The Natural History of Adrenal Insufficiency in X-Linked Adrenoleukodystrophy: An International Collaboration

Abstract

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.

X‐linked adrenoleukodystrophy: Pathology, pathophysiology, diagnostic testing, newborn screening and therapies

“…The lifetime incidence of adrenal disease in ALD males is about 80% with 46.7% developing adrenal hormone deficiency in childhood, 6 months–10 years of age, 28.6% ages 10–40 years and only 5.6% after the age of 40 years (Huffnagel, Laheji, et al, ). The fetal adrenal in ALD males has the abnormal pathology and biochemistry found in adrenals of postnatal males with ALD.…”

“…The site of adrenal dysfunction is in good agreement with the fact that ABCD1 protein is found in the adrenal cortex but not in the adrenal medulla, while ABCD2 shows the opposite distribution (Troffer‐Charlier et al, ). The VLCFA in the cell membranes may also interfere with ACTH and gonadotropin binding to their receptors (Burtman & Regelmann, ; Huffnagel, Laheji, et al, ). Similar biochemical changes and pathology are found in the Leydig cells of the testes leading to defective hormonogenesis.…”

“…About 20% of adult males with AMN also develop cerebral disease that rapidly progresses to disability and death (van Geel, Bezman, Loes, Moser, & Raymond, ). Additionally, the adrenal glands are commonly affected with a lifetime risk of adrenal insufficiency of ~80% in ALD males (Huffnagel, Laheji, et al, ).…”

“…Early diagnosis through family screening of at‐risk males, and as of December 2013 in the USA, newborn screening has provided hope for successful treatment for ALD (Raymond, Moser, & Fatemi, ). Adrenal insufficiency is rare in ALD females but early identification of adrenal disease will save the lives of ALD males who may succumb to adrenal crisis without stress hormone administration (Dubey et al, ; Huffnagel, Laheji, et al, ; Kemp, Huffnagel, Linthorst, Wanders, & Engelen, ).…”

Anesthetic management of pediatric patients diagnosed with X‐linked adrenoleukodystrophy: A single‐center experience

“…A retrospective study by Huffnagel et al found that the first manifestation of X‐ALD was adrenal insufficiency in 37.7% of cases, followed by spinal cord disease (25.2%) and cerebral disease (14.5%). While almost all male patients with X‐ALD will develop adrenal insufficiency during their life and 80% are diagnosed before adulthood, the disease may remain clinically silent for some time .…”