Association of Diagnosis of Leukodystrophy With Race and Ethnicity Among Pediatric and Adolescent Patients
Association of Diagnosis of Leukodystrophy With Race and Ethnicity Among Pediatric and Adolescent Patients
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DOI：
10.1001/jamanetworkopen.2018.5031
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发表时间：
2018-11-01
影响因子：
13.8
通讯作者：
Stoddard, Greg
中科院分区：
文献类型：
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作者：
Bonkowsky, Joshua L.;Wilkes, Jacob;Stoddard, Greg
重要性 遗传性脑白质营养不良是一组影响髓磷脂的神经系统疾病，可导致严重的发病和死亡。及时、正确的诊断对于开始治疗、设计疾病筛查以及为患者和家属提供护理和指导非常重要。 目的 确定不同种族背景的脑白质营养不良诊断是否存在差异。 设计、设置和参与者 这项病例对照研究对 18 岁或以下被诊断患有 4 种脑白质营养不良（异染性脑白质营养不良、异染性脑白质营养不良、 2015 年 10 月 1 日至 2017 年 9 月 30 日期间，美国儿童医院协会儿科健康信息系统数据库中存在 X 连锁肾上腺脑白质营养不良、克拉伯病和 Hurler 病。 主要结果和措施 分析了脑白质营养不良的诊断和患者的种族背景。通过控制性别、保险类型、城市或农村状况、2010 年患者邮政编码的家庭收入中位数、住院天数和首次就诊年龄，获得了调整后的脑白质营养不良患病率估计值。使用 gnomAD 数据库确定了不同种族背景中 ABCD1、ARSA、GALC 和 IDUA 的致病性脑白质营养不良基因等位基因频率。 结果 在 557 名确诊患有脑白质营养不良的患者中（221 名 [40%] 女性；321 名非西班牙裔白人；54 名非西班牙裔黑人 [10%] 和 51 名白人 [9%]）西班牙裔；中位数[范围]年龄，7 [0-18]岁），非白人种族，包括非西班牙裔黑人、西班牙裔黑人。和西班牙裔白人，与没有脑白质营养不良的诊断有关。非西班牙裔白人患者脑白质营养不良诊断的校正患病率为每 10 万名患者 13.8 例（95% CI，10.6-17.9），而这一比例为 5.8（95% CI，3.8-8.9）和 2.4（95% CI，1.1-5.2）。在非西班牙裔黑人、西班牙裔黑人和西班牙裔白人患者中，每 100 000 人分别有 7.4 和 7.4 (95% Cl. 5.2-10.4)。诊断率的下降与儿科健康信息系统数据库中不同种族的频率不成比例。在拉丁裔和非洲裔人群中，检测到致病性脑白质营养不良基因等位基因的错义或功能丧失等位基因的频率相似或更高。例如，对于 ABCD1，拉丁裔或非洲裔的等位基因频率为 2.1 x 10(-5) 和 2.2 x 10(-5)，而欧洲非芬兰裔的等位基因频率为 1.4 x 10(-5)。 结论和相关性 少数种族/族裔患者，包括黑人、西班牙裔黑人和西班牙裔白人背景的患者，被诊断为患有脑白质营养不良。在拉丁裔或非洲裔人群中，脑白质营养不良疾病相关的等位基因频率相同或更高，这反对遗传创始人效应导致诊断率较低。这种诊断不足对新生儿筛查计划和治疗可及性产生影响，并可能反映出儿科神经系统和孤儿疾病中更普遍的问题。
IMPORTANCE Inherited leukodystrophies are a group of neurological diseases affecting myelin that cause significant morbidities and death. Timely and correct diagnosis is important for initiating treatment, designing disease screening, and offering care and guidance to patients and families.OBJECTIVE To determine whether there are disparities in leukodystrophy diagnosis in different racial backgrounds.DESIGN, SETTING, AND PARTICIPANTS This case-control study involved a retrospective review of patients aged 18 years or younger who were diagnosed with 1 of 4 leukodystrophies (metachromatic leukodystrophy, X-linked adrenoleukodystrophy, Krabbe disease, and Hurler disease) in the US Children's Hospital Association's Pediatric Health Information System database from October 1, 2015, through September 30, 2017.MAIN OUTCOMES AND MEASURES Leukodystrophy diagnosis and racial background of the patients were analyzed. Adjusted prevalence estimates of leukodystrophies were obtained by controlling for sex, insurance type, urban or rural status, 2010 median household income for patient zip code, number of inpatient days, and age at first visit. Pathogenic leukodystrophy gene allele frequencies in different racial backgrounds for ABCD1, ARSA, GALC, and IDUA were determined using the gnomAD database.RESULTS Of the 557 patients identified with a leukodystrophy (221 [40%] female; 321 [58%] white non-Hispanic, 54[10%] black non-Hispanic, and 51 [9%] white Hispanic; median [range] age, 7 [0-18] years), nonwhite race, including black non-Hispanic, black Hispanic. and white Hispanic, was associated with not having a leukodystrophy diagnosis. The adjusted prevalence for a leukodystrophy diagnosis in white non-Hispanic patients was 13.8 (95% CI, 10.6-17.9) per 100 000 patients, compared with 5.8 (95% CI, 3.8-8.9), 2.4 (95% CI, 1.1-5.2). and 7.4 (95% Cl. 5.2-10.4) per 100 000 in black non-Hispanic, black Hispanic, and white Hispanic patients, respectively. This reduced rate of diagnosis was out of proportion to the frequency of the different races in the Pediatric Health Information System database. Similar or higher frequencies of missense or loss-of-function alleles were measured in populations of Latino and African descent for the pathogenic leukodystrophy gene alleles. For example, for ABCD1, allele frequencies in those of Latino or African descent were 2.1 x 10(-5) and 2.2 x 10(-5), as compared with 1.4 x 10(-5) for those of European non-Finnish descent.CONCLUSIONS AND RELEVANCE Patients of racial/ethnic minorities, including those from black, black Hispanic, and white Hispanic backgrounds, were significantly less likely to be diagnosed with a leukodystrophy. Leukodystrophy disease-associated allele frequencies were the same or higher in populations of Latino or African descent, arguing against a genetic founder effect being responsible for the lower diagnosis rates. This underdiagnosis has implications for newborn screening programs and treatment access and may reflect a more widespread problem in pediatric neurological and orphan diseases.