Guidelines for management

November 2nd, 2014 |

Marc Engelen, M.D., Ph.D. and Stephan Kemp, Ph.D.

The text on this page is a summary of the paper: “X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management”. The full paper was published as Open Access in Orphanet Journal of Rare Diseases (for readability, the references have been removed). The full text can be viewed and downloaded (as a pdf).

Introduction

The clinical spectrum in males with ALD ranges from isolated adrenal insufficiency and slowly progressive myelopathy (AMN) to devastating cerebral demyelination (cerebral ALD). The majority of affected females will develop symptoms by the age of 60 years. In the absence of a genotype–phenotype correlation, it is not possible to predict disease course; not even within individual families. This article focuses on the management of patients with ALD and provides a guideline for clinicians that encounter patients with this highly complex disorder.

The flowchart below summarizes the recommendations for follow-up of boys and men with ALD.

Outpatient management of ALDBoys with ALD

Follow-up in boys with ALD is important for two reasons: 1) early detection of adrenal insufficiency and 2) early detection of cerebral ALD to propose allogeneic hematopoietic stem cell transplantation (HSCT) if a HLA-matched donor or cord blood is available. Despite significant mortality risk, allogeneic HSCT remains the only therapeutic intervention that can arrest the progression of cerebral demyelination in ALD, provided the procedure is performed very early, i.e., when affected boys have no or minor symptoms due to cerebral demyelinating disease.

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 allogeneic HSCT, once the very encouraging results obtained in the first two treated patients will have been extended to a larger number of patients with cerebral ALD.

If boys do not have Addison’s disease it is recommended that an endocrinologist evaluates them yearly for adrenal dysfunction by measuring the plasma ACTH levels and performing an ACTH 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 HSCT. 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 HSCT 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.

Adult men with ALD

Follow-up in men with ALD is important for the early detection of adrenal insufficiency. If men do not have Addison’s disease it is recommended that an endocrinologist evaluates them yearly for adrenocortical dysfunction by measuring the plasma ACTH levels and performing an ACTH test. Steroid replacement therapy can then be initiated if necessary.

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. There is no proven treatment for cerebral ALD in adults. It seems likely that allogeneic HSCT 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 HSCT 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.

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. 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.

Women with ALD

Women with ALD should be evaluated for the development of neurologic symptoms. Since women with ALD very rarely develop adrenal insufficiency or cerebral involvement, periodic evaluation of adrenal function and brain MRI is not mandatory. Greater awareness among physicians that women can develop neurologic symptoms is important for counseling but also to prevent unnecessary diagnostic tests and erroneous diagnosis. We know of cases of women with ALD who underwent cervical laminectomy for presumed cervical spondylogenic myelopathy. For symptomatic women with ALD, we advise (as for men with AMN) a yearly evaluation by a neurologist to discuss the indication of rehabilitation, the referral to an urologist and treatment of spasticity and neuropathic pain.

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