Lipid Metabolism and Neurotoxicity | Lab GMD

X-linked adrenoleukodystrophy: to unravel, to predict and to treat

The ALD group (principal investigators: Stephan Kemp and Marc Engelen) is part of the Laboratory Genetic Metabolic Diseases and the department of (pediatric) neurology of the Academic Medical Center (AMC) in Amsterdam.

Research aim

Identical gene mutations should lead to specific phenotypes; however, this simplistic view does not adequately address the widely varying phenotypes that are commonly observed in many inborn errors of metabolism. Indeed, even identical mutations can lead to widely variable clinical phenotypes, which suggests that additional factors modify disease manifestations.

This situation is clearly exemplified 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 mutation in a single gene (ABCD1) and accumulate very-long-chain fatty acids (VLCFA). The disease, however, is characterized by a striking and unpredictable variation in disease course among men, ranging from adrenal insufficiency to rapidly progressive and fatal cerebral demyelination (cerebral ALD). In adulthood, virtually all men, and 80% of women, with ALD develop progressive spinal cord disease (that is, adrenomyeloneuropathy (AMN)). In the absence of a genotype–phenotype correlation, predicting the disease course is impossible, even within individual families.

Treatment options are limited. For boys with early stage cerebral ALD, a bone-marrow transplant may be curative. However, for AMN, which represents 85% of ALD cases (males and females), no disease modifying therapy is available. Our goal is to understand disease pathogenesis, develop predictive biomarkers, and translate this knowledge into a platform that will lead to effective treatments.

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



Introduction figure

Contact

+31 20 566 6039
s.kemp@amc.uva.nl

Address
Laboratory Genetic Metabolic Diseases
Academic Medical Center
Meibergdreef 9
1105 AZ Amsterdam
The Netherlands
Room F0-116