This research provides a novel data set and analysis regarding symptomatic disease in ALD, thereby adding to existing knowledge of ALD and its core clinical manifestations. This information can be used by researchers, therapeutic developers, clinicians, and patients who seek to better understand ALD (and all of the phenotypes) from the patient’s point of view. In this study, qualitative interviews were conducted, in which individuals with ALD identified numerous problematic symptoms that affect their lives. The subsequent cross-sectional study, with a large, international cohort of adults with ALD determined the prevalence and impact of these symptoms and themes.

In ALD, the symptomatic themes with the highest prevalence were also those with the highest relative impact: problems with balance, limitations with mobility or walking, and leg weakness. The overlap of most prevalent issues with issues that are most impactful is seen in some, but not all, diseases [20, 25,26,27]. Moreover, the importance of these themes in ALD corroborates existing literature [29, 30]. Raymond et al. [29] report the symptom set that affects 40–45% of individuals with ALD (specifically, AMN) to include progressive stiffness and weakness in the legs, and Percy and Rutledge [30] report that boys with ALD (specifically, cerebral ALD) typically present with neurological deterioration that includes development of quadriparesis. In our cross-sectional study, we observed that 54.1% of respondents used some kind of ambulation assistance (cane, crutches, walker, wheelchair, or motorized scooter), and that 84.4% and 86.2% of respondents had stiffness and leg weakness, respectively.

Furthermore, Winkelman et al. [31] show, through diagnositic phone interviews with 32 patients and chart reviews, that progressive gait and balance problems, leg discomfort, pain, and sleep disturbances (related to restless leg syndrome) are highly prevalent and interconnected in adults with ALD. Indeed, we found 90.8% of participants had problems with balance, 74.3% had pain, 71.6% had impaired sleep or daytime sleepiness, and 74.1% had restless legs. Corre et al. [32] present that, in addition to gait and balance issues, bladder and bowel issues are very common in adults with ALD; in their cross-sectional study of 109 adults with ALD, 76.9% of participants had experienced at least one bladder symptom, and 67.3% had experienced at least one bowel symptom. In our study, 86.1% of participants reported trouble with bladder control, and 66.3% reported trouble with bowel control.

Subgroup analysis provides insight into how specific symptomatic themes differ in prevalence based on the characteristics of individuals with ALD; these are general associations and do not indicate a causal relationship. Female participants with ALD (specifically, AMN) communicated trouble getting around at a lower frequency than male participants. The fact that only up to 80% of females develop any kind of symptoms related to ALD during their lifetimes and most of those who do get symptoms experience them after the age of 40–60 years, with the clinical course being less severe, likely explains the lower prevalence of symptoms when compared to men [33, 34]. Participants above the mean age of 51 years showed greater frequency in problems related to mobility and walking. This worsening of physical symptoms related to the spinal cord and peripheral nerves, particularly motor disability of the lower limbs, spasticity, and pain, as individuals get older is consistent with the clinical classification and prognosis of ALD (specifically, AMN) as a progressive disorder [9, 29, 30, 35].

In the analysis of those who identified as having AMN (as opposed to those without AMN), three symptomatic themes were found to be more common: limitations with mobility or walking, stiffness, and numbness. Indeed, these are hallmark symptom areas of AMN, as confirmed by the literature, and these areas need to be appropriately addressed when caring for patients with this condition. [7, 12] In the examination of those who said they have Addison’s disease (as opposed to those without Addison’s disease), one symptomatic theme was found to be more recurrent: trouble getting around. This may relate to the fatigue and muscle weakness that are recognized as cardinal signs of this condition [17]. In the investigation of those with the cerebral form of ALD, we did not find any significant differences in symptomatic theme prevalence, despite the literature denoting cognitive and behavioral impairements, vision problems, and seizures as more common in this cohort [13]. The difference in findings may be attributed to the small sample of patients with cerebral ALD in our study, such that statistical changes could not be detected.

Interestingly and as shown in several other studies with similar methodology to ours, employment status, especially change in employment, had a significant association with symptomatic theme prevalence [19, 20, 22,23,24,25,26,27]. In our cross-sectional study cohort, not working was associated with higher frequency of 2 symptomatic themes, and a change in employment status or choice due to ALD was associated with higher symptomatic burden in 11 areas. As effective therapies are developed for ALD, it is possible that these therapies will not only reduce individual patient burden but also allow for more open, productive, and meaningful employment opportunities.

We found that the prevalence of two symptomatic themes was associated with a longer time since the onset of symptoms: problems with shoulders or arms and breathing difficulties. In the clinical setting, these two symptomatic themes should be monitored for progression and may be worthy targets for therapeutic interventions [29, 30, 35].

Some of the most widespread differences in symptomatic theme prevalence were seen in those who reported functional disability, those who had speech changes, those who required mobility assistance, and those who received home health aide. The etiology behind the interconnectedness between these concepts and patient-reported symptomatic burden is worth further exploration during future studies.

We acknowledge that there are limitations to this research. The large cohort of individuals with ALD who participated in the cross-sectional study is not a perfect representation of the larger ALD patient population. Although more than 100 adults with all phenotypes of ALD provided data, these participants were limited to those enrolled in one of the national or international registries used for recruitment. In addition, participants self-reported their diagnoses in this study, and these diagnoses were not verified by the registries or by the researchers. Although AMN, cerebral ALD, Addison’s disease, and asymptomatic women with ALS are all considered subsets of ALD, some participants may have misinterpreted their condition. For example, some participants may have had AMN but considered themselves to have ALD only (without AMN) if that was the term commonly used by their physician; or vice versa, some participants may have had AMN and thought of themselves to have AMN only (and not ALD) if they were unfamiliar with the classification of AMN as a subtype of ALD.

Study participants could have differed from the broader ALD patient population in that they represented those with moderate disease burden; asymptomatic individuals or those with very severe symptoms may not have had the willingness or capability to engage in this study. Relatedly, the inclusion of some asymptomatic women with ALD may have diluted the average symptomatic burden found in women overall [34], and the inclusion of younger individuals (more of whom would be asymptomatic or presymptomatic) may have lessened the overall disease burden reported for the entire sample [9].

Our study cohort also included a high percent of participants who identified as white (89.9%) and non-Hispanic (86.2%), and far fewer from minority races and ethnicities. The lack of minority participation in research is a longstanding challenge but one that our clinical research team and organization are working to address through continued and more diversified outreach in the community.

Our recruitment and cross-sectional survey study were conducted primarily online, so individuals without email or access to the internet were also probably underrepresented. Nevertheless, the results from our study do likely reflect the responses for the section of the ALD population that is likely to seek care and participate in research and clinical trials in the future.