Boys and adult males with X-ALD
Follow-up in boys and men with X-ALD is important for two reasons: 1) early detection of adrenocortical insufficiency and 2) early detection of cerebral ALD to propose allogeneic hematopoietic stem cell transplantation (HCT) if a HLA-matched donor or cord blood is available. Despite significant mortality risk, allogeneic HCT remains the only therapeutic intervention that can arrest the progression of cerebral demyelination in X-ALD, provided the procedure is performed very early, i.e., when affected boys or men have no or minor symptoms due to cerebral demyelinating disease [81, 82].
In the future, transplantation of autologous hematopoietic stem cells that have been genetically corrected with a lentiviral vector before re-infusion might become an alternative to autologous HCT, once the very encouraging results obtained in the first two treated patients will have been extended to a larger number of patients with cerebral X-ALD .
If boys or men do not have Addison’s disease it is recommended that they are evaluated yearly by an endocrinologist for adrenocortical dysfunction by measuring the plasma ACTH levels and performing an ACTH stimulation test . Steroid replacement therapy can then be initiated if necessary.
Boys without neurological deficits should be monitored closely for radiological signs of cerebral ALD. CCALD has not been reported before the age of 2.5 years . We recommend an MRI of the brain every 6 months in boys aged 3 to 12 years old to screen for early signs of CCALD. If symptoms occur suggestive of cerebral ALD (for instance declining school performance) the MRI should be performed at the earliest available opportunity, but it is our experience that the detection of brain MRI abnormalities precedes any detectable cognitive dysfunction by at least 6 months to 1 year. After the age of 12 years, the incidence of CCALD decreases, but an MRI scan must be performed yearly or earlier if new symptoms occur. It is important to detect cerebral ALD as early as possible, preferably in the asymptomatic stage with only moderate radiological abnormalities to discuss the possibility to perform allogeneic HCT. Accordingly, if a brain MRI shows abnormalities, even very limited such as an increased signal intensity on T2 or FLAIR sequences in the splenium or genu of the corpus callosum, brain MRI must be repeated within 3 months to evaluate disease progression and in particular to identify the presence of gadolinium rim enhancement of lesions. Because the disease can be very rapidly progressive, it is strongly advised to discuss the possibility of allogeneic HCT as soon as brain MRI abnormalities typical of cerebral ALD are detected. After a successful transplant, the lesions on MRI stabilize and even regress. Treatment results are better the earlier treatment is started .
For adult men with or without signs of AMN, we advise evaluation by a neurologist yearly or bi-annually to screen for symptoms of AMN and to administer symptomatic treatment if necessary (for instance, medication against spasticity). Referral to a rehabilitation physician and urologist will often become necessary.
Adult men can develop cerebral ALD and in our centers, we offer an MRI of the brain every single year [30, 45]. There is no proven treatment for cerebral ALD in adults. It seems likely that allogeneic HCT is also effective in adults with early stage cerebral ALD, but there are no published studies or cases describing this treatment. We tend to consider allogeneic HCT in an adult patient with early stage cerebral ALD, after carefully counseling the patient about the lack of evidence for the treatment and the risk of the procedure which is significantly higher than in boys. Whereas the onset of demyelinating lesions involving the corpus callosum and adjacent parieto-occipital or frontal white matter leaves no doubt about the onset of cerebral ALD, the situation is different when there are only slightly increased signal abnormalities in the pyramidal tracts of AMN patients that gradually become more intense and involve the white matter of the centrum semiovale. This can herald the onset of cerebral ALD, but can also reflect Wallerian degeneration in severe AMN.
For AMN there is no effective disease modifying therapy available yet. Although Lorenzo’s oil (LO) had great promise, several open-label trials have shown that the disease progresses even when plasma VLCFA are normalized by LO treatment [84, 85]. A large randomized placebo-controlled clinical trial was designed to provide a definitive answer, but was unfortunately aborted before completion by the safety monitoring board because of presumed side effects of the placebo treatment. There is also a retrospective study suggesting that if presymptomatic boys are started on LO, it may delay the onset of neurological symptoms . We consider the scientific evidence to support the efficacy of LO weak, and do not offer this treatment to our patients. Regular follow-up in AMN remains important, however, mainly to provide symptomatic treatment.
Lovastatin also lowered plasma VLCFA , but a placebo-controlled trial revealed that lovastatin did not have an effect on the C26:0 levels in peripheral blood lymphocytes and erythrocytes nor on the VLCFA content of the low-density lipoprotein fraction .
More research and new treatments strategies are desperately needed, especially for those affected by AMN, which is relentlessly progressive and causes severe disability. Antioxidants reduce markers for oxidative stress and axonal degeneration in the spinal cord of Abcd1 knockout mice . Based on this observation a clinical trial with anti-oxidants in X-ALD is ongoing in Spain.