Nationwide Study of the Epidemiology and Clinical Features of X-Linked Adrenoleukodystrophy in Denmark

This nationwide, single-cohort study provides a comprehensive analysis of the epidemiology of X-linked adrenoleukodystrophy (ALD) in Denmark. We examined incidence, age at symptom onset, and sex-stratified survival outcomes to explore differences in symptom development. Findings were compared with international cohorts to contextualize the Danish results.

We included all individuals with genetically confirmed ALD residing in Denmark, with no age restrictions. Patients were born between 1911 and 2020. Clinical data were retrospectively extracted from medical records. Where available, dried blood spots collected at birth and stored in the Danish National Biobank were analyzed using liquid chromatography-mass spectrometry to quantify C26:0-lysophosphatidylcholine (C26:0-LPC). Cumulative incidence functions were used to estimate the risk of developing specific ALD phenotypes over time.

A total of 113 individuals (49 males, 64 females) met inclusion criteria. The point prevalence of ALD was 1.42 per 100,000, and the average birth incidence from 1932 to 2023 was 1.81 per 100,000 (males: 1.7; females: 1.9). Thirty-four distinct pathogenic ABCD1 variants were identified, with c.1679C > T, p.(Pro560Leu) being the most common (21 cases). By age 60, 76 % of males had developed adrenomyeloneuropathy (AMN), 44 % had developed cerebral ALD (cALD), and 44 % had adrenal insufficiency. Among females, 80 % had developed AMN by the same age. AMN was associated with the longest diagnostic delay, averaging 8 years in males and 9 years in females.

This study offers a rare, nationwide view of ALD spanning over a century of births alongside measurement of C26:0-LPC in historical, neonatally collected dried blood spot cards from 14 individuals in this cohort. While the birth incidence aligns with some other natural history studies, it remains lower than in countries with universal newborn screening. The high frequency of AMN in both sexes highlights the need for greater clinical awareness. Notably, our findings confirm that the majority of women with ALD will develop neurological symptoms over time, challenging the long-standing perception of female carriers as largely asymptomatic. The relatively low detection of cALD and adrenal insufficiency in adults suggests possible underdiagnosis and calls for improved long-term follow-up, especially in adult neurology and endocrinology.