X-linked Adrenoleukodystrophy (X-ALD) is a rare inherited peroxisomal neurodegenerative disorder, chronically debilitating and potentially life-threatening, and has an incidence of 6-8 in 100.000 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, development of white matter brain lesions and subsequent 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.

In terms of CNS, there are two manifestations:

Cerebral ALD (cALD) is characterized by demyelinating brain lesions that may become rapidly progressive, leading to acute neurological decline and death. These lesions can produce severe symptoms such as loss of voluntary movements, inability to swallow, loss of communication, cortical blindness and total incontinence and when progressive death with a mean survival of 3 to 4 years. Cerebral ALD with Gd-positive lesions occurs in 31-35% of X-ALD patients in childhood with typical onset between the age of 2-12 and additionally up to 60% of adult patients.

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 increasing disabilities in several body systems with reduced life expectancy.

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 most US states and certain other countries, including Spain.