X-linked adrenoleukodystrophy (or ALD) is a genetic disorder linked to the X chromosome that can begin in childhood, adolescence or adulthood. It is characterised by progressive demyelination of the central and peripheral nervous system associated with adrenal insufficiency and the accumulation of very long chain fatty acids (LCFA) in the body. Its frequency is 1 per 17,000 births.
Note: X-linked ALD should be clearly differentiated from neonatal adrenoleukodystrophy which is a variant of Zellweger syndrome.
The different forms of the disease
• Inflammatory demyelinating brain forms (5-12 years)
• Chronic non-inflammatory demyelinating brain forms (10-15 years)
• AMN adrenomyeloneuropathy (20-60 years)
• Adrenomyeloneuropathy complicated by inflammatory demyelinating brain damage (20-45 years)
• Adrenal insufficiency (Addison’s disease): 5-40 years
• Testicular failure:> 20 years
• Adrenomyeloneuropathy (40-50 years)
Demyelinating brain forms:
They affect boys between 5 and 12 years old and 35% of men between 20 and 40 years old. Women with the mutation (or carriers) are not affected
• Demyelinating brain forms in children
They evolve in three phases:
A latent phase with the appearance of slowly developing demyelination lesions.
A second phase in which clinical signs appear simultaneously, a significant and rapid progression of demyelination lesions which become inflammatory.
A stabilisation phase with major motor and intellectual sequelae (bedridden state) which can lead to death.
Clinical symptoms depend on the location of the demyelination lesions. In general, the disease progresses faster when it starts early.
• Demyelinating brain forms in adults
Even if their evolution is identical to the brain forms of the child, the initial period of latency is much longer (5 to 10 years). All adults with demyelinating brain damage also show signs of damage to the spinal cord.
• Chronic brain forms
Less than 5% of demyelinating brain forms do not progress to an inflammatory stage. The demyelination lesions evolve very gradually. Patients do not develop visual or motor disturbances except when AMN appears in adulthood.
This form affects 60% of men with an ABCD1 gene mutation and 50% of women who carry ALD. The first symptoms of AMN appear between the ages of 20 and 50, peaking between 20 and 30 years in men. AMN is characterised by the onset of progressive spastic paralysis associated with balance disturbances and urinary disturbances. This paralysis leads to more or less severe motor disability in 10 to 15 years.
In female drivers, the first symptoms usually appear after the age of 40. Spastic paralysis can either progress rapidly over 5 years to significant motor impairment (walking with a cane) or progressively progress over 15 to 20 years without a period of remission. In general, a female driver with signs of AMN has a milder, progressive form of the disease than in men, but the pain is more frequent and severe. 35% of men with AMN subsequently develop demyelinating brain damage (see above). This risk is major between 20 and 30 years. Female drivers never develop brain damage.
Adrenal Insufficiency (Addison’s Disease)
About 70% of patients with ALD eventually develop adrenal insufficiency at some point in their life. It can precede (sometimes for several tens of years) or occur during one of the forms of ALD. It can be seen from the age of 3-4 years by a more marked brown pigmentation on the face, neck and back of the hands, scars or flexion folds of the fingers, increased fatigue, digestive disorders, nausea or a lack of appetite. In female drivers with symptoms of AMN, the existence of adrenal insufficiency is rare.
Testicular failure / ovarian abnormality
Men often show laboratory signs of testicular failure without clinical signs. Female drivers do not have any abnormalities in ovarian function.