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X-Linked Adrenoleukodystrophy

Summary

  • X-linked peroxisomal disorder causing accumulation of very long-chain fatty acids (VLCFAs) in tissues, leading to progressive demyelination of cerebral white matter and adrenal insufficiency
  • Presents in childhood with behavioural changes, cognitive decline, and visual/auditory deficits, progressing to severe neurologic disability
  • MRI shows characteristic posterior-predominant white matter demyelination with enhancement at the advancing edge

Pathophysiology

  • Mutation in ABCD1 gene on chromosome Xq28 encoding adrenoleukodystrophy protein (ALDP)
  • Defective peroxisomal beta-oxidation leads to accumulation of VLCFAs (C24:0 and C26:0)
  • Three main phenotypes:
    • Childhood cerebral form (35-40%)
    • Adrenomyeloneuropathy (40-45%) - adult onset with spinal cord involvement
    • Addison disease only (10%)
  • Inflammatory demyelination with perivascular lymphocytic infiltration
  • Progressive destruction of myelin with relative sparing of U-fibres initially
  • Zones of demyelination:
    • Central zone: gliosis and cavitation
    • Intermediate zone: active inflammation and demyelination
    • Peripheral zone: active demyelination with gadolinium enhancement

Demographics

  • X-linked recessive inheritance pattern
  • Incidence: 1 in 17,000 males
  • Childhood cerebral form: onset 4-10 years (peak 7 years)
  • Adrenomyeloneuropathy: onset 20-30 years
  • Female carriers: usually asymptomatic or mild symptoms after 40 years
  • No ethnic predilection

Diagnosis

  • Clinical presentation:
    • Behavioural changes, ADHD-like symptoms
    • Progressive cognitive decline
    • Visual and auditory deficits
    • Gait disturbances
    • Seizures in advanced stages
    • Adrenal insufficiency (may precede neurologic symptoms)
  • Laboratory findings:
    • Elevated plasma VLCFAs (C26:0, C24:0/C22:0 ratio)
    • ACTH stimulation test abnormal in 85%
    • Genetic testing for ABCD1 mutations
  • Loes score: MRI-based severity scoring system (0-34 points)

Imaging

  • MRI findings:
    • T2/FLAIR: symmetric hyperintense signal in parieto-occipital white matter
    • Splenium of corpus callosum involved early
    • Progression in centrifugal pattern
    • Corticospinal tract involvement (pyramidal tract sign)
    • Auditory pathway involvement (lateral lemniscus, inferior colliculus)
    • T1: hypointense in areas of demyelination
    • T1+C: peripheral enhancement at advancing edge ("leading edge enhancement")
    • Indicates active inflammation
    • Correlates with disease progression
    • DWI: restricted diffusion at actively demyelinating edge
    • Facilitated diffusion in central necrotic zones
    • SWI: usually normal, occasional microhaemorrhages in severe cases
    • MR Spectroscopy: elevated choline, decreased NAA, presence of lipid/lactate peaks
  • Pattern variations:
    • 80% posterior predominant (parieto-occipital)
    • 20% frontal predominant
    • Rare: unilateral, cerebellar, or isolated corticospinal tract involvement
  • CT findings:
    • Symmetric hypodensity in periventricular white matter
    • Calcifications rare
    • Less sensitive than MRI for early detection

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  • A 35-year-old male presented with cognitive impairment and personality change.
  • Imaging showed a diffuse anterior-predominant leukoencephalopathy with a centrifugal pattern of enhancement.
  • MR spectroscopy showed a reduction in NAA and the presence of lactate.
  • X-ALD was confirmed on identification of a hemizygous ABCD1 pathogenic variant on molecular genetic testing.

Treatment

  • Hematopoietic stem cell transplantation (HSCT):
    • Most effective if performed early (Loes score <9)
    • Can halt progression in 80-90% if done in early stages
    • High morbidity/mortality if performed in advanced disease
  • Lorenzo's oil:
    • Combination of oleic and erucic acids
    • May lower VLCFA levels but limited clinical efficacy
    • Potential benefit in asymptomatic patients
  • Gene therapy:
    • Lent

Differential diagnosis

Differential diagnosis Differentiating feature
Adrenomyeloneuropathy Predominantly spinal cord dorsal column involvement with minimal cerebral white matter changes; no posterior parieto-occipital predominance or garland enhancement
Multiple sclerosis Periventricular and juxtacortical lesions without posterior predominance; calloso-septal interface lesions; short cord lesions; no zonal garland enhancement
Metachromatic leukodystrophy Frontal and parietal predominance with "tigroid" or "leopard skin" T2 pattern; corticospinal tract involvement; no garland enhancement zone
Krabbe disease Peritrigonal white matter T2 signal with corticospinal tract and cerebellar involvement; thalamic T2 hypointensity; optic radiation changes
Alexander disease Frontal predominance with basal ganglia and thalamic involvement; periventricular garland enhancement can overlap but anterior distribution
Acute disseminated encephalomyelitis (ADEM) Bilateral multifocal white matter lesions involving grey and white matter; incomplete ring enhancement; no posterior predominant zonal pattern
Pelizaeus-Merzbacher disease Hypomyelination pattern with reduced white matter T2 signal rather than T2 hyperintensity; tigroid pattern; no enhancement