Early diagnosis of cerebral X-linked adrenoleukodystrophy in boys with Addison’s disease improves survival and neurological outcomes

Abstract

Approximately one-third of boys with X-linked adrenoleukodystophy (X-ALD) develop an acute, progressive inflammatory process of the central nervous system, resulting in rapid neurologic deterioration and death. Hematopoietic cell transplantation (HCT) can halt the progression of neurologic disease if performed early in the course of the cerebral form of X-ALD. We describe a retrospective cohort study of 90 boys with X-ALD evaluated at our institution between 2000 and 2009, to determine if early diagnosis of X-ALD following the diagnosis of unexplained adrenal insufficiency (AI) improves outcomes. We describe 7 cases with a delay in the diagnosis of X-ALD, and compare their outcomes to 10 controls with the diagnosis of ALD made within 12 months following diagnosis of AI. At the time of evaluation for HCT, boys with a delay in the diagnosis of X-ALD had more extensive cerebral involvement and more limited functioning. These boys also were 3.9 times more likely to die, and had significant advancement of cerebral disease after HCT, compared to boys with a timely diagnosis of X-ALD.Conclusion-Early diagnosis of cerebral X-ALD following the diagnosis of unexplained AI, and subsequent treatment with HCT, improves both neurological outcomes and survival in boys with cerebral X-ALD.

Clinical, biochemical, neuroimaging and molecular findings of X-linked Adrenoleukodystrophy patients in South China

“…For example, in 1997, Korenke et al reported that adrenal symptoms preceded neurological symptoms in 92 % of children with CCALD (Korenke et al 1997). In 2011, LE Polgreen et al noted that adrenocortical insufficiency was the first symptom of X-linked adrenoleukodystrophy in 38 % of patients (Polgreen et al 2011). Our observation was consisted with the current clinical data.…”

“…c Patient 11, the white matter highintensity lesions on FLAIR T2-weighted images involved the trigon of lateral ventricles and the splenium of corpus callosum before transplantation. d Patient 11, compared to the pre-transplantation MRI, the white matter high-intensity signals on FLAIR T2-weighted images extended to parietal lobe, midbrain, pons and cerebral peduncle 1 year after transplantation with a Loes score B0^, would improve both neurological outcomes and survival (Polgreen et al 2011). Weston P. Miller et al recently suggested that for patients without cerebral disease at the time of X-linked adrenoleukodystrophy diagnosis, serial neurologic, neuropsychometric and radiopraphic (brain MRI) testing with expeditious HSCT at the earliest evidence of active cerebral disease were recommended .…”

Clinical Reasoning: A 56-year-old man with progressive spasticity

“…Surveillance for affected males includes periodic reevaluation (at least annually) of adrenocortical function by measuring ACTH and cortisol levels. 4 In select circumstances, an ACTH stimulation test may be necessary, but it should be noted that most individuals (.70%) will develop adrenal insufficiency.…”

No evidence for the reversal of adrenal failure after hematopoietic cell transplantation in X-linked adrenoleukodystrophy

“…The diagnosis of cerebral ALD was based on the presence of increased plasma VLCFA levels and characteristic white matter changes on MRI. 5 A pre-transplant diagnosis of AI was made at either the referring institutions or at our institution as recently published. 5 A group of 20 ALD patients, who returned for a follow-up visit, had a low-dose Cosyntropin (synthetic adrenocorticotropic hormone (ACTH) 1 - 24) stimulation test 1 - 7 years post HCT (one patient did not proceed with the stimulation test because a random ACTH level was markedly elevated at 1749 pg/mL).…”

“…Cortisol level was measured at baseline and + 15, + 30, and + 60 min after i.v. administration of 1 mcg of Cosyntropin, 5 with AI diagnosed if the peak stimulated cortisol level was less than 20 mg/dL. A low-dose ACTH stimulation test was chosen because it is more sensitive for the diagnosis of subclinical AI than a standard dose (250 mcg) test.…”