Self‐reported quality of life in symptomatic and asymptomatic women with X‐linked adrenoleukodystrophy

Abstract Background Up to 80% of women with X‐linked adrenoleukodystrophy (X‐ALD) develop symptoms of myelopathy and peripheral neuropathy during their lifetime. The study's objective was to compare symptomatic versus asymptomatic women with X‐ALD regarding their physical and mental well‐being and quality of life. Methods Data were obtained from a prospective, international, cross‐sectional cohort study of women with X‐ALD recruited both clinically and population based. Symptoms, quality of life, and physical and mental co‐morbidities were assessed by questionnaires. Women were considered symptomatic if they reported any sign of myelopathy or peripheral neuropathy. Group differences between symptomatic versus asymptomatic women and between age groups were examined using χ 2 tests for categorical and independent sample t tests or analysis of variance for continuous variables. Results Complete data were available from N = 180 women (mean age: 51.2 ± 13.6 years, range: 18–85), of whom 71.7% were classified as symptomatic, with prevalence increasing with age. Symptomatic versus asymptomatic women reported poorer physical and mental health, with 26.4% meeting the criteria for a clinical depression, 73.6% reporting chronic pain, 80.6% sleeping disturbances, 38.2% sexual dysfunction, and 47.3% restless legs syndrome. Large group differences were found on the physical health, but not on the mental health component of quality of life, where symptomatic women only differed when controlling for having a boy affected by X‐ALD (small effect) and treatment frequency (medium effect). Conclusions Symptomatic women with X‐ALD present with physical and psychological co‐morbidities significantly reducing individuals’ quality of life. The findings emphasize the need to develop new multi‐disciplinary treatment options tailored to women's specific needs.


INTRODUCTION
X-linked adrenoleukodystrophy (X-ALD) is one of the most common inborn errors of metabolism caused by mutations in the ABCD1 gene.
The ABCD1 transporter, located at the peroxisomal membrane, shuttles activated very long chain fatty acids (VLCFA) into the organelle for further degradation. Dysfunction of the transporter in the diseases leads to toxic accumulation of saturated VLCFA in all body fluids and tissues. In males, the clinical spectrum ranges from adrenal insufficiency without neurological symptoms to a rapidly progressive, fatal cerebral demyelinating disease that usually occurs in childhood (childhood cerebral ALD [CCALD]) or adulthood (adult cerebral ALD [ACALD]) (Kemp et al., 2016;Köhler et al., 2018). The most frequent X-ALD phenotype affecting both adult males and females is adrenomyeloneuropathy (AMN), a slowly progressive myelopathy and peripheral neuropathy, characterized primarily by progressive spastic paraparesis, sensory ataxia, and bladder and bowel dysfunction (Köhler et al., 2018;Lynch et al., 2019;Turk et al., 2020;Zhu et al., 2020), while cognitive functions generally remain unimpaired (Schäfer et al., 2021).
Due to the X-linked inheritance, it has long been assumed that women with X-ALD are merely carriers and remain asymptomatic.
However, recent findings suggest that up to 80% of women with X-ALD develop symptoms of myelopathy and peripheral neuropathy (Engelen et al., 2014), with gait disorders found in 65% (Engelen et al., 2014), bladder and bowel dysfunction in over 79% (Corre et al., 2021;Hofereiter et al., 2015), sensory complaints in 81% (Engelen et al., 2014), restless leg syndrome (RLS) in 48% (Winkelman et al., 2022), and neuropathic pain in over 80% of symptomatic women (Bachiocco et al., 2021;Huffnagel et al., 2019). As symptomatic courses in women progress slower, have a later onset in life (> 40 years of age), and do not usually convert to ACALD (<1%) (Engelen et al., 2014;Habekost et al., 2015;Huffnagel et al., 2019;Kemp et al., 2016;Schirinzi et al., 2019), symptoms in women with X-ALD are frequently underestimated, overlooked, or misinterpreted, for example, as multiple sclerosis (Di Filippo et al., 2011;Stöckler et al., 1993). In addition, women with X-ALD appear to be at higher risk for psychological distress (Kuratsubo et al., 2008), for example, depressive grief over the loss of a boy affected by CCALD and/or feeling guilty about passing the gene defect to male offspring. Further, symptomatic women with X-ALD face particular barriers to accessing appropriate treatment on a regular basis, for example, because they are fully engaged in taking care of a diseased child or because they are not taken seriously by their local physicians who might be not aware of symptoms occurring in women with X-ALD. Due to the slower clinical progression of symptoms in women, which is hardly detectable with current outcome measures (Huffnagel et al., 2019), women are not suitable participants in clinical trials evaluating new symptomatic treatment approaches, and curative therapy is lacking for both males and females with X-ALD. As a consequence, many symptomatic women with X-ALD, though often living with untreated chronic pain, bladder and bowel dysfunction, walking difficulties, depression, and psychological distress, fall out of diagnostic and therapeutic focus.
To date, research on the natural history of symptoms in women with X-ALD and its impact on quality of life is scarce (Corre et al., 2021;Engelen et al., 2014;Hofereiter et al., 2015;Huffnagel et al., 2019).
By using the well-established Short Form (36) Health Survey (SF-36) (Ware, 2000), two studies indicated lower quality of life related to physical disability in symptomatic versus asymptomatic women with X-ALD, whereas no effect of symptomatic status was found on the SF-36 mental health component (Engelen et al., 2014, Huffnagel et al., 2019. Lack of group differences in mental well-being and its impact on quality of life may be due to relatively small sample sizes (N = 46-65).
Raising awareness for the needs of affected women and a deeper understanding of disease progression in women with X-ALD appears to be crucial, finally resulting in an important contribution to the development of future treatment tailored to women's specific needs. Against this background, our study's objectives were to evaluate the impact of symptomatic courses in women with X-ALD on various quality-of-life, physical, and mental health measures, and determine the additional effect of being the mother of an affected boy as well as treatment frequency on the quality of life of affected individuals in a prospective, large-sized, both clinical and population-based international sample.

Participants and study design
Women with X-ALD were recruited from the Leukodystrophy Outpa-

Neurological symptoms
Based on the disease-specific Adult ALD Clinical Score (AACS) (Köhler & Sokolowski, 1999), a 10-item questionnaire was developed to assess the presence of symptoms of myelopathy and/or peripheral neuropathy in women with X-ALD on three domains: gait disorders, bladder and bowel dysfunction, and sensory complaints. Women were considered symptomatic if they reported signs of myelopathy and/or peripheral neuropathy in at least one domain.
Suicidal thinking was rated by the total score of the Beck Scale for Suicide Ideation (BSSI) (Beck & Steer, 1991), ranging from 0 to 38, with higher scores indicating stronger suicidal ideation. Participants were classified as suicidal if they scored >0 on item 4 (desire to make active suicide attempt) or item 5 (passive suicide desire) in the screening part of the BSSI.
Chronic pain and its impact on participants' daily functioning was assessed by computing the total scores of the subscales pain severity (range: 0-40) and pain interference (range: 0-70) of the Brief Pain Inventory-short form (BPI-sf) (Cleeland & Ryan, 1994) in patients who self-reported chronic pain (item 1 of the BPI-sf), with higher scores indicating greater pain severity and pain interference, respectively.
The total score of the Modified Fatigue Impact Scale (MFIS, range: 0-84) (Larson, 2013) was applied to measure the impact of fatigue on participants' quality of life, with higher scores indicating greater fatigue.
Sleep quality and disturbances were assessed by the total score of the Pittsburgh Sleep Quality Index (PSQI) (Buysse et al., 1989), ranging from 0 to 21, with higher scores indicating poorer sleep. Participants were classified as bad sleeper if their total score was ≥5.
The total score of the Female Sexual Function Index (FSFI) (Rosen et al., 2000) was used to assess self-reported sexual function among participating women, ranging from 4 to 95, with lower scores indicating higher sexual dysfunction. Women were classified as at risk for sexual dysfunction if their total score was ≤26 (Wiegel et al., 2005).
The total score of the International Restless Legs Syndrome Study Group rating scale (IRLS) (Walters et al., 2003) was used to assess the presence and severity of RLS on a range of 0 (no RLS) to 40 (very severe RLS). Based on total scores, participants were additionally assigned to the following categories: 0 (no RLS), 1-10 (mild RLS), 11-20 (moderate RLS), 21-30 (severe RLS), and 31-40 (very severe RLS).

Sociodemographic and control variables
Sociodemographic data included participants' age, nationality, employment status, and treatment frequency (i.e., frequency of regular medical check-ups for X-ALD), which was classified as at least every 1-2 years, less frequently than every 2 years, and no treatment at all. To control for the impact of being a mother of an affected boy with X-ALD on participants' quality of life and mental and physical well-being, women were categorized as having no affected boy or at least one affected boy for additional analyses.

Statistical analysis
Data were analyzed with SPSS Version 27.0, and all statistical tests were two-tailed with a significance level set at α = .05. Differences between age groups and symptomatic vs. asymptomatic women regarding sociodemographic data, self-reported symptoms, quality of life, and mental and physical co-morbidities were examined using χ 2 tests for categorical and independent sample t tests for continuous variables. Analyses of variance were performed when more than two groups were compared for continuous dependent variables, and posthoc tests with Bonferroni correction were used to reveal the location of pair-wise differences when omnibus tests were significant. In terms of violation of normality and homogeneity of variances, non-parametric tests were used and reported if results differed from the parametric tests.

Neurological symptoms
Of all symptomatic women, 90.7% reported gait disorders, 80.6% bladder and bowel dysfunction, and 79.8% sensory complaints (  (Cohen, 1988). a This questionnaire was added later (October 2020), causing a reduction in sample size.

F I G U R E 1 Frequency of symptomatic status by age group
was found on bladder and bowel dysfunction (p = .795) and sensory complaints (p = .971).

Quality of life and co-morbidities
Symptomatic women reported significantly decreased health-related quality of life on all subscales of the SF-36 compared to asymptomatic women (ps ≤ .050, medium-to-large sized effects except for the small effect found on mental health;

DISCUSSION
To date, physical and mental well-being and its impact on quality of life in symptomatic vs. asymptomatic women with X-ALD have never been studied in detail, for example, using eligible self-report questionnaires. This currently largest, prospective, cross-sectional cohort study of women with X-ALD found that the quality of life in symptomatic women is tremendously impaired in several areas of daily life and well-   (Strober et al., 2020). The results of the present study highlight the need for a multi-approach diagnostic and treatment process in symptomatic women with X-ALD that not only focuses on disease-specific symptoms such as spasticity and bladder and bowel dysfunction, but takes into account multiple physical and mental co-morbidities that affect the individual's quality of life.
Although determined by self-report, the prevalence of RLS found in the present sample of symptomatic women with X-ALD (47.3%) is consistent with recent findings based on diagnostic telephone interviews (47.6%) (Winkelman et al., 2022). Of note, a significant proportion of women (20.8%) who were classified as asymptomatic due to the absence of signs of myelopathy and peripheral neuropathy reported mild to moderate symptoms of RLS, which were above the prevalence rate found in the general population (3.9%-14.3%) (Allen et al., 2005;, while the prevalence rates of other physical and mental co-morbidities were within the normal range. This finding suggests that RLS in asymptomatic women with X-ALD might be an early sign of myelopathy; however, this question should be investigated in future studies with longitudinal designs. In contrast to previous findings (Engelen et al., 2014;Huffnagel et al.,  physical and mental health status in symptomatic women with X-ALD (Engelen et al., 2014) but impaired psychological and social functioning in parents of children with a rare disease (Boettcher et al., 2021;Kuratsubo et al., 2008;Pelentsov et al., 2016). This again highlights the importance of a multi-disciplinary approach in the clinical care of women with X-ALD, which, in addition to symptomatic treatment of neurological symptoms, also takes into account psychological support and social work (Dimitrova et al., 2021), especially for women with familial clustering of the disease and particular burden of caring for relatives.
Consistent with previous, mainly clinically recruited cohort studies, the prevalence of self-reported symptoms in women increased steeply with age, finally affecting more than 91% of women older than 60 years.
The current data support the previously reported cut-off of 41 years being crucial for symptom onset in more than 80% of women with X-ALD (Schirinzi et al., 2019). In addition, symptoms were already present in approximately 20% of women younger than 40 years in the current sample (Azar et al., 2020), and a few women were asymptomatic in selfreport even in old age. However, the prevalence rates for symptomatic courses in women with X-ALD found in our and previous samples should be interpreted with caution and most likely represent an overestimation of the actual prevalence in the general population due to recruitment bias. Despite great efforts to also reach women with X-ALD from the general population and across age range, 46.1% of the present sample comprised women aged 40-59 years, mainly symptomatic and clinically recruited. It remains unclear how high the real prevalence of asymptomatic women in the general population is who are unaware of their gene defect, or of symptomatic women running under a false diagnosis, for example, multiple sclerosis (Di Filippo et al., 2011;Stöckler et al., 1993), before receiving a proper diagnosis at later ages. Thus, estimating the real prevalence of symptomatic courses in women with X-ALD remains challenging due to these biases that cannot be overcome as long as X-ALD is not included in newborn screening in both genders (Lee et al., 2020;Matteson et al., 2021).
Whereas the presence and severity of gait disorders in symptomatic women increased by age (from 66.7% in women <40 years to 92.5% in women >60 years of age), bladder and bowel dysfunction and sensory complaints, even of high severity, were common symptoms in women independent of age (>80%). The self-reported prevalence rates are consistent with recent findings from studies using objective measures, such as those assessing bladder and bowl dysfunction in women with X-ALD (Corre et al., 2021). Remarkably, 66.7% of young symptomatic women reported occasional incontinence and 33.3% permanent loss of sensation or pain in the legs. This finding highlights the need to consider rare diseases like X-ALD in the differential diagnosis of women presenting to their physician with these complaints and unclear etiology.
In terms of treatment frequency, the current data show that more symptomatic women than asymptomatic women seek medical checkups for X-ALD every 1-2 years. In addition, sub-analyses showed that high physical disability was associated with higher treatment frequency among symptomatic women, while those without X-ALDspecific treatment reported significantly lower mental health and higher depression scores. This may suggest that regular medical checkups for X-ALD improve the mental well-being of symptomatic women and/or that high psychological distress and depression are barriers to seeking X-ALD-specific treatment. Thus, 30.6% of symptomatic women in our sample do not present for regular check-ups (<2 years), although recommended (Engelen et al., 2012), and 39.1% of asymptomatic women do not seek medical evaluation at all. This suggests that the clinical management of women with X-ALD is still lagging behind the standards of men and that there is a high need for raising awareness and breaking through barriers.
Strengths of this study include the prospective design, the large sample size allowing for even detecting small-to-medium sized effects, and the international clinical-and population-based recruitment. Physical and mental status and its impact on quality of life were assessed multi-dimensionally using various state-of-the-art questionnaires. The results of the present study are limited by the assessment of myelopathy and peripheral neuropathy symptoms and co-morbidities in selfreports, risking over-or underreporting. Further, the results of the present study might be biased by additional effects of the COVID-19 pandemic on individuals' psychological well-being and quality of life (Chung et al., 2020;Halley et al., 2021). Moreover, due to the cross-sectional design, no conclusions can be drawn about causal relationships.
In summary, the current study indicates a high prevalence of physical and psychological co-morbidities in symptomatic women with

ACKNOWLEDGMENTS
The authors thank all staff involved in data collection at the University Hospital Leipzig. The Research Project was carried out on Leuconnect platform in partnership with ELA International (Contract ELA 2020-P001) and was funded by the Open Access Publishing Fund of Leipzig University supported by the German Research Foundation within the program Open Access Publication Funding.

CONFLICTS OF INTEREST
The authors declare no conflict of interest.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

PEER REVIEW
The peer review history for this article is available at https://publons. com/publon/10.1002/brb3.2878