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.

Adrenomyeloneuropathy (AMN) is the most common form of X-ALD, occurring in all male patients reaching adulthood and with an onset of symptoms typically 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, hence with a poor prognosis. Life expectancy of AMN patients is reduced when patients additionally develop cerebral ALD.  

X-ALD patients can also develop an acute form, cerebral ALD (cALD). This results in brain inflammation and demyelination leading to permanent disability and death within 2-4 years. cALD typically affects boys with an age of onset between 4-8 years. However, up to 60% of adult males with AMN can also develop this aggressive phenotype. For cALD the only currently available treatments are based on Hematopoietic stem cell transplantation (HSCT), but in adult patients this procedure is associated with significant risks and many AMN patients are not eligible for it.

Female AMN is increasingly recognized as a relevant form, because up to 80% of heterozygous females (with one of the two X-chromosomes affected) will develop AMN symptoms with onset typically, between 40 to 50 years of age. The symptoms are similar to males with AMN, but usually, women do not develop cerebral involvement.

X-ALD is initially diagnosed with a simple blood test that measures the VLCFA levels, followed by a confirmatory genetic test. Recently a newborn screening test has been established in several US states and other countries.