Identical gene mutations should result in specific phenotypes; however, this simplistic view does not adequately address the highly variable phenotypes that are commonly observed in many inborn errors of metabolism. In fact, even identical mutations can result in highly variable clinical phenotypes, suggesting that additional factors modify disease manifestations.

This situation is clearly illustrated by X-linked adrenoleukodystrophy (ALD), which is the most common leukodystrophy but also one of the most puzzling inborn errors of metabolism of the central nervous system.

All ALD patients have a pathogenic variant in a single gene (ABCD1) and accumulate very long-chain fatty acids (VLCFA). However, the disease is characterized by a striking and unpredictable variation in disease progression in males, ranging from adrenal insufficiency to a rapidly progressive and fatal leukodystrophy (cerebral ALD). In adulthood, virtually all males and 80% of females develop progressive spinal cord disease. In the absence of a genotype-phenotype correlation, it is impossible to predict the course of the disease, even within families.

Treatment options are limited. For boys with early-stage cerebral ALD, bone marrow transplantation may be curative. However, there is no disease-modifying therapy for the myelopathy. The goals of our research are to elucidate the pathophysiology of ALD, to predict the clinical outcome of newborns with ALD, to develop a treatment for ALD, and to implement newborn screening for ALD in as many countries as possible. After a very successful pilot project (SCAN study), newborn screening for ALD started in the Netherlands on October 1, 2023.

The strength of our research lies in the close interaction between clinicians involved in the care of ALD patients and researchers. This enables us to translate new scientific findings into the clinic and, conversely, to translate clinical questions into their scientific components.