Lutter Michael
Precision Psychiatry, 8105 Rasor Blvd #235, Plano, TX, 75024, USA.
J Eat Disord. 2025 Jul 15;13(1):140. doi: 10.1186/s40337-025-01323-w.
People with anorexia nervosa (AN) exhibit a strong aversion to eating calorically dense foods, especially those high in fat. It has previously been reported that these patients display altered metabolism of fatty acids, however it is unclear if these metabolic disturbances represent a primary biological substrate underlying predisposition to restrictive eating behaviors or occur secondarily to malnutrition.
We report the frequency of rare (minor allele frequency < 1%), damaging (CADD > 15) mutations in the BBOX1 gene of 183 patients with anorexia nervosa who received whole exome sequencing (WES) as part of their psychiatric evaluation. The observed frequency from our cohort was then compared to the rate of rare, damaging mutations in BBOX1 reported in the gnomAD database to determine if there was an excessive burden of damaging mutations.
The 11-27127338-G-A single nucleotide polymorphism in BBOX1 was observed to be shared by four sisters with a history of AN. Subsequent analysis found that this variant was also present in five out of 182 patients who had WES results. Six more unrelated patients out of 182 were found to have one of five additional rare, damaging mutations in BBOX1. In total, 12 out of 183 patients (6.6%) with AN were found to have a rare, damaging mutation in BBOX1 compared to an expected count of 4.4 (2.4%) from the gnomAD database (odds ratio 2.86; p = 0.0117).
Patients with a history of AN have an increased burden of rare, damaging mutations in the BBOX1 gene. Because BBOX1 is required for synthesis of carnitine, a nutrient required for transport of long-chain fatty acids into the mitochondria for beta-oxidation, this finding suggests that impaired utilization of long-chain fatty acids may increase the risk of developing AN in a subset of patients. Identification of this group of patients by genetic or blood testing may lead to improved treatment outcomes and/or secondary prevention of relapse.
神经性厌食症（AN）患者对高热量食物，尤其是高脂肪食物表现出强烈的厌恶。此前有报道称，这些患者脂肪酸代谢发生改变，但尚不清楚这些代谢紊乱是限制饮食行为易感性的主要生物学基础，还是继发于营养不良。
我们报告了183例接受全外显子测序（WES）作为精神评估一部分的神经性厌食症患者中，BBOX1基因罕见（次要等位基因频率<1%）、有害（CADD>15）突变的频率。然后将我们队列中观察到的频率与gnomAD数据库中报告的BBOX1罕见有害突变率进行比较，以确定是否存在有害突变的过度负担。
观察到BBOX1基因中的11-27127338-G-A单核苷酸多态性在有神经性厌食症病史的四姐妹中共有。随后的分析发现，该变体也存在于182例有WES结果的患者中的5例中。在182例无关患者中，又有6例被发现有BBOX1基因另外5种罕见有害突变之一。在183例神经性厌食症患者中，共有12例（6.6%）被发现有BBOX1基因的罕见有害突变，而gnomAD数据库的预期数量为4.4例（2.4%）（优势比2.86；p=0.0117）。
有神经性厌食症病史的患者，BBOX1基因中罕见有害突变的负担增加。由于左旋肉碱的合成需要BBOX1，而左旋肉碱是长链脂肪酸转运到线粒体进行β氧化所需的一种营养素，这一发现表明长链脂肪酸利用受损可能会增加一部分患者患神经性厌食症的风险。通过基因检测或血液检测识别这组患者，可能会改善治疗效果和/或对复发进行二级预防。
