ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This retrospective chart review included 116 patients aged 0 to 17 y (M:F 94%:6%) with X-linked adrenoleukodystrophy (ALD) managed in one expert medical center from 2006 to 2022. It assessed the impact of newborn screening (which began in the U.S. in 2013 based on measurement of a lysophosphatidylcholine derivative of a very long chain fatty acid (VLCFA) C26:0-LPC, followed if abnormal by ABCD1 gene sequencing), on the age and presentation of adrenal insufficiency (AI) in ALD. AI was detected in 80% of males and most often before age 10 y. All patients were either on maintenance and/or stress dose glucocorticoid treatment.

Newborn screening (NBS) accounted for 31 patients (27%; M:F 26:5). Age at ALD diagnosis decreased with time, and was younger in those diagnosed by NBS (NBS vs. non-NBS diagnosis: 28% vs. 4% by age 1 y; 47% vs. 19% by age 3 y). Mean time to AI detection was shorter in patients diagnosed by NBS (3.9 y) than in those with non-NBS diagnosis (7.1 y). The overall prevalence of AI was 74%. Of these, 51% had symptomatic AI and 41% had latent AI (4% had insufficient data, all with later diagnosis). Of interest, 13 were diagnosed with AI prior to their diagnosis of ALD.

In all patients who developed AI, the median time to transition from stress to maintenance glucocorticoid treatment was 1.46 y. There was a trend to younger glucocorticoid transition in the NBS diagnosis group, likely due to current recommendations for repeated AI screening in ALD patients¹. When maintenance glucocorticoid treatment was initiated, both ACTH and peak cortisol levels were lower in patients diagnosed by NBS, although median values were abnormal in both NBS and non-NBS diagnosis groups.

Many unknowns remain. There is insufficient understanding of the genotype-phenotype relationships. Controversy exists concerning the management of positive NBS findings in females. While women with ALD develop myelopathy (typically at an older age than men), adrenal insufficiency and cerebral ALD are fortunately very rare². Finally, future studies should consider the inclusion of other forms of peroxisomal disorders in NBS. Recent data suggests that Zellweger Spectrum Disorder can be picked up in ALD screening programs; such patients also are at risk of AI but their natural history is not yet fully predictable or understood^3,4.

References: 1. Engelen M, van Ballegoij WJC, Mallack EJ, Van Haren KP, Köhler W, Salsano E, van Trotsenburg ASP, Mochel F, Sevin C, Regelmann MO, Tritos NA, Halper A, Lachmann RH, Davison J, Raymond GV, Lund TC, Orchard PJ, Kuehl JS, Lindemans CA, Caruso P, Turk BR, Moser AB, Vaz FM, Ferdinandusse S, Kemp S, Fatemi A, Eichler FS, Huffnagel IC. International Recommendations for the Diagnosis and Management of Patients With Adrenoleukodystrophy: A Consensus-Based Approach Neurology. 2022 Nov 22;99(21):940-951. doi: 10.1212/WNL.0000000000201374.2. Kemp S, Huffnagel IC, Linthorst GE, Wanders RJ, Engelen M. Adrenoleukodystrophy - neuroendocrine pathogenesis and redefinition of natural history. Nat Rev Endocrinol. 2016 Oct;12(10):606-15. doi: 10.1038/nrendo.2016.90.3. Mares Beltran CF, Tise CG, Barrick R, Niehaus AD, Sponberg R, Chang R, Enns GM, Abdenur JE. Newborn Screening for X-Linked Adrenoleukodystrophy (X-ALD): Biochemical, Molecular, and Clinical Characteristics of Other Genetic Conditions. Genes (Basel). 2024 Jun 26;15(7):838. doi: 10.3390/genes15070838.4. Bose M, Yergeau C, D’Souza Y, Cuthbertson DD, Lopez MJ, Smolen AK, Braverman NE. Characterization of Severity in Zellweger Spectrum Disorder by Clinical Findings: A Scoping Review, Meta-Analysis and Medical Chart Review. Cells. 2022 Jun 10;11(12):1891. doi: 10.3390/cells11121891.