Life unexpected Unraveling the natural history of adrenoleukodystrophy

X-linked adrenoleukodystrophy (ALD) is a truly puzzling inborn error of metabolism. Although all patients have ABCD1 mutations, the clinical course is variable and unpredictable in individual patients. In this thesis we continue the effort to unravel the natural history of ALD by delineating the clinical spectrum, improving diagnostics, working towards clinical trial readiness and searching for surrogate outcome measures. Key elements of the clinical spectrum of ALD include primary adrenal insufficiency, cerebral inflammatory demyelination and myelopathy. We retrospectively describe lifetime prevalence of adrenal insufficiency and propose age-dependent follow-up recommendations for the adrenal function. In addition, we evaluate cognitive function in the absence of cerebral disease, and, in a case series, we are the first to describe patients with reactivation of spontaneously arrested cerebral lesions. Timely diagnosis of key manifestations of ALD can prevent severe morbidity and mortality and therefore, implementation of newborn screening has been initiated. We compare C26:0-carnitine to C26:0-lysoPC for the diagnosis of ALD in newborns. Moreover, we evaluate if C26:0-lysoPC and C26:0-carnitine are superior in comparison to routine measurements for the diagnosis of ALD in women. Besides adrenal insufficiency and brain involvement, myelopathy is the key manifestation of ALD in adulthood. We evaluate the rate of progression of myelopathy in both women and men. Moreover, we evaluate the potential of diffusion MRI and optical coherence tomography as surrogate outcome measures for myelopathy. This thesis provides new quantitative data on natural history and will hopefully make life a little less unexpected for ALD patients.