Effects of combined nutritional interventions on the natural history of X-linked adrenoleukodystrophy in female carriers

Abstract

Female carriers of X-linked adrenoleukodystrophy (X-ALD) frequently develop neurodegenerative phenotypes resembling adrenomyeloneuropathy. However, evidence supporting disease-modifying nutritional strategies remains limited. We evaluated the effects of Aldixyl®, a derivative of Lorenzo's Oil, and dietary interventions on neurological progression, very-long-chain fatty acids (VLCFAs) levels, adrenal function, and systemic safety in X-ALD women. We conducted a single-center retrospective longitudinal study including ABCD1 heterozygous women followed at Bambino Gesù Children's Hospital between 2001 and 2025. Neurological disability was measured by Adult ALD Clinical Score (AACS), Expanded Disability Status Scale (EDSS), and Timed 25-Foot Walk (T25-FW). Outcomes were compared between patients treated with Aldixyl® plus dietary prescriptions (group A) and those receiving diet-only (group B). Thirty-six patients were included (mean age 41.6 years), 36.1% were neurologically symptomatic at baseline (mean AACS 2.7 ± 2.6). Median C26:0 levels were mildly elevated (1.59 μmol/L). Group A (n = 20) was older and more neurologically impaired at baseline than group B (n = 16) (AACS 3.45 vs. 0.38). Over a median follow-up of 69 months, neurological progression was significantly slower in group A according to AACS (LS mean difference −2.26) and EDSS (−1.03), while T25-FW did not change. Aldixyl® exposure was associated with sustained VLCFA reduction (β = −0.40 μmol/L). Adrenal function and metabolic parameters remained stable, although a mild, uncomplicated decrease in platelet count was observed. In female X-ALD carriers, Aldixyl® is associated with sustained VLCFA reduction and signals suggestive of a more favorable neurological trajectory, while preserving adrenal function and demonstrating an acceptable safety profile. These findings warrant confirmation in prospective, controlled studies.