Neurocognitive benchmarks following transplant for emerging cerebral adrenoleukodystrophy

Abstract

<jats:sec><jats:title>Objective</jats:title><jats:p>To quantify benchmark treatment outcomes that may be enabled by newborn screening surveillance for X-linked adrenoleukodystrophy (ALD), we report neurocognitive, neuropsychiatric, and MRI change for boys who underwent hematopoietic stem cell transplant (HSCT) at initial stages of demyelination, prior to neurocognitive signs of disease.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Retrospective chart review identified 36 patients whose cerebral ALD was detected and treated early, with lesion severity less than 5 on the ALD-specific MRI scoring system. Median age at transplant was 7.3 years (range, 4.0–16.1). Progression of radiologic disease on MRI in the 2 years following HSCT was examined relative to the severity of the initial lesion for 33 patients, and longitudinal neurocognitive and neuropsychiatric outcomes were studied for 30 patients.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Patients whose pretransplant lesion extended beyond the splenium of the corpus callosum and adjacent periventricular white matter (MRI severity score &gt;2) demonstrated lower posttransplant neurocognitive scores, more neuropsychiatric symptoms, and more disease progression on MRI than patients with a less severe lesion. Changes from baseline neurocognitive functioning were greater at 2 years posttransplant as compared to 1 year. There was greater variance and risk of lesion progression as pretransplant MRI severity increased.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>To realize the full benefits of newborn screening, clinicians must detect very small demyelinating lesions during surveillance and intervene quickly. Novel interventions that reduce risks inherent in allogeneic transplantation are needed. Trial endpoints should include direct neurocognitive assessment and extend at least 2 years posttreatment to provide the greatest sensitivity to detect neurocognitive morbidity.</jats:p></jats:sec>

MRI surveillance of boys with X‐linked adrenoleukodystrophy identified by newborn screening: Meta‐analysis and consensus guidelines

“…Less often they appear in the corticospinal tracts or cerebellar white matter. 7 Very early lesions may not exhibit clear gadolinium enhancement; alternatively a subset of early lesions may self-arrest 15,21 (Figure 1A,B). If an early-stage lesion is detected, an urgent referral should be made to a physician or center with expertise in monitoring and treating CCALD.…”

“…In the absence of presymptomatic neuroimaging surveillance, CCALD lesions grow silently for months or even years before they are large enough to cause overt clinical symptoms. ALD boys who presented with CCALD as their first symptom translated to large CCALD lesions on MRI (Figure 1E,F), continued accumulation of neurologic deficits, and poor HSCT outcomes 3,18‐21 . Importantly, several studies have demonstrated that HSCT can arrest CCALD progression if performed early, when the MRI is abnormal but neurological symptoms are not yet apparent 2,9‐11,22‐24 .…”

“…ALD boys who presented with CCALD as their first symptom translated to large CCALD lesions on MRI (Figure 1E,F), continued accumulation of neurologic deficits, and poor HSCT outcomes. 3,[18][19][20][21] Importantly, several studies have demonstrated that HSCT can arrest CCALD progression if performed early, when the MRI is abnormal but neurological symptoms are not yet apparent. 2,[9][10][11][22][23][24] In addition, a recent clinical trial of autologous hematopoietic stem-cell gene therapy in boys with early-stage CCALD has produced encouraging results, and may soon become an additional treatment approach.…”

A Longitudinal Analysis of Early Lesion Growth in Presymptomatic Patients with Cerebral Adrenoleukodystrophy

“…Restricted Data Set Analysis To understand the growth of small lesions from the earliest time points, we recalculated the nonparametric local-weighted regression curves and linear mixed-effects model analyses from a subset of the data meeting more restricted criteria: LS # 2 on the first MRI with abnormal findings. 13 To illustrate lesion growth across time, we plotted raw volumes in months from t 0 . This section of the analysis was performed by a biostatistician using R statistical and computing software, Version 3.5.3 (http://www.r-project.org/).…”

“…8 HSCT is most successful when initiated in the window before the onset of neurologic symptoms. 7,[9][10][11] However, the presymptomatic window is narrow, 12,13 and only a minority of patients with…”