A proposed synergistic effect of CSF1R and NMUR2 variants contributes to binge eating in hereditary diffuse leukoencephalopathy with spheroids.

BACKGROUND: The genetic mechanisms of binge eating (BE) as a disease identity remain obscure. BE is usually viewed as a part of the behavioral variant of frontotemporal dementia (bvFTD) features. We encountered a family with hereditary diffuse leukoencephalopathy with spheroids (HDLS) that manifested uniformly with binge-eating-onset dementia. The genetic factors associated with the rare phenotype were investigated.
METHODS: The detailed phenotypes of the patients were described. We performed whole-exome sequencing (WES) of family members and repeat-primed PCR to analyze the patients' expansion size of C9orf72, a well-established gene causing FTD. The WES results of additional HDLS patients without BE manifestations were also investigated.
RESULTS: All affected individuals had a BE-dementia-epilepsy pattern of disease progression. A recurrent disease-causing mutation in CSF1R established the diagnosis of HDLS in the family. No abnormalities in the expansion size of C9orf72 were detected. The concurrence of a recurrent CSF1R mutation and a rare variant in NMUR2, a gene functionally related to BE, was revealed in the affected family members. No potentially pathogenic variants in other known BE-associated genes were identified. Both the NMUR2 variant and the CSF1R mutation cosegregated with the BE-dementia-epilepsy phenotype in the family. In three additional HDLS patients without BE, no pathogenic variants in NMUR2 were detected.
CONCLUSIONS: We propose that synergistic genetic effects of NMUR2 and CSF1R variants may exist and contribute to the development of the BE phenotype in HDLS. NMUR2 is one of the potential susceptible genes in BE and may contribute in a background of a disrupted structural neuronetwork. Further studies in other BE-related disorders are required. 2020 Annals of Translational Medicine. All rights reserved.