Association of Diagnosis of Leukodystrophy With Race and Ethnicity Among Pediatric and Adolescent Patients
Authors: Joshua L. Bonkowsky, Jacob Wilkes, Tyler Bardsley, Veronica M. Urbik, Greg Stoddard
Journal: JAMA Network Open (2018)

<h3>Importance</h3> 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. <h3>Objective</h3> To determine whether there are disparities in leukodystrophy diagnosis in different racial backgrounds. <h3>Design, Setting, and Participants</h3> 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. <h3>Main Outcomes and Measures</h3> 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<i>ABCD1</i>,<i>ARSA</i>,<i>GALC</i>, and<i>IDUA</i>were determined using the gnomAD database. <h3>Results</h3> 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% CI, 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<i>ABCD1</i>, allele frequencies in those of Latino or African descent were 2.1 × 10<sup>−5</sup>and 2.2 × 10<sup>−5</sup>, as compared with 1.4 × 10<sup>−5</sup>for those of European non-Finnish descent. <h3>Conclusions and Relevance</h3> 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.