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.

Epidemiology
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.

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

Phenotypes
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.

Pathology
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
Markers
markedly elevated VLCFA concentrations in plasma and cultured skin fibroblasts
11,13
Radiographic features
MRI
Abnormal MRI findings precede clinical findings in all forms of
adrenoleukodystrophy 13.

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

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
frontal lobe or genu of the corpus callosum (15.5%, mostly in adolescents)
frontopontine or corticospinal projection fibres (12%, mostly in adults)
cerebellar white matter (1%, mostly in adolescents)
combined parieto-occipital and frontal white matter (2.5%, mostly children)
There tends to be cortical and subcortical U-fibre sparing.

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

Treatment and prognosis

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 diagnosis
Differential consideration of the classic pattern include:

acetyl CoA oxidase deficiency (pseudo adrenoleukodystrophy): has a different

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

See also
dysmyelinating disorder
leukodystrophy