*3.1. X-Linked Adrenoleukodystrophy*

X-linked adrenoleukodystrophy (X-ALD, OMIM # 300100) is the most frequent peroxisomal disorder but is still classified as a rare disease, with an estimated incidence of 1:17,000 [81]. Recent therapeutic successes [82,83], and the feasibility and reliability of a diagnosis method based on VLCFA quantification from blood spot [84,85], have prompted some countries to establish systematic screening of newborns. This complex and fatal neurodegenerative disorder is characterized by a huge clinical variability both in the age of onset and in the symptoms [31]. The two main forms are the childhood cerebral ALD (ccALD), characterized by inflammatory demyelination of the central nervous system and the adult form, called adrenomyeloneuropathy (AMN), consisting of a non-inflammatory, slowly progressive demyelination affecting the spinal cord and peripheral nerves. X-ALD is also the main cause of Addison's disease and adrenal insufficiency may remain the unique symptom of the disease. Since the disease is linked to chromosome X, boys and men are the most severely affected patients. Female carriers usually remain quasi asymptomatic or present only a mild phenotype, but severe forms have also been described [86].

In 1993, using positional cloning, the team of Hugo Moser identified the ABCD1 gene as being responsible for X-ALD [30]. Mutations in the ABCD1 gene have been found in every X-ALD patient and are collected in the X-ALD database (https://adrenoleukodystrophy. info/ accessed on 1 June 2021). In spite of almost 900 non-recurrent mutations, no genotypephenotype correlation has been described. It is important to note that the majority of missense mutations affect protein stability and result in the absence of the protein. ABCD1 defect results in the accumulation of VLCFAs, mainly C26:0 and C26:1, which accumulate as free FAs or in esterified forms in membrane lipids and cholesteryl esters. This accumulation results from the impossibility of their entry into the peroxisome for their degradation by β-oxidation, but also from an increased endogenous biosynthesis [87]. While the toxicity of VLCFAs has been recognized [88], the sequence of events leading to neurodegeneration and inflammation is still debated. Oxidative stress and cellular components, especially microglial functions, seem to play a major role in the pathogenesis of X-ALD [89–91].

Therapeutic strategies depend on the clinical symptoms of patients. A majority of X-ALD patients present adrenal insufficiency and require a careful patient follow-up, but hormone-replacement therapy successfully manages the adrenal defect and prevents a potentially fatal Addisonian crisis. Hematopoietic stem cell transplantation (HSCT) has proven efficiency to halt neurological involvement in X-ALD. Since 1990 and the first success of this therapy [92], allogeneic graft has been indicated for boys with ccALD at an early stage of the disease when a compatible donor exists. In 2009, autologous HSCT was demonstrated to be successful to halt cerebral demyelination in two boys with no compatible donors who received their own genetically corrected stem cells [82]. Lentiviral correction of bone marrow derived stem cells and autologous transplantation proved effective in 15 patients in 2017 [83]. These promising results suggest that such a therapeutic strategy may be as effective as allogeneic HSCT. In addition, efforts to find pharmacological strategies targeting oxidative stress, inflammation, or compensatory mechanisms (antioxidant cocktail [93], leriglitazone [94], sobetirome [50,54,55]) are still present. It remains to be evaluated whether such treatments would be useful per se or in combination with HSCT strategies, at least to delay the onset of neurological concerns and permit a lengthening of the time window to allow transplantation.
