Vitamin D Status and Latitude Predict Brain Lesions in Adrenoleukodystrophy

Abstract Objectives Approximately 40% of boys with X‐linked adrenoleukodystrophy (ALD) develop inflammatory demyelinating brain lesions (cerebral ALD, cALD) and are at risk for death or severe disability. Risk factors for cALD are poorly understood. Our objective was to evaluate whether vitamin D status, which influences immune function, is associated with risk for cALD. Methods We used two independent cohorts to assess whether low vitamin D status is correlated with cALD. We used complementary proxies for vitamin D status: plasma 25‐hydroxyvitamin D levels and latitude. In our first cohort, we measured 25‐hydroxyvitamin D in biobanked plasma samples from ALD boys with initially normal brain MRIs followed at two expert centers. In a second cohort, we measured latitude (using home ZIP code) among ALD boys identified in a national administrative database (PHIS) covering 51 US pediatric hospitals. We used logistic regression models to estimate the odds of developing cALD in each cohort. Results In the first cohort, we identified 20 ALD boys with a total of 53 plasma sample timepoints who met inclusion criteria; 50% (n = 10) subsequently developed cALD. Average 25‐hydroxyvitamin D levels were lower among boys who developed cALD than those who did not (median 28.9 vs 36.6 ng/ml); p = 0.019. For each 10 ng/mL decrease in 25‐hydroxyvitamin D, the odds ratio for developing cALD was 6.94; p = 0.044. In the second cohort, we identified 230 ALD boys across 28 states; 57% of boys (n = 132) developed cALD. Each 2° increase in latitude conferred an odds ratio of 1.17 (95% confidence interval, 1.01, 1.35); p = 0.036 for developing cALD. Conclusions Using independent cohorts, we found that ALD boys with lower pre‐morbid plasma levels of 25‐hydroxyvitamin D, or more northerly latitude of residence, were more likely to develop cALD. These findings offer complementary lines of evidence that vitamin D and/or ultraviolet light exposure influence cALD risk.