Adrenoleukodystrophy (ALD)
From the paper ‘A Longitudinal Analysis of Early Lesion Growth in Presymptomatic Patients with Cerebral Adrenoleukodystrophy’ by Mallack et al (2021) – access: http://www.ajnr.org/content/early/2021/09/09/ajnr.A7250
X-linked adrenoleukodystrophy (X-ALD) is caused by mutations the gene ABCD1, which carries the instructions for making a cellular protein of the same name. Any number of mutations in ABCD1 may disrupt the function of the protein ABCD1. However, it isn’t possible to correlate the effect of a given ABCD1 mutation with the course of disease a person affected by X-ALD will experience. In research, this is known as a genotype-phenotype correlation (i.e., the influence a gene or a genetic mutation has on a person’s physical health).
There are several subtypes of X-ALD, and being able to distinguish between these subtypes at an early stage is extremely important, as it influences the treatment plan. Most people with ABCD1 mutations develop cerebral adrenoleukodystrophy (CALD). The majority of these patients experience a progressive form of CALD, which unfortunately has a poorer prognosis than ‘arrested CALD’. In arrested CALD, a person will undergo ‘spontaneous arrest of disease’, meaning symptoms cease to advance in the absence of medical intervention. Patients with arrested CALD are not suitable candidates for haematopoietic stem cell transplantation (i.e., a bone marrow transplant). This procedure, although it does have the potential to improve the symptoms of CALD in certain patients, is not without risk and is associated with significant and serious side effects. For those patients for whom a bone marrow transplant could be of benefit, the procedure is most successful when initiated before the onset of neurological symptoms. It has more recently been shown that alternative gene therapy treatment approaches are more effective when the patient is younger too. As it not possible to use genetic analysis (i.e., the nature of the mutation in ABCD1) to predict how CALD will progress, the researchers in this study have attempted to investigate if there is utility in using the results of brain MRI scans.
Specifically, the aim of this study was to investigate how the results of brain MRI scans changed over time (longitudinally) in patients with CALD, starting from when these patients were pre-symptomatic. This study was carried out retrospectively, meaning the researchers used existing MRI records of various CALD patients (rather than enrolling any patients into an active study, such as usually occurs in a clinical trial). The researchers used 174 MRIs from 36 pre-symptomatic patients, some of whom have progressive CALD, and some of whom have the arrested form of the disease. Starting with the earliest scans, the researchers used specialist image analysis software to calculate the size of the cerebral lesions in each image. A lesion is an area of tissue that has been damaged through injury or disease, and occur in CALD as a result of the cell damage caused by ABCD1 mutation. This damaged tissue reacts differently with the magnetic field used to conduct an MRI scan, and it will therefore appear contrasted against the healthier brain tissue surrounding the lesion. Once they had a value for volume of the lesion, the researchers were then able to assess how this measurement changed over time by plotting lesion volume against the age at which the patient had had the scan on a graph. It was found that there was an inverse correlation between patient age and a couple of parameters of lesion growth; meaning the younger the patient, the faster the lesion was developing.
Overall, the researchers found that there is utility in measuring and assessing how newly developing cerebral lesions change over time using their technique. Indeed, it was found that the trajectories of lesion growth differ between the progressive and arrested subtypes of CALD before symptom onset. For example, those patients in whom newly developed lesions grew rapidly were those with progressive CALD. Cerebral lesions in patients known to have arrested CALD were found to not have grown at the same rate as those with the progressive subtype. Importantly, the researchers also noted that their way of measuring how cerebral lesions were developing was more sensitive than the standard method for measuring the extent of neurological damage in CALD. For example, they found significant differences in the size of a given lesion correlated to the severity of symptoms experienced by an individual which both had an ‘LS score’ (the standard method of scoring) of 1. This study is especially important in light of the recent addition of adrenoleukodystrophy to the Recommended Uniform Screening Programme. It should now be possible to monitor for new cerebral lesions from birth and accurately predict which patients are eligible for therapy.