Cognitive Functions in Adult‐Onset Phenotypes of X‐Linked Adrenoleukodystrophy

Abstract

Objective: X-linked adrenoleukodystrophy (X-ALD) is a rare genetic disorder characterized by progressive demyelination ranging from mild myelopathic forms (adrenomyeloneuropathy [AMN]) to severe cerebral variants (adult cerebral adrenoleukodystrophy [ACALD]). The aim of this study was to compare cognitive function in adult-onset X-ALD phenotypes. Methods: Cognitive function in various domains (intelligence, attention, memory, executive function, and processing speed) was assessed in 172 adults (117 with AMN, 30 with arrested ACALD, and 25 with acute ACALD) using comprehensive neuropsychological batteries. Phenotype differences were examined by analyses of variance. Results: X-ALD phenotypes significantly differed in nonverbal intelligence, sustained attention, verbal encoding, nonverbal recognition, and processing speed (ps < 0.050). No group differences emerged regarding verbal intelligence, verbal retrieval and recognition, and executive function (ps > 0.050). Specifically, patients with acute ACALD showed severe cognitive deficits compared to AMN and normal data, with largest effects on processing speed. Contrary, cognition was overall intact in patients with AMN, independent of sex and corticospinal tract involvement, and those with arrested ACALD showed mild cognitive dysfunction, particularly in verbal encoding and processing speed. Interpretation: Cerebral demyelination in patients with X-ALD causes white matter dementia, mainly characterized by an extreme slowdown in processing speed associated with deficits in attention and learning. Most patients with AMN show intact cognitive function. Future prospective, longitudinal studies with more sensitive imaging techniques are required to clarify whether early mild cognitive dysfunction found in some patients with AMN may be associated with subtle myelin abnormalities that do not yet appear as white matter lesions on cerebral MRI (cMRI) but have the potential to serve as early predictors of later cerebral progression.

Defective neuritogenesis inAbcd1/2deficient rat neurons due to intrinsic and astrocyte-dependent mechanisms

“…It was argued that 'subclinical transcriptional alterations could create a different starting point in HD relative to non-HD brain' in responses to injury 27 , as well as cause mild cognitive impairment in the absence of motor symptoms 37 . Extending these scenarios to X-ALD, cognitive reserve and circuit plasticity may confer resilience against VLCFA accumulation, but perhaps not total protection, as mild psychiatric symptoms and below average performance in some cognitive tests are not rare in adults harboring ABCD1 mutations, even in 'pure AMN' with no MRI abnormalities, all in all pinpointing abnormal brain circuitries in AMN [32][33][34][35][36] . Subclinical or mild neural-circuit dysfunction may accelerate homeostasis loss in injury, hamper repair as well as exacerbate dysfunction in ABCD1 deficient glia, for glia responses to injury are under the control of neuronal networks 86,88 .…”

“…Arguably, X-ALD has not been considered a neurodevelopmental disorder because no gross anatomical or cytoarchitectural abnormalities characteristic of other peroxisomal disorders have been detected in brains of patients with X-ALD 30 , nor are there cognitive deficits in asymptomatic children carrying mutated ABCD1 31 . However, mild neuropsychiatric alterations or below average performances in cognitive tests have been reported in AMN patients with no cerebral pathology according to MRI [34][35][36] . Since X-ALD is a genetic disorder, we posit that the mild mental problems are due to structural deficits in neural circuits owing to ABCD1 malfunction and lipid dyshomeostasis during brain development.…”

White matter dementia then… and now

“…This concept thus led to the proposal of a new syndrome that departed from the conventional understanding of dementia, and our idea, form a different perspective than the powerful corticocentric bias in clinical neuroscience (6), met with only modest enthusiasm. As time and knowledge advanced, with MRI and neuropsychological testing regularly demonstrating correlations between white matter lesions and cognitive loss, the construct of WMD slowly attracted more attention (7)(8)(9)(10)(11)(12), and this issue of Frontiers in Neurology embraces the concept with a series of articles dedicated to the topic. In this introductory paper, I will offer a focused review of the original formulation of WMD, its clinical characterization, its importance in the study of connectivity and distributed neural networks, its relevance to neurodegenerative diseases, and new perspectives in treatment, prevention, and recovery.…”

The Role of Oxidative Stress and Inflammation in X-Link Adrenoleukodystrophy

“…Various phenotypes are presented in X-ALD, including cerebral ALD (CALD), adrenomyeloneuropathy (AMN), Addison-only (AO), and presymptomatic ALD, among which the most severe is CALD (9,10). Approximately one-third of boys with X-ALD develop CALD under the age of 12 years (11), characterized by initial learning and behavioral problems, followed by a rapid and severe progressive inflammatory demyelination resulting in a severe cognitive and physical disorder with a total disability that develops within 6 months to 2 years and dies within 5-10 years of the diagnosis (12)(13)(14). Besides, AMN, which is another prominent clinical phenotype of X-ALD that mainly manifests in adults, develops progressive stiffness and weakness of the legs, an impaired sense of vibration, and sphincter disturbances.…”