International Recommendations for the Diagnosis and Management of Patients With Adrenoleukodystrophy: A Consensus-Based Approach.

Pathogenic variants in the ABCD1 gene cause adrenoleukodystrophy (ALD), a progressive metabolic disorder characterized by 3 core clinical syndromes: a slowly progressive myeloneuropathy, a rapidly progressive inflammatory leukodystrophy (cerebral ALD), and primary adrenal insufficiency. These syndromes are not present in all individuals and are not related to genotype. Cerebral ALD and adrenal insufficiency require early detection and intervention and warrant clinical surveillance because of variable penetrance and age at onset. Newborn screening has increased the number of presymptomatic individuals under observation, but clinical surveillance protocols vary. We used a consensus-based modified Delphi approach among 28 international ALD experts to develop best-practice recommendations for diagnosis, clinical surveillance, and treatment of patients with ALD. We identified 39 discrete areas of consensus. Regular monitoring to detect the onset of adrenal failure and conversion to cerebral ALD is recommended in all male patients. Hematopoietic cell transplant (HCT) is the treatment of choice for cerebral ALD. This guideline addresses a clinical need in the ALD community worldwide as the number of overall diagnoses and presymptomatic individuals is increasing because of newborn screening and greater availability of next-generation sequencing. The poor ability to predict the disease course informs current monitoring intervals but remains subject to change as more data emerge. This knowledge gap should direct future research and illustrates once again that international collaboration among physicians, researchers, and patients is essential to improving care.

Presymptomatic Lesion in Childhood Cerebral Adrenoleukodystrophy: Timing and Treatment.

BACKGROUND AND OBJECTIVES: We sought to characterize the natural history and standard of care practices between the radiologic appearance of brain lesions, the appearance of lesional enhancement, and treatment with hematopoietic stem cell transplant or gene therapy among boys diagnosed with presymptomatic childhood-onset cerebral adrenoleukodystrophy (CCALD). METHODS: We analyzed a multi-center, mixed retrospective/prospective cohort of patients diagnosed with presymptomatic CCALD (Neurologic Function Score [NFS] = 0, Loes Score [LS] = 0.5 - 9.0, Age < 13 years old). Two time-to-event survival analyses were conducted: (1) Time from CCALD lesion-onset-to-lesional enhancement, (2) Time from enhancement-to-treatment. The analysis was repeated in the subset of patients with (1) the earliest evidence of CCALD, defined as an MRI LS < 1, and (2) patients diagnosed between 2016 - 2021. RESULTS: Seventy-one boys were diagnosed with presymptomatic cerebral lesions at a median age of 6.4yo [2.4 - 12.1] with a LS of 1.5 [0.5 - 9.0]. Fifty percent of patients had lesional enhancement at diagnosis. In the remaining 50%, the median KM-estimate of time from diagnosis-to-lesional enhancement was 6.0 months [95%CI 3.6 - 17.8]. The median KM-estimate of time from enhancement-to-treatment is 3.8 months [95%CI 2.8 - 5.9]; two patients (4.2%) developed symptoms prior to treatment. Patients with a diagnostic LS < 1 were younger (5.8yo [2.4 - 11.5]), had a time-to-enhancement of 4.7mo [95%CI 2.7 - 9.30], and were treated in 3.8mo [95%CI 3.1 - 7.1]; no patients developed symptoms prior to treatment. Time from CCALD diagnosis-to-treatment decreased over the course of the study (ρ = -0.401, p = 0.003). CONCLUSION: Our findings offer a more refined understanding of the timing of lesion formation, enhancement, and treatment among boys with presymptomatic CCALD. These data offer benchmarks for standardizing clinical care and designing future clinical trials.