The natural history of adrenal insufficiency in X-linked adrenoleukodystrophy: an international collaboration
Open accessAbstract
Context: Primary adrenal insufficiency is an important clinical manifestation of X-linked adrenoleukodystrophy (ALD). Other manifestations include spinal cord disease and/or inflammatory demyelinating cerebral disease. Implementation of newborn screening requires natural history data to develop follow-up recommendations. Objective: To delineate the natural history of adrenal insufficiency in male patients with ALD and to assess associations between the risk for developing adrenal insufficiency, spinal cord disease, or cerebral disease and plasma C26:0/C22:0 and C24:0/C22:0 ratios, which are diagnostic biomarkers for ALD. Design: Retrospective review of medical records. Setting: Two international tertiary referral centers of expertise for ALD. Patients: Male patients with ALD followed at the centers between 2002 and 2016. Main Outcome Measures: The primary endpoint was adrenal insufficiency; secondary endpoints were spinal cord and cerebral disease. Results: Data on 159 male patients was available. The probability of developing adrenal insufficiency was described with survival analysis. Median time until adrenal insufficiency was 14 years (95% CI, 9.70 to 18.30 years). The cumulative proportion of patients who developed adrenal insufficiency was age-dependent and highest in early childhood [0 to 10 years, 46.8% (SEM 0.041%); 11 to 40 years, 28.6% (SEM, 0.037%); >40 years, 5.6% (SEM, 0.038%)]. No association between clinical manifestations and plasma ratios was detected with Cox model or Spearman correlation. Conclusions: Lifetime prevalence of adrenal insufficiency in male patients with ALD is ~80%. Adrenal insufficiency risk is time-dependent and warrants age-dependent follow-up. Besides on-demand testing if symptoms manifest, we suggest a minimum of adrenal testing every 4 to 6 months for patients age ≤10 years, annual testing for those age 11 to 40 years, and solely on-demand testing for those age >40 years.
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The cumulative probability of experiencing PAI reached its peak by age 10 years (46.8%), remained notably elevated up to 40 years of age (an additional 28.6%), and subsequently declined significantly beyond that point (an additional 5.6%).
“the cumulative probability of experiencing PAI reached its peak by the age of 10 years (46.8%), remained notably elevated up to 40 years of age (an additional 28.6%), and subsequently declined significantly beyond that point (an additional 5.6%) (26).”
From X-linked adrenoleukodystrophy and primary adrenal insufficiency (2023) · cites this paper as [26]
Due to the absence of comprehensive prospective investigations into the natural progression of the disease, the extent to which PAI develops in individuals with X-ALD remains uncertain, with different studies indicating a penetrance of 50-100%.
“Due to the absence of comprehensive prospective investigations into the natural progression of the disease, the extent to which PAI develops in individuals with X-ALD remains uncertain, with different research studies indicating a penetrance of 50-100% (26).”
From X-linked adrenoleukodystrophy and primary adrenal insufficiency (2023) · cites this paper as [26]
Mineralocorticoid function remains functional in approximately 50% of patients with X-ALD-related PAI.
“the relative preservation of the zona glomerulosa aligns with the observation that mineralocorticoid function remains functional in approximately 50% of the patients (26).”
From X-linked adrenoleukodystrophy and primary adrenal insufficiency (2023) · cites this paper as [26]
PAI was identified in X-ALD patients as young as 7 months and 5 months old; these individuals showed biochemical irregularities associated with PAI but did not exhibit clinical symptoms.
“PAI was identified in X-ALD patients as young as 7 months and 5 months old. These individuals showed biochemical irregularities associated with PAI but yet did not exhibit any clinical symptoms (25, 26).”
From X-linked adrenoleukodystrophy and primary adrenal insufficiency (2023) · cites this paper as [26]
The risk of developing cerebral disease is highest in childhood but remains present throughout life.
“The risk of developing cerebral disease is highest in childhood but remains present throughout life.1,29,33-39”
From International Recommendations for the Diagnosis and Management of Patients With Adrenoleukodystrophy (2022) · cites this paper as [33]
Adrenal insufficiency is characterized by low or normal early morning cortisol levels with high levels of ACTH.
“Adrenal insufficiency is characterized by low or normal early morning cortisol levels with high levels of ACTH.1,33”
From International Recommendations for the Diagnosis and Management of Patients With Adrenoleukodystrophy (2022) · cites this paper as [33]
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ABCD1 dysfunction alters white matter microvascular perfusion
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“Adrenal insufficiency develops in approximately 80% of patients with ALD [19], but often this is an isolated glucocorticoid deficiency due to preferential accumulation of VLCFA in the adrenal zona fasciculata where”
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- Authors
- Huffnagel, I. C., Laheji, F. K., Aziz-Bose, R., Tritos, N. A., Marino, R., Linthorst, G. E., Kemp, S., Engelen, M., & Eichler, F.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- Massachusetts General Hospital (US)
- Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts
- Harvard University (US)
- Corresponding author
- Engelen, Marc
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2018-09-24
- Volume
- 104
- Issue
- 1
- Pages
- 118-126
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2893932486
- Cited by
- 147
- References
- 7
- Citations by year
- 2026: 13 · 2025: 18 · 2024: 24 · 2023: 21 · 2022: 21 · 2021: 23 · 2020: 16 · 2019: 10
- FWCI
- 9.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- 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 › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- X-linked adrenoleukodystrophy, adrenal insufficiency, natural history (disease), male patients, spinal cord disorders, brain demyelination, diagnostic biomarkers, newborn screening
- MeSH terms
- Adolescent, Adrenal Insufficiency, Adrenoleukodystrophy, Adult, Aged, Brain Diseases, Child, Child, Preschool, Female, Humans, Infant, Infant, Newborn, Male, Middle Aged, Retrospective Studies, Spinal Cord Diseases, Biomarkers, Prevalence, Survival Analysis, Risk Assessment, Endpoint Determination, Young Adult
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