Foreword

In the second decade of the last century, P. Schilder (8) described the neuropathology of one child who had suffered from a familial inflammatory demyelinating disease that was named encephalitis periaxialis difusa. Schilder's disease was later proven to be a heterogenous group of disorders including what is known today as X‐linked adrenoleukodystrophy (X‐ALD). Involvement of the adrenal gland was reported a few years after Schilder's discovery, and X‐linked inheritance was suspected in the mid 60s. H. H. Schaumburg and J. Powers (7) described the lamellar structure of inclusions in adrenal cells, and, subsequently, M. Igarashi (4) demonstrated that these inclusions were rich in very long chain fatty acids (VLCFA). Several phenotypes have been reported including a childhood cerebral form with a demyelinating inflammatory phenotype and adrenomyeloneuropathy with a predominant axonal degenerative phenotype. I. Singh and collaborators (9) further suggested impaired VLCFA oxidation, and S. Tsuji (10) and H. W. Moser (5) showed that increased VLCFA levels in cultured skin fibroblasts and plasma were biomarkers of the disease. Allogeneic hematopoietic cell transplantation emerged as the only hope capable of halting disease progression when performed early (1).

X‐adrenoleukodystrophy emerged into the public limelight in the early 90s when the story of an affected child whose parents of nonscientific background found that a combination of glycerol trioleate and glycerol trierucate normalized VLCFA levels was portrayed in the movie Lorenzo's oil. In parallel, the gene responsible for the disease was identified by a positional cloning approach, fruit of a collaborative effort lead by J. L. Mandel and P. Aubourg (6). This allowed functional studies, generation of mouse models and designing of gene therapy approaches. Only a few months ago, an innovative strategy combining lentiviral‐mediated gene therapy to correct the defective gene in the patient's hematopoietic stem cells arrested disease progression in two children. This is the first time that a gene therapy approach has been efficacious against a disease of the nervous system (2).

As gene therapy and haematopoietic bone marrow transplant interventions are restricted in time to a narrow window of opportunity, investigation of novel pharmacological therapies is still needed. Mouse models are invaluable tools that have allowed gaining insight into pathogenesis, such as identifying oxidative damage as an early contributing factor to the neurodegenerative cascade (3). It is anticipated that molecular dissection of deregulated pathways will pinpoint drug‐treatable targets. Improved mouse models that more closely resemble the demyelinating neuroinflammatory phenotype are needed to shed light on the many remaining underlying enigmas, such as the variegated phenotypic expression and the transition from metabolic to inflammatory and demyelinating stages. Breakthroughs in therapeutics and in the molecular mechanisms of neurodegeneration are expected to broaden our knowledge and improve the treatment possibilities of X‐ALD.