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

Area of Science:

• Genetics and rare diseases
• Pediatric neurology
• Hematology and stem cell transplantation

Background:

• X-linked adrenoleukodystrophy (ALD) presents diverse clinical manifestations, with cerebral ALD (cALD) progressing rapidly.
• Early hematopoietic stem cell transplantation (HSCT) offers the best outcomes for cALD.
• The Loes score is a critical imaging biomarker for guiding HSCT timing, where lower scores indicate a better prognosis.

Purpose of the Study:

• To characterize clinical phenotypes of ALD in a Chinese pediatric cohort.
• To expand the spectrum of ABCD1 mutations associated with ALD.
• To evaluate the outcomes of HSCT in pediatric patients with ALD.

Main Methods:

• Retrospective review of 31 male children diagnosed with ALD between 2015 and 2023.
• Analysis of clinical features, adrenal function, brain MRI (Loes scores), and ABCD1 mutations.
• Comparison of overall survival between early-stage cALD patients who underwent HSCT and those who did not.

Main Results:

• Twenty-four patients had cALD, and seven had adrenal-only disease. Neurologic symptoms included visual/hearing impairment, seizures, and cognitive decline.
• Adrenal insufficiency was observed in 62.5% of cALD patients.
• Twenty-nine ABCD1 variants were identified, including three novel pathogenic variants. Early-stage cALD patients receiving HSCT showed a trend toward improved 5-year overall survival (78% vs. 29% for non-transplanted), with a pre-transplant Loes score < 9 being crucial.

Conclusions:

• The study identified three novel ABCD1 variants, expanding the known mutation spectrum.
• Early HSCT in patients with a Loes score < 9 provides a significant survival advantage.
• Diagnostic delays in the cohort emphasize the necessity of newborn screening for ALD to enable timely intervention within the optimal therapeutic window.