X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management

The number of false-positives from reference ranges is too large to allow screening for X-ALD in neurologically affected patients with an incidence at birth of approximately 1:17,000.

“This number of false-positives is too large to allow screening for X-ALD in neurologically affected patients with an incidence at the birth of ~ 1:17,0002.”

VLCFAs are regarded as the most important biomarkers for the majority of peroxisomal disorders.

“Although VLCFAs are regarded as the most important biomarkers for the majority of peroxisomal disorders, false-positive results have been reported in approximately 2.5% of the healthy population, hemolyzed samples, and patients with a ketogenic diet [35,36].”

False-positive VLCFA results have been reported in approximately 2.5% of the healthy population, hemolyzed samples, and patients with a ketogenic diet.

“Although VLCFAs are regarded as the most important biomarkers for the majority of peroxisomal disorders, false-positive results have been reported in approximately 2.5% of the healthy population, hemolyzed samples, and patients with a ketogenic diet [35,36].”

Progression of these lesions is unpredictable; it can be severe and rapid in the childhood cerebral form and milder and slower in adult-onset forms.

“The progression of these lesions is unpredictable; it can be severe and rapid in the childhood cerebral form; milder and slower in forms with adult onset (11, 22).”

In approximately 85% of individuals with clinical symptoms, brain MRI shows a characteristic pattern of symmetric confluent hyperintense lesions in T2 and FLAIR images, usually first appearing in the parieto-occipital region of both hemispheres.

“In approximately 85% of the individuals with clinical symptoms, brain magnetic resonance imaging (MRI) shows a characteristic pattern of symmetric confluent hyperintense lesions in T2 and FLAIR images, usually first appearing in the parieto-occipital region of both hemispheres.”

CerALD is the most severe form of X-ALD, typically affecting young boys between 4 and 8 years of age, and is characterized by progressive inflammatory demyelination in the cerebral white matter.

“This is the most severe form of X-ALD, typically affecting young boys (typically between 4 and 8 years of age). It is characterized by progressive inflammatory demyelination in the cerebral white matter.”

The same ABCD1 mutation can cause either childhood cerebral inflammatory demyelination or, more often, adult-onset progressive spinal cord axonopathy.

“Strikingly, the same ABCD1 mutation causes either devastating brain inflammatory demyelination during childhood or, more often, progressive spinal cord axonopathy starting in middle-aged adults.”

Slowly progressive AMN symptoms occur in approximately 65% of heterozygous women by age 60 due to inactivation of the non-mutated X chromosome and mosaic expression of X-linked genes in neural cells.

“Although ALD is an X-linked disease, slowly progressive AMN symptoms occur in ~65% of heterozygous women by the age of 60 years [31,47,59,60] due to the inactivation of the non-mutated X chromosome and the mosaic expression of X-linked genes in neural cells [60,61,62,63].”

In some X-ALD patients, pyramidal tract signals may become as intense as in cALD.

“In some patients, the pyramidal tract signals may become as intense as in cALD [31].”

No curative therapy is currently available for AMN, and treatment is limited to symptomatic therapy of adrenal or gonadal insufficiency, neuropathic pain, and spasticity.

“Thus, no curative therapy is currently available for AMN, and treatment is limited to symptomatic therapy of adrenal or gonadal insufficiency, neuropathic pain, and spasticity.2”

Patients with X-ALD caused by mutations in ABCD1 often develop the severe cerebral form of the disease between ages 3 and 10, with rapid progression and neuroinflammation.

“Patients with X-ALD, caused by mutations in ABCD1, the transporter responsible for peroxisomal import of straight-chain VLCFAs, often develop the severe cerebral form of the disease between ages 3 and 10, with rapid progression and neuroinflammation (Engelen et al., 2012).”

AMN is the most common form of adult-onset X-ALD.

“AMN is the most common form of adult-onset X-ALD.”

AMN primarily affects hemizygous males, although heterozygous females can also be affected to a lesser extent, with similar but later progression usually after the 4th or 5th decade of life.

“It primarily affects hemizygous males, although heterozygous females can also be affected to a lesser extent, with a similar but later progression of symptoms (usually after the 4th-or 5th decade of life).”

AMN is characterized by spinal cord involvement, leading to progressive motor dysfunction and sensory deficits.

“It is characterized by spinal cord involvement, leading to progressive motor dysfunction and sensory deficits.”

At more advanced stages, typical confluent and symmetrical areas of T2 hyperintensity reflect demyelination in the splenium of the corpus callosum, parieto-occipital or frontal white matter, or pyramidal tracts within the internal capsules, pons, and brainstem.

“At more advanced stages, typical confluent and symmetrical areas of T2 hyperintensity reflect demyelination in the splenium of the corpus callosum, parieto-occipital or frontal white matter, or pyramidal tracts within the internal capsules, pons, and brainstem.”

MRI can detect early demyelinating lesions in X-ALD generally localized in the splenium of the corpus callosum, which progress to involve adjacent parieto-occipital white matter.

“During the follow-up of a patient’s brother with elevated VLCFAs or a child found positive at neonatal screening, MRI is able to detect early demyelinating lesions generally localized in the splenium of the corpus callosum (a region with a very high density of OLs), which progress to involve the adjacent parieto-occipital white matter [14,31,90,91,92].”

Gadolinium extravasation, a hallmark of neuroinflammation and blood-brain barrier breach, can occur early when demyelinating lesions are still restricted to the corpus callosum or pyramidal tracts but is often seen later, once lesions have extended.

“Gadolinium extravasation, a hallmark of neuroinflammation and blood–brain barrier (BBB) breach, can occur early when demyelinating lesions are still restricted to the corpus callosum or pyramidal tracts but is often seen later, once the demyelinating lesions have extended [31,93,94].”

Brain lesions in cAMN may enter an active phase of neuroinflammation with gadolinium enhancement.

“Those brain lesions may enter an active phase of neuroinflammation with gadolinium enhancement [31].”

In patients with pure AMN, brain MRI remains normal or shows subtle abnormalities, such as moderately increased signal intensities on FLAIR and T2 sequences in the pyramidal tracts in the internal capsules, brainstem, and/or pons.

“In patients with “pure” AMN, brain MRI remains normal or shows subtle abnormalities, such as moderately increased signal intensities on FLAIR and T2 sequences in the pyramidal tracts in the internal capsules, brainstem, and/or pons [31].”