X-linked Adrenoleukodystrophy (X-ALD) is a rare inherited peroxisomal neurodegenerative disorder, chronically debilitating and potentially life-threatening, and has an incidence of 1 in 17,000 births. The disease is caused by inactivation of the peroxisomal ABCD1 gene located on the X-chromosome. The defective function of the transporter leads to an accumulation of very long-chain fatty acids (VLCFA) in several tissues and a pathogenic cascade of events that contribute to membrane destabilization of the myelin sheath, mitochondrial dysfunction, oxidative stress, neuroinflammation and compromised blood brain barrier (BBB) integrity.

X-ALD is characterized by central inflammatory demyelination in the brain, axonal degeneration in the spinal cord and adrenal insufficiency. There is currently no satisfactory therapeutic treatment available for AMN, and the only treatment option for cALD is allogeneic Human Stem Cell Transplant (HSCT) which requires prior myeloablation with all inherent risks.

Cerebral ALD (cALD) is characterized by rapid cerebral demyelination with onset typically before 12 years of age, and mostly evolving to dementia and death within a few years. It affects 40% of X-ALD patients from birth until age 18 years. Current standard of care in childhood based on hematopoietic stem cell transplant, although it does not prevent the development of AMN during adulthood.

Adrenomyeloneuropathy (AMN) is the most common form of X-ALD, occurring in almost all male patients reaching adulthood and with an onset of symptoms at the age of 20-30 years. This form is progressively debilitating, affecting the spinal cord and peripheral nerve with spastic paraparesis, sensory dysfunction and incontinence. Life expectancy of AMN patients is reduced when patients additionally develop cerebral demyelination and neuroinflammation, which occurs in about 20% of AMN patients within 10 years.

Female AMN is increasingly recognized as a relevant form, because 80% of heterozygous females (with one of the two X-chromosomes affected) will develop AMN symptoms with an onset typically, between 40 to 50 years of age. The symptoms are similar to males with AMN, but usually with slower progression.

X-ALD is initially diagnosed with a simple blood test which measures the VLCFA levels, followed by a confirmatory genetic test. More recently, a newborn screening test has been developed to detect elevated VLCFA levels (as C26:0-lysoPC) in drops of blood. Since 2013, several states in the US and other countries (i.e. The Netherlands) have started newborn screening programs or have initiated processes intended to add adrenoleukodystrophy to their existing newborn screening program (i.e. some other EU countries).