From tissue to clinical practice and back again A translational approach to adrenoleukodystrophy

X-linked adrenoleukodystrophy (ALD) is the most common genetic white matter disease of the central nervous system. It is characterized by a quickly progressive leukodystrophy in the brains of a large proportion of affected boys and men, and as a more slowly progressive myeloneuropathy in the spinal cords of all adult men and most women. While the clinical and biochemical features of ALD have been well documented, its underlying pathophysiology and the reasons for variability between patients remain poorly understood. This thesis investigates the pathology of ALD and, through a translational approach, seeks to link disease mechanisms to clinical manifestations. Part I examines the pathology of ALD: chapter 2 presents a literature review and proposes a working model for its disease mechanisms, while chapter 3 applies quantitative MRI techniques to non-invasively assess tissue-level changes. Part II focuses on the clinical spectrum of ALD, relating it to lipidomics (chapter 4), movement analysis (chapter 5), and established conventional outcome measures in trials (chapter 6). Part III places the clinical impact of ALD in a broader societal context by exploring the perspectives of affected individuals on its inclusion in the Dutch newborn screening program.