Autism spectrum disorder comorbid with obsessive compulsive disorder and eating disorder in a woman with NBEA deletion.
There is a high rate of comorbidity between autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD) and eating disorders (EDs). Furthermore, neuropsychological studies and genetic studies support the presence of shared background among these disorders.1-4 All of these findings suggest shared pathophysiology of these disorders. NBEA encodes neurobeachin and has been strongly implicated in ASD risk by the identification of de novo loss-of-function variants of this gene in multiple unrelated cases.5-7 Neurobeachin regulates recycling of GluN2B-NMDA receptors, and is involved in neurotransmission, synaptic formation and plasticity by a haploinsufficient genetic mechanism.8 Although we also identified an ASD patient with rare deletion disrupting this gene in a study of copy number variation (CNV),2 only limited knowledge was available about the clinical implications of NBEA deletion. It is important to accumulate high-quality case reports to improve the clinical management of patients with such CNVs. Therefore, we report a 10-year clinical course of an ASD patient with NBEA deletion, who had comorbidities of OCD, ED, and intellectual disability (ID). The patient was a 41-year-old Japanese female. Her father had a broad autism phenotype. During infancy, language developmental delay, insistence on the same clothes and foods, tactile hypersensitivity, and impairments in communication and social interactions were noticed. She had very little social contact with her peers throughout her school career. After she graduated from junior college, she had several part-time jobs but soon quit because of interpersonal conflicts in the workplace. Her developmental history is summarized in Table S1. At the age of 31, she had recurrent episodes of overeating and rapidly gained weight. In response to this sudden weight gain, she began to restrict her food intake. Thereafter, her body mass index (BMI) decreased to 12.3 from 21.1 kg/m2 in 6 months. She was hospitalized with a diagnosis of unspecified feeding or eating disorder according to the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5) diagnostic criteria. Additionally, during the hospitalization, she was diagnosed with ASD. Psychoeducation about ED and ASD and supportive psychotherapy were provided. Although she did not meet the diagnostic criteria for major depressive disorders, pharmacotherapy was initiated to target her depressive symptoms. Gradually, her food intake increased, her BMI recovered to 15.4 kg/m2, and she was discharged in 3 months. After regaining weight, overeating was observed, but improved after discontinuing olanzapine medication. The patient continued to receive outpatient treatment, but obsessive-compulsive symptoms with obsessive thoughts appeared. She developed compulsive behaviors such as hand or body washing, and she spent a lot of time performing such behaviors. She was diagnosed with OCD and received medication (selective serotonin reuptake inhibitors and atypical antipsychotics) and cognitive behavioral therapy, but the symptoms were intractable. Since her last hospitalization, her symptoms have been under control. The clinical time course is summarized in Fig. 1a. Her intelligence quotient score was 62 (Table S2). Array comparative genomic hybridization using NimbleGen 720k Whole-Genome Tiling Array detected a 447-kb deletion spanning exons 11–41 of NBEA2 (Fig. 1b,c). Parental CNV analysis revealed that NBEA deletion was paternally inherited (Fig. 1d). Gene expression analysis revealed that the NBEA mRNA expression level was reduced below the 15th percentile of the control group (N = 29) (Fig. 1e, Appendix S1). We reported an ASD patient with OCD, ED, ID, and NBEA deletion. Neuropsychological studies support the presence of shared traits among ASD, OCD, and EDs.1 As shown in Table S2, ASD patients with NBEA deletion have been reported.6, 7 This is the first case report of an adult with NBEA deletion. Though previously reported cases did not mention OCD and EDs, these patients had not reached the peak age of onset of these disorders. Heterozygous Nbea knockout mice exhibit not only autistic behaviors but also impaired extinction of contextual fear memory, which is associated with OCD, and abnormal feeding behavior, episodically overconsuming tastants.9, 10 Thus, the clinical phenotypes of the patient were similar to those of heterozygous Nbea knockout mice, raising the possibility that exonic NBEA deletion was responsible for the symptoms in this patient. As Nbea knockout mice show hyperphagia, patients with NBEA deletion may be more prone to episodic overeating. The patient we reported showed rapid weight gain during olanzapine medication. Choosing medicines carefully and monitoring weight are important. In conclusion, NBEA deletion may be a shared genetic underpinning of ASD, OCD, and EDs. The accumulation of clinical data of patients with NBEA deletion including the present case may contribute to establishment of appropriate clinical management of these patients in the future. We thank the patient and her family members for participating in this study. We also thank Mami Yoshida, Kiyori Monta, and Yukari Mitsui for their technical assistance. This research was supported by research grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT) and the Ministry of Health, Labour and Welfare of Japan; the Japan Agency for Medical Research and Development (AMED) under Grant Nos. JP20dm0107087, JP21wm0425007, JP21dm0207075, JP21ak0101113, JP21dk0307075, JP20dk0307081, JP21dk0307103, JP21ek0109488, JP21km0405216, and JP21ek0109411; the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Nos. 17H05090, 15K19720, 18H04040, 21K07543, 21H00194, 21H04815, and 20K20602; the Uehara Memorial Foundation; and the SENSHIN Medical Research Foundation. H.K., I.K., A.Y., K.I., K.I., and B.A. declare no conflict of interest. N.T. has received research support or speakers' honoraria from, or has served as a consultant to, Otsuka, Shionogi, Takeda, Janssen, and Pfizer, outside the submitted work. T.O. has received lecture fees from Shionogi and Mochida, outside the submitted work. N.O. has received research support or speakers' honoraria from, or has served as a consultant to, Sumitomo Dainippon, Eisai, Otsuka, KAITEKI, Mitsubishi Tanabe, Shionogi, Eli Lilly, Mochida, DAIICHI SANKYO, Nihon Medi-Physics, Takeda, Meiji Seika Pharma, EA Pharma, Pfizer, MSD, Lundbeck Japan, Taisho Pharma, outside the submitted work. This study was approved by the ethics committee of the Nagoya University Graduate School of Medicine and this study complied with all the provisions of the Declaration of Helsinki. The patient and her parents gave written informed consent for genetic testing and publishing of this report. Appendix S1. Supplementary Appendix. Methods of gene expression analysis Appendix S2. Author Contributions Table S1. Time course of the patient's developmental history. Table S2. Clinical summary of cases with NBEA deletion Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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