Five men with arresting and relapsing cerebral adrenoleukodystrophy

Abstract

Background

X-linked adrenoleukodystrophy (ALD) is the most common genetic peroxisomal disorder with an estimated prevalence of 1:15,000. Approximately two-thirds of males with ALD manifest the inflammatory demyelinating cerebral phenotype (cALD) at some disease stage, in which focal, inflammatory lesions progress over months to years. Hematopoietic stem-cell transplantation can permanently halt cALD progression, but it is only effective if initiated early. Although most cALD lesions progress relentlessly, a subset may spontaneously arrest; subsequent reactivation of these arrested lesions has not been previously detailed.

Objective

We describe a novel arresting-relapsing variant of cALD.

Methods

Salient clinical and radiographic studies were reviewed and summarized for cALD patients with episodic deteriorations.

Results

We report a series of five unrelated men with spontaneously arrested cALD lesions that subsequently manifested signs of clinical and radiologic lesion progression during longitudinal follow-up. In three of five patients, functional status was too poor to attempt transplant by the time the recurrence was identified. One patient experienced reactivation followed by another period of spontaneous arrest.

Conclusions

These cases emphasize the need for continued clinical and radiologic vigilance for adult men with ALD to screen for evidence of new or reactivated cALD lesions to facilitate prompt treatment evaluation.

Introduction

X-linked adrenoleukodystrophy (ALD) is the most common genetic peroxisomal disorder (1:15,000) [1]. ALD is caused by mutations in a single gene, ABCD1, which result in accumulation of very long-chain fatty acids in neuroendocrine and immune tissues. Two-thirds of ALD males will develop an inflammatory, cerebral demyelinating phenotype (cALD) characterized by expanding, contrast-enhancing white matter lesions that share histologic similarities with multiple sclerosis lesions [2]. Most cALD lesions enlarge relentlessly with accompanying disability and death. Hematopoietic stem-cell transplantation (hSCT) can permanently arrest cALD lesion growth, but it is only effective if initiated, while the lesion is small [3]. Lesion arrest is demarcated by the resolution of gadolinium enhancement and clinical stabilization. Importantly, 10–20% of cALD lesions may spontaneously arrest without hSCT [4-7]. Subsequent reactivation of these arrested lesions has not been previously detailed. Here, we report a series of five unrelated men with arrested cALD lesions that subsequently reactivated during longitudinal follow-up.

Case series

Patient 1

Patient 1 was diagnosed with ALD at the age of 34 via ABCD1 mutation analysis in the context of a mild gait disturbance, urge incontinence, and a positive family history. Initial MRI revealed a bifrontal white matter lesion without contrast enhancement (Fig. 1a, left). He remained stable until the age of 49 when symptom progression prompted an MRI that revealed interval enlargement of the lesion and associated contrast enhancement, consistent with reactivation of this cALD lesion (Fig. 1a, right). His neurologic disability was considered too advanced to benefit from hSCT.

Fig. 1.

Brain images from periods of remission and relapse for Patients 1 through 5. T2 FLAIR hyperintense lesions without associated contrast enhancement delineate periods of remission (first two columns). Subsequent MRI studies for each patient revealed interval enlargement of T2 FLAIR lesion size and corresponding contrast enhancement (3rd and 4th columns; arrows demarcate contrast enhancement)

Patient 2

Patient 2’s neurologic symptoms began at the age of 4 with the gradual onset and stabilization of severe behavioral issues. At the age of 15, he was hospitalized with fever and altered mental status. Diagnostic work-up revealed adrenal insufficiency, non-enhancing bifrontal white matter lesions (Fig. 1b, left), elevated VLCFAs, and an ABCD1 mutation. He recovered to his prior condition and remained stable for several years with behavioral issues but no motor deficit. He subsequently developed progressive diplegia that left him wheelchair bound, prompting a repeat MRI at age 20 that demonstrated interval progression of white matter lesions, now with associated contrast enhancement consistent with reactivation of cALD lesion (Fig. 1b, right). His neurologic disability was considered too advanced to benefit from hSCT.

Patient 3

Patient 3 was diagnosed with a pathogenic ABCD1 mutation at age 13 during an evaluation for growth delay. Initial MRI demonstrated biparietal white matter lesions without enhancement. Annual MRIs remained stable up to age 22 (Fig. 1c, left), and he completed a 4-year college degree with excellent grades. During his final months of college, he indulged in heavy alcohol consumption, a deviation from his previously healthy lifestyle. During this period, he noticed a gradual decline in his attention and executive function. An MRI revealed interval enlargement of lesions, which were now contrast-enhancing consistent with reactivation of cALD lesion (Fig. 1c, right). Three months later, repeat MRI during hSCT triage revealed that lesion enhancement had resolved, consistent with spontaneous cALD arrest (image not shown).

Patient 4

Patient 4 was diagnosed with a pathogenic ABCD1 mutation at age 14 after his brother presented with advanced cALD. His neurologic examination and school performance were normal. His lab results identified subclinical adrenal insufficiency. Initial MRI demonstrated a subtly enhancing lesion centered at the genu of the corpus callosum. Family declined hSCT, preferring serial MRI surveillance to monitor lesion progression. Lesion enhancement resolved within 1 year without further enlargement of the lesion over the next 5 years (Fig. 1d, left). At age 20, he suffered a serious head trauma with loss of consciousness after a high-speed bicycle accident. Serial imaging over the next 6 months revealed an enhancing lesion at a new location in the left corticospinal tract, with corresponding mild limb weakness (Fig. 1d, right). He was subsequently treated with hSCT with resolution of both motor deficit and lesion enhancement over the next 12 months consistent with hSCT-related cALD arrest.

Patient 5

Patient 5 was diagnosed with ALD at the age of 22 years during evaluation for a gait disorder and adrenal dysfunction. An MRI of the brain at the time of diagnosis was normal. At the age of 33 years, he had a severe spastic diplegia and was wheelchair bound. An MRI of the brain revealed extensive white matter abnormalities in the genu of the corpus callosum extending into the frontal white matter without associated enhancement (Fig. 1e, left). A follow-up scan 3 months later was unchanged. At the age of 37, he presented with cognitive and behavioral problems that developed over the past year. MRI brain revealed clear progression of the white matter lesions with associated enhancement (Fig. 1e, right). His neurologic disability was considered too advanced to benefit from hSCT. He died several months later in a nursing home.

Discussion

Improved understanding of the natural history of cALD lesions will inform clinical decision-making, disease pathogenesis, and therapeutic development. Here, we offer the first detailed description of cALD lesion reactivation after a period of spontaneous arrest in five ALD men (Fig. 2). The treatment window for cALD is narrow [8]; by the time lesion relapse was recognized, three of the five patients were deemed unsuitable for hSCT. These cases emphasize the need for vigilant clinical and radiologic surveillance for adult men with ALD to screen for evidence of new or reactivated cALD lesions in a timeframe suitable for hSCT triage (e.g., MRI every 6–12 months depending on age) [9].

Fig. 2.

Overview of cALD lesion activity over time

This arresting-relapsing phenomenon could harbor insights into cALD pathophysiology. The primary impairment of fatty acid metabolism that underlies ALD confers a variety of physiologic disturbances, but the mechanisms underpinning the genesis and progression of cALD lesions remain almost entirely unresolved [1]. The arresting–remitting cALD lesion pattern observed in our series may imply a more malleable disturbance of immune, metabolic, and/or blood–brain-barrier homeostasis, and suggests the possibility of as yet unknown biological levers (aside from head trauma which has been previously documented [10]) that might one day offer therapeutic targets.

The natural history of cALD lesions is more variable than previously assumed. Improved knowledge of cALD lesion progression is important: it will inform our current paradigm of hSCT timing, risks, and benefits; it will facilitate the design and interpretation of future therapeutic trials; and it may shed new insights into the homeostatic mechanisms that might one day be leveraged to the advantage of boys and men with ALD.