Clinical and radiological characteristics of adult-onset X-linked adrenoleukodystrophy: a Chinese cohort study and review of the literature.

Background: Adrenoleukodystrophy (ALD) is a rare X-linked genetic metabolic disorder characterized by the accumulation of very long chain fatty acids (VLCFA) within the adrenal glands, as well as the central and peripheral nervous systems. Adult-onset ALD is particularly uncommon and easily misdiagnosed. The objective of this study is to facilitate the early diagnosis and treatment of adult-onset ALD.

Case presentation: Seven adult-onset ALD patients of Chinese descent were enrolled in the study. Detailed clinical characteristics, laboratory results, imaging findings and genetic testing of the patients were collected and analyzed. All seven patients diagnosed with adult-onset ALD were male, including two with adult cerebral ALD (ACALD), one with adrenomyeloneuropathy (AMN), and four presenting with the spinocerebellar variant. The primary clinical manifestations of the two ACALD patients were progressive cognitive dysfunction and psychiatric symptoms. The AMN patient showed chronic progressive spastic paraplegia and displayed non-specific thoracic spinal cord atrophy on MRI. Symptoms observed in the four patients with spinocerebellar variant included cerebellar ataxia, dysarthria, spastic paraplegia, peripheral neuropathy, sphincter dysfunction, and alopecia. These four patients all demonstrated symmetrical white matter hyperintensity (WMH) in the cerebellum on brain magnetic resonance imaging (MRI). Additionally, two of these patients exhibited abnormal MRI signals in the pyramidal tract. All the patients had an elevation of VLCFAs, which is diagnostic for ALD. One patient exhibited elevated adrenocorticotropic hormone (ACTH) and decreased cortisol levels, while six patients displayed slightly elevated ACTH levels and normal cortisol levels without any clinical signs of adrenal insufficiency. Genetic testing identified four known ABCD1 pathogenic variants as well as two novel pathogenic variants.

Conclusions: Progressive cognitive impairment and behavioral abnormalities are common clinical manifestations of ACALD. AMN and the spinocerebellar variant are prevalent phenotypes of adult-onset ALD. Patients with adult-onset ALD may present with isolated WMH in the cerebellum on brain MRI. Routine screening for ALD should be conducted in male patients diagnosed with Addison's disease. Subclinical adrenal cortex insufficiency is a common finding in adult-onset ALD. Elevated levels of VLCFA function as a reliable clinical biomarker for ALD. The identification of novel pathogenic variants in ABCD1 broadens the genetic spectrum of ALD.