Measuring myelopathy in adrenoleukodystrophy Towards clinical trial readiness

X-linked adrenoleukodystrophy (ALD) is a neurometabolic disorder caused by mutations in the ABCD1-gene on the X-chromosome. Progressive myelopathy is the main clinical manifestation, occurring in all male and >80% of female patients. Clinically, it presents as a slowly progressive gait disorder due to spastic paraparesis and sensory ataxia. Treatment is currently supportive only, but disease modifying treatments are under development. For these therapies to be tested in clinical trials, there is a need for sensitive outcome measures. In this thesis, we evaluate the potential of several clinical (standardized neurological examination, clinical disability scales, timed walking activities) and surrogate outcomes (spinal cord MRI/DTI, optical coherence tomography, blood neurofilament light and GFAP, postural body sway) to measure disease severity and progression in ALD. We demonstrate that some of these outcome measures are more sensitive and reproducible than the currently available ‘traditional’ outcomes. Especially when combining clinical and surrogate outcomes with different test characteristics, they can complement each other in demonstrating a treatment effect, bringing ALD a step closer towards clinical trial readiness.