ACTH RECEPTOR DEFECT IN ADRENOLEUKODYSTROPHY (ALD)

Abstract

ACTH insensitivity is a cardinal feature of ALD, but the mechanism is unknown. We studied a 10 year old hyperpigmented boy with glucocorticoid insufficiency of 8 years duration and a history of two generalized tonic clonic seizures associated with febrile episodes with normal blood glucose. His neurological exam was normal, EEG showed non-specific slowing with normal auditory evoked responses, and Magnetic Resonance Imaging showed areas of increased signal intensity in the cerebral peduncles and the internal capsule. ALD was documented by increased plasma very long chain fatty acids, i.e., C26/C22 = 0.055 (control = 0.01 ± 0.01); C26= 1.572 μg/ml (control = 0.33 ± 0.18 pg/ml). Basal ACTH was elevated at 1840 pg/ml (normal = <100 pg/ml). Cortisol was 7.0 μg/dl with no response to exogenous ACTH. Basal and stimulated renin and aldosterone were normal. The child's leukocytes had no detectable ACTH binding sites in a radioligand binding study. In contrast, normal mononuclear leukocytes possess high and low affinity receptors for ACTH that appear identical to the prototype adrenal receptors. These studies suggest that the adrenal failure associated with ALD is secondary to an ACTH receptor defect. Whether the ACTH receptor defect is primary or secondary to the long chain lipid abnormality is under investigation.