Comparison between approaches to assess spinal cord disease show that the neurological tool Expanded Disability Status Scale (EDSS) can assess disease progression in women with adrenoleukodystrophy (ALD), but only when viewed in a long time window (about eight years). This suggests that more sensitive assessment tools are needed.
A study with those results, “Disease progression in women with X-linked adrenoleukodystrophy is slow,” was published on the Orphanet Journal of Rare Diseases.
While ALD affects both men and women, women previously were considered to be asymptomatic carriers of the disease. However, more than 80 percent of the women who carry the disease develop progressive spinal cord disease (adrenomyeloneuropathy,or AMN) later in life and with a slower progression.
Also, while very long chain fatty acids (VLCFAs) plasma levels — the conventional diagnostic marker for ALD — are reliable in diagnosing ALD in men, about 15-20 percent of women with ALD have normal VLCFA levels.
Those are reasons why better biomarkers of ALD disease are needed.
Now, a team led by researchers from the Academic Medical Center, University of Amsterdam, in The Netherlands, conducted a single-center, follow-up study in ALD women and evaluated disease progression using three commonly used scales to assess spinal cord disease: EDSS, the AMC Linear Disability Scale (ALDS), and the quality of life questionnaire Short Form Health Survey (SF-36).
The team also performed a lipidomics analysis (a large-scale study of cellular lipids, or fats) to find reliable diagnostic biomarkers for ALD.
The study enrolled 34 of 46 invited women with ALD (mean age at baseline of 49.2 years), who had participated in a previous study. The study also included an additional 19 women with newly identified ALD, and who had not participated in the previous study.
In total, data from 65 baseline assessments (34 plus 19 participants) and 34 follow-up assessments were available. The median time between baseline and follow-up was 7.8 years.
Researchers assessed symptomatic traits (confirming spinal cord disease) by measuring walking limitations, urge incontinence for urine or feces, and sensory complaints (numbness or tingling skin sensation) in the lower extremities. EDSS scores, ALDS (disability-evaluating survey), and SF-36 values also were assessed in all patients. SF-36 values were compared with norm values of the Dutch population.
Evaluation of the three assessment tools at follow-up showed that EDSS could detect progression of spinal cord disease, while ALDS and SF-36 assessments were not sensitive enough.
At baseline, participants had a mean score of 2.5 (out of 10) EDSS points, indicating minimal disability in two functional systems.
EDSS scores from participants with both baseline and follow-up assessments showed a total disease progression rate of 0.08 points per year, indicating a very slow progression.
Participants who were symptomatic at baseline showed a yearly disease progression of 0.06 EDSS points, while asymptomatic participants showed a 0.17 point disease progression. However, although the observed EDSS scores were statistically significant, they were not considered clinically relevant to be used as an endpoint (goal) in clinical trials.
The other tools, ALDS and SF-36 scores, detected no disease progression rate.
Researchers found that increasing age and duration of symptoms were associated with more disability, meaning higher EDSS scores.
The team also performed a pilot-study — a lipidomics analysis — on 20 ALD women (15 with increased VLCFA levels, and five with normal levels), and 10 controls, to investigate potential plasma biomarkers with a better sensitivity than conventional VLCFA.
Researchers found 56 potential lipid biomarkers that were not overlapping between ALD patients and controls, and 100 potential biomarker ratios with strong anti-correlations that could be more robust predictors of ALD compared with biomarkers alone.
“Although these biomarker ratios should be validated in an external cohort [group], they represent a candidate list of potentially good diagnostic biomarkers,” the researchers wrote.
Overall, the researchers concluded that ALD in women is characterized by a very slow disease progression, and that “progression of spinal cord disease can be detected with EDSS, but not with ALDS or SF-36 after a follow-up period of almost 8 years. Moreover, age and the duration of symptoms seem positively associated with the rate of progression,” they wrote.
However, the fact that disease progression “seems so slow that it cannot be detected by current outcome measures,” unless a study lasts for at least eight years, it is concerning, the team noted.
The researchers emphasized that more sensitive tools to assess spinal cord disease progression are needed to detect disease changes in a more practical time-period.
“Although a significant progression was measurable, it was below the rate generally conceived as clinically relevant. Therefore, EDSS, ALDS and SF-36 are not suitable as primary outcome measures in clinical trials for spinal cord disease in ALD women,” the team concluded.