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Disease progression in women with X-linked adrenoleukodystrophy is slow

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Huffnagel, Irene C., Dijkgraaf, Marcel G. W., Janssens, Georges E., van Weeghel, Michel, van Geel, Björn M., Poll-The, Bwee Tien, Kemp, Stephan, Engelen, Marc·2019·Orphanet Journal of Rare Diseases
DOI 10.1186/s13023-019-1008-6PMC PMC6367840
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Abstract

BACKGROUND: Over 80% of women with X-linked adrenoleukodystrophy (ALD) develop spinal cord disease in adulthood for which treatment is supportive only. For future clinical trials quantitative data on disease progression rates are essential. Moreover, diagnosis can be challenging in ALD women, as the most important diagnostic biomarker is normal in 15-20%. Better biomarkers are needed. The purpose of this single centre cross-sectional follow-up study in women with ALD was to assess whether Expanded Disability Status Scale (EDSS), AMC Linear Disability Scale (ALDS) and Short Form (36) Health Survey (SF-36) can detect disease progression and to model the effect of age and duration of symptoms on the rate of progression. Moreover, we performed a pilot study to assess if a semi-targeted lipidomics approach can identify possible new diagnostic biomarkers. RESULTS: In this study 46 women (baseline clinical data published by our group previously) were invited for a follow-up visit. Newly identified women at our center were also recruited. We analysed 65 baseline and 34 follow-up assessments. Median time between baseline and follow-up was 7.8 years (range 6.4-8.7). Mean age at baseline was 49.2 ± 14.2 years, at follow-up 55.4 ± 10.1. EDSS increased significantly (+ 0.08 points/year), but the other outcome measures did not. Increasing age and duration of symptoms were associated with more disability. For the pilot study we analysed plasma of 20 ALD women and 10 controls with ultra-high performance liquid chromatography coupled to high-resolution mass spectrometry, which identified 100 potential biomarker ratios with strong differentiating properties and non-overlapping data distributions between ALD women and controls. CONCLUSIONS: 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. 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. In addition, a semi-targeted lipidomics approach can identify possible new diagnostic biomarkers for women with ALD.

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  • Slowly progressive AMN symptoms occur in approximately 65% of heterozygous women by age 60 due to inactivation of the non-mutated X chromosome and mosaic expression of X-linked genes in neural cells.

    “Although ALD is an X-linked disease, slowly progressive AMN symptoms occur in ~65% of heterozygous women by the age of 60 years [31,47,59,60] due to the inactivation of the non-mutated X chromosome and the mosaic expression of X-linked genes in neural cells [60,61,62,63].”

    From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [60]

    The Background (page not provided) says that more than 80% of women with ALD eventually develop progressive spinal cord disease, and the Results > Progression rates section describes progression as very slow. The paper does not give the claimed ~65% prevalence by age 60 or attribute symptoms to inactivation of the non-mutated X chromosome and mosaic expression in neural cells. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The majority of women with ALD are not merely carriers but may develop some degree of myeloneuropathy leading to gait, bowel, and bladder dysfunction.

    “It is becoming increasingly recognized that the majority of women are not merely carriers, but may develop some degree of myeloneuropathy leading to gait, bowel, and bladder dysfunction [14,15,63].”

    From Structure and Function of the ABCD1 Variant Database: 20 Years, 940 Pathogenic Variants, and 3400 Cases of Adrenoleukodystrophy (2022) · cites this paper as [15]

  • Women with ALD develop myeloneuropathy, whereas men can develop all three core syndromes.

    “Women develop myeloneuropathy; men can develop all 3 syndromes.7-9”

    From International Recommendations for the Diagnosis and Management of Patients With Adrenoleukodystrophy (2022) · cites this paper as [8]

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Cited by

Sorted by citations

Authors
Huffnagel, I. C., Dijkgraaf, M. G. W., Janssens, G. E., van Weeghel, M., van Geel, B. M., Poll-The, B. T., Kemp, S., & Engelen, M.
Affiliations
Amsterdam UMC Location University of Amsterdam (NL)
Corresponding author
Engelen, Marc
ORCID
Venue
Orphanet Journal of Rare Diseases
Publisher
Springer Science and Business Media LLC
Published
2019-02-07
Volume
14
Issue
1
Pages
30-30
ISSN
1750-1172 (ISSN-L)
DOI
10.1186/s13023-019-1008-6
PMC
PMC6367840
OpenAlex
W2916744594
Cited by
100
References
4
Citations by year
2026: 11 · 2025: 16 · 2024: 19 · 2023: 10 · 2022: 10 · 2021: 16 · 2020: 14 · 2019: 4
FWCI
7.61
Type
journal article
Language
en
Open access
Licence
Locations
  • Orphanet Journal of Rare Diseases (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (submittedVersion, cc-by)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Nederlandse Organisatie voor Wetenschappelijk Onderzoek (016.156.033)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
Keywords
X-linked adrenoleukodystrophy, spinal cord disorders, disease progression, Expanded Disability Status Scale, SF-36, plasma lipidomics, diagnostic biomarkers, clinical trial outcome measures
MeSH terms
Adrenoleukodystrophy, Adult, Cross-Sectional Studies, Female, Humans, Middle Aged, Spinal Cord Diseases, Biomarkers, Logistic Models, Disease Progression, Computational Biology

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