A proposed synergistic effect of and 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 established the diagnosis of HDLS in the family. No abnormalities in the expansion size of C9orf72 were detected. The concurrence of a recurrent mutation and a rare variant in , 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 variant and the mutation cosegregated with the BE-dementia-epilepsy phenotype in the family. In three additional HDLS patients without BE, no pathogenic variants in were detected.

CONCLUSIONS

We propose that synergistic genetic effects of and variants may exist and contribute to the development of the BE phenotype in HDLS. 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.