Adrenoleukodystrophy (X-Linked Adrenoleukodystrophy): MRI White Matter Disease in Adults – Pathophysiology, Imaging Features, Diagnosis, and Management

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Introduction

Adrenoleukodystrophy (ALD) is one of the most clinically important genetic leukodystrophies, characterized by progressive white matter degeneration, adrenal insufficiency, and variable neurological manifestations. Among its forms, X-linked adrenoleukodystrophy (X-ALD) is the most common and clinically relevant, with diverse phenotypes ranging from childhood cerebral disease to adult-onset myeloneuropathy.

Although classically considered a pediatric disorder, adult-onset cerebral adrenoleukodystrophy and symptomatic female carriers are increasingly recognized due to advances in MRI, genetic testing, and biochemical assays. This article presents a 26-year-old woman with seizures diagnosed with adrenoleukodystrophy, illustrating the imaging spectrum, diagnostic approach, and clinical implications of this rare but devastating disease.

This comprehensive review integrates the attached case images, current international consensus guidelines, and landmark neuroradiology literature, making it particularly valuable for radiologists, neurologists, and physician exam candidates.

Pathophysiology of Adrenoleukodystrophy

X-linked adrenoleukodystrophy results from pathogenic mutations in the ABCD1 gene, located on chromosome Xq28. This gene encodes a peroxisomal membrane transporter protein responsible for the import and degradation of very long-chain fatty acids (VLCFAs).

Key Pathophysiologic Mechanisms

  • Accumulation of VLCFAs (C24:0, C26:0) in:

    • Central nervous system white matter

    • Adrenal cortex

    • Testes

  • Myelin instability and destruction

  • Secondary neuroinflammation and microglial activation

  • Progressive axonal loss and cerebral atrophy

Importantly, genotype does not reliably predict phenotype, explaining the broad clinical variability seen even within the same family.

Epidemiology

  • Estimated prevalence: 1 in 15,000 newborns

  • Affects all ethnic groups

  • Males: higher risk of severe cerebral disease

  • Females (heterozygous carriers):

    • Often asymptomatic in childhood

    • May develop adult-onset myeloneuropathy

    • Cerebral involvement and adrenal insufficiency are rare but documented

Clinical Presentation

Common Clinical Phenotypes

  1. Cerebral ALD

    • Cognitive decline

    • Behavioral changes

    • Seizures

    • Rapid neurological deterioration

  2. Adrenomyeloneuropathy (AMN)

    • Progressive spastic paraparesis

    • Sensory ataxia

    • Bladder dysfunction

  3. Primary Adrenal Insufficiency (Addison’s disease)

    • Fatigue

    • Weight loss

    • Hyperpigmentation

    • Chronic corticosteroid use (as in this case)

Case Context

The presented 26-year-old woman arrived with seizures and no prior documented medical history. Subsequent pharmacy records revealed long-term corticosteroid therapy, strongly suggesting undiagnosed adrenal insufficiency, a key clinical clue toward X-linked adrenoleukodystrophy.

Imaging Features of Adrenoleukodystrophy

MRI is the gold standard for detecting and monitoring cerebral ALD.

Figure-Based Imaging Interpretation


Figure 1. T1-Weighted Post-Contrast MRI (T1WI C+)

Axial T1-weighted post-contrast image shows diffuse cerebral volume loss without abnormal parenchymal enhancement, indicating chronic non-active disease.

Figure 2. Axial T2-Weighted MRI

Diffuse T2 hyperintensity of the cerebral white matter, extending from subcortical regions to deep periventricular white matter, involving both supratentorial and infratentorial compartments.


Figure 3. Axial FLAIR MRI

FLAIR imaging confirms confluent symmetric white matter hyperintensity, including corpus callosum involvement, a hallmark of advanced leukodystrophy.


Figure 4. Axial Diffusion-Weighted Imaging (DWI)

No diffusion restriction is observed, suggesting absence of acute inflammatory demyelination.


Figure 5. Axial Apparent Diffusion Coefficient (ADC) Map

ADC values are not reduced, further supporting chronic white matter degeneration rather than active disease.

Figure 6. Follow-Up CT (15 Years Later)

Axial and coronal CT images demonstrate marked cerebral and cerebellar atrophy with diffuse white matter hypodensity, consistent with end-stage adrenoleukodystrophy.

Typical MRI Patterns in ALD

  • Symmetric parieto-occipital white matter involvement (classic)

  • Corpus callosum (splenium > genu)

  • Corticospinal tracts (common in adults)

  • Cerebellar white matter involvement

  • Progressive global cerebral atrophy

  • Disease severity quantified using the Loes score (0–34)

Differential Diagnosis of Adult White Matter Disease

When evaluating diffuse white matter abnormalities in adults, consider:

  • Multiple sclerosis

  • Metachromatic leukodystrophy

  • Krabbe disease

  • Alexander disease

  • CADASIL

  • Progressive multifocal leukoencephalopathy (PML)

  • Small vessel ischemic disease

  • Chemotherapy-induced leukoencephalopathy

In this case, the combination of adrenal insufficiency, diffuse symmetric white matter involvement, and female carrier status strongly supports X-linked adrenoleukodystrophy.

Diagnosis

Confirmatory Diagnostic Tools

  • Plasma very long-chain fatty acid (VLCFA) quantification

  • C26:0-lysoPC measurement

  • Genetic testing for ABCD1 mutation (gold standard)

  • Family screening

  • MRI-based disease staging

Treatment

Current Therapeutic Strategies

  • Allogeneic hematopoietic stem cell transplantation (HSCT)

    • Effective only in early-stage cerebral ALD

    • Limited benefit in adults with advanced disease

  • Adrenal hormone replacement therapy

  • Symptomatic treatment:

    • Antiepileptic drugs

    • Physical rehabilitation

    • Supportive care

In the presented patient, management consisted of hormone replacement and seizure control.

Prognosis

  • Cerebral ALD: often rapidly progressive

  • Adult-onset disease: variable progression

  • Female carriers: generally milder course

  • Advanced MRI abnormalities predict poor neurological outcome

Quiz

Question 1

Where is the primary abnormality in this patient?

A. Cortex
B. White matter
C. Deep gray nuclei
D. Ventricles
E. Brainstem

Answer: B
Explanation: MRI demonstrates diffuse symmetric white matter T2/FLAIR hyperintensity with corpus callosum involvement.

Question 2

What is the most likely diagnosis?

A. Multiple sclerosis
B. Metachromatic leukodystrophy
C. X-linked adrenoleukodystrophy
D. Krabbe disease
E. CADASIL

Answer: C
Explanation: Chronic adrenal insufficiency and diffuse leukodystrophy are classic for X-linked adrenoleukodystrophy.

Question 3

Which test best confirms the diagnosis?

A. Brain biopsy
B. CSF analysis
C. Plasma glucose
D. ABCD1 genetic testing
E. EEG

Answer: D
Explanation: Genetic confirmation of an ABCD1 mutation is the definitive diagnostic method.

References

  1. M. Engelen et al., “International recommendations for the diagnosis and management of patients with adrenoleukodystrophy,” Neurology, vol. 99, no. 21, pp. 940–951, 2022.

  2. D. S. Lynch et al., “Practical approach to adult-onset leukodystrophies,” J Neurol Neurosurg Psychiatry, vol. 90, no. 5, pp. 543–554, 2019.

  3. L. L. Resende et al., “Adult leukodystrophies: A step-by-step diagnostic approach,” Radiographics, vol. 39, no. 1, pp. 153–168, 2019.

  4. M. Engelen et al., “X-linked adrenoleukodystrophy in women,” Brain, vol. 137, no. 3, pp. 693–706, 2014.

  5. F. Eichler et al., “MRI detection of lesion progression in adult X-ALD,” Arch Neurol, vol. 64, no. 5, pp. 659–664, 2007.

  6. H. W. Moser et al., “X-linked adrenoleukodystrophy: Overview and prognosis,” Neuropediatrics, vol. 31, no. 5, pp. 227–239, 2000.

  7. S. I. W. van de Stadt et al., “Imaging in X-linked adrenoleukodystrophy,” Neuropediatrics, vol. 52, no. 4, pp. 252–260, 2021.

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