Pediatric X-linked adrenoleukodystrophy: phenotypes, variants, and HSCT outcomes

X-linked adrenoleukodystrophy (ALD) presents variable neurologic and adrenal manifestations. Early diagnosis is critical for effective hematopoietic stem cell transplantation (HSCT). This study aims to characterize clinical phenotypes, expand the ABCD1 mutational spectrum, and evaluate HSCT outcomes in a Chinese pediatric cohort. We retrospectively reviewed 31 male children diagnosed with ALD from 2015 to 2023. Clinical features, adrenal function, brain MRI findings, and ABCD1 mutations were analyzed. Loes scores were determined for cerebral ALD (cALD). Overall survival was compared between early-stage cALD patients who underwent allogeneic HSCT and those who did not. Twenty-four patients had cALD, and seven presented with adrenal-only disease. Neurologic symptoms in cALD included visual/hearing impairment (37.5%), seizures (29.2%), and cognitive decline (16.7%). Adrenal insufficiency occurred in 62.5% of cALD patients. Genetic analysis identified 29 ABCD1 variants, including three novel pathogenic variants (c.77C > G, c.1119_1120insTC, c.1291C > T). While statistical significance was limited by sample size (P = 0.24), early-stage cALD patients receiving HSCT showed a clinically meaningful trend toward improved 5-year OS (78%) compared to non-transplanted patients (29%). A pre-transplant Loes score < 9 was a critical determinant of superior outcomes.

We expanded the ABCD1 spectrum with three novel variants. Our findings confirm that early-stage HSCT (Loes < 9) offers a distinct survival advantage. The diagnostic delays observed in our cohort underscore the urgent need for implementing newborn screening to capture patients within the optimal therapeutic window.

• X-linked adrenoleukodystrophy (ALD) shows marked clinical heterogeneity; cerebral ALD progresses rapidly, and early HSCT offers the best outcomes. • The Loes score is a key imaging biomarker guiding transplant timing, with lower scores predicting superior prognosis.

• We report a Chinese pediatric cohort expanding the ABCD1 mutation spectrum with three novel pathogenic variants. • Survival analyses reinforce that HSCT at Loes < 9 confers a clinically meaningful advantage, highlighting diagnostic delays and the need for newborn screening.