Adrenoleukodystrophy

Adrenoleukodystrophy (ALD) is an X-linked inherited metabolic peroxisomal disorder characterised by a lack of oxidation of very long chain fatty acids (VLCFAs) that results in severe inflammatory demyelination of the periventricular deep white matter with posterior-predominant pattern and early involvement of the splenium of the corpus callosum and parietal white matter changes. Most patients will demonstrate characteristic MRI findings.

The estimated incidence of adrenoleukodystrophy is 1:20,000-50,000. Due to its X-linked inheritance, it classically affects young males, although carrier females can be affected.

Presentation will depend on the phenotype (see below). Some individuals can be asymptomatic.

Up to eight phenotypes have been described but the three main types in males are  3,11,12:

  • childhood cerebral adrenoleukodystrophy (40%)
    • presents at 4-8 years with progressive impairment motor and cognitive function, vision and hearing
  • adrenomyeloneuropathy (35-40%)
    • presents in the late 20s with progressive paraparesis, sphincter dysfunction, sexual dysfunction, and adrenocortical deficiency
  • Addison disease only (~10%), i.e. primary adrenocortical deficiency
    • no symptomatic leukodystrophy

Approximately 20% of female carriers will be affected, although onset is late (>35 years) with milder paraparesis 11.

The conditions result from the accumulation of very long-chain fatty acids (VLCFAs) due to genetic deficiency in the peroxisomal oxidation of fatty acids. This is thought to result from a mutation in the protein-encoding ABCD1 gene located on Xq28 5,11. The affected cerebral white matter is typically split into three different zones (also referred to as Schaumberg zones 3, 2, and 1, respectively):

  • central (inner) zone: irreversible gliosis and scarring
  • intermediate zone: active inflammation and breakdown of the blood-brain barrier
  • peripheral (outer) zone: leading edge of active demyelination
  • markedly elevated VLCFA concentrations in plasma and cultured skin fibroblasts 11,13

Abnormal MRI findings precede clinical findings in all forms of adrenoleukodystrophy 13.

Loes et al 10 described five different MRI patterns of adrenoleukodystrophy based on the involved anatomic locations and MR patterns of progression:

  1. deep white matter in the parieto-occipital lobes and splenium of the corpus callosum (66% of cases, chiefly in children); may include lesions of the visual and auditory pathways
  2. frontal lobe or genu of the corpus callosum (15.5%, mostly in adolescents)
  3. frontopontine or corticospinal projection fibres (12%, mostly in adults)
  4. cerebellar white matter (1%, mostly in adolescents)
  5. combined parieto-occipital and frontal white matter (2.5%, mostly children)

There tends to be cortical and subcortical U-fibre sparing.

Signal changes can vary according to the zonal distribution within the affected white matter.

  • T1
    • central zone: hypointense
    • intermediate zone
    • peripheral zone
  • T1 C+ (Gd)
    • enhancement is seen in around 50% of cases according to one study and is thought to be associated with disease progression 6
    • with contrast infusion, serpiginous, garland-shaped enhancement may be visible in the anteriormost periphery of the lesions 7
  • T2
    • central zone: markedly hyperintense
    • intermediate zone: isointense to hypointense
    • peripheral zone: moderately hypointense

Spectroscopy may show evidence of neuronal loss manifested by a decrease in the NAA peak and an elevation in the lactate peak 2,14.

Bone marrow transplantation is thought to be favourable in the early stages of the disease. Restriction of VLCFAs has also been trialled. Steroid replacement can be used in patients with adrenocortical insufficiency.

Differential consideration for the classic pattern include:

It is thought to have originally been described by Siemerling and Creutzfeldt in 1923 1.

Inborn errors of metabolism
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Article information

rID: 10259
Synonyms or Alternate Spellings:
  • X-linked adrenoleukodystrophy
  • Adrenoleukodystrophies
  • ALD
  • X-linked adrenoleukodystrophy (X-ALD)
  • Adrenoleukodystrophy (ALD)

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