Neurocognitive Trajectory of Patients with Childhood Cerebral Adrenoleukodystrophy Who Received Allogeneic Hematopoietic Cell Transplantation at an Early Stage of Cerebral Disease

Adrenoleukodystrophy (ALD) is an X-linked disorder of very long chain fatty acid metabolism which may manifest with adrenal gland and/or central nervous system disease. Thirty-five percent of affected boys develop cerebral involvement (cALD) during childhood. Characterized by progressive cerebral demyelination and resulting in devastating neurological and cognitive decline, cALD is usually fatal within years of clinically-evident disease. The only treatment known to enhance long-term survival and stabilize cerebral disease for boys with cALD is hematopoietic cell transplantation (HCT). It is well-established that the risk for negative long-term outcomes is significantly lower when HCT occurs at an earlier stage of cerebral white matter disease (ALD MRI severity score [Loes score] < 10). Nevertheless, there is limited knowledge of broad-based neurocognitive outcomes of patients transplanted with early-disease cALD. We studied all patients who underwent HCT for cALD at the University of Minnesota between January 1, 1991 and October 20, 2014. HCT preparative regimens varied with time, although most patients underwent myeloablative conditioning. Transplant allograft sources varied. Neurocognitive data were available for 63 patients who had a pre-transplant Loes MRI severity score < 10. Within this cohort, patients with less extensive cerebral disease (Loes ≤ 4) at the time of HCT had significantly higher scores on baseline tests of intellectual functioning than those with more cerebral involvement (Loes >4). This difference was particularly apparent on measures of nonverbal (visual) reasoning and processing speed. Furthermore, patients with more MRI-evident white matter disease at HCT showed more dramatic declines in neurocognitive test performance over time. In a subset of 20 patients who were followed for at least 4 years post-transplant, 15 patients (75%) demonstrated significant neurocognitive deficits (>1.5 SD below the mean) in at least one of the following domains: overall intellectual functioning (30%), attention (39%), verbal memory (33%), visual-motor integration (40%) and fine motor skills (58%). Results of this study provide evidence that within this patient group (boys undergoing HCT for cALD with Loes score < 10), patients have better neurocognitive outcomes when minimal cerebral disease is evident on neuroimaging prior to transplant. These data represent the largest analysis of cognitive outcomes in patients with early-disease cALD who underwent HCT. Our findings provide a benchmark for comparison to alternative or additional interventions for patients with cALD. Opportunities to enhance standard methods of detecting early cerebral disease and to intervene at the earliest possible stage of cALD should be explored. The emergence of newborn screening for adrenoleukodystrophy will provide avenues for improved pre-transplant monitoring and timing of intervention to preserve cognitive functioning and quality of life among patients with cALD.