) and in mothers of children with ASD and control mothers (cohort C). CASPR2 antibodies were five times more common in mothers of children given a diagnosis of MR/DPD, but not different between mothers of children with ASD and control mothers. Endpoint dilution antibody titres were generally low to modest, 1:100 (screening dilution) to 1:300, consistent with the scores shown. ASD, autism spectrum disorder; CASPR2, contactin-associated protein-like 2; MR/DPD, mental retardation and/or disorders of psychological development.