Adrenoleukodystrophy/ adrenomyeloneuropathy

X-linked adrenoleukodystrophy is the most common type of leukodystrophy, affecting close to 30% of cases registered by the European Leukodystrophies Association (ELA).

Adrenomyeloneuropathy (or AMN) is the adult form of this condition.

Description

X-linked adrenoleukodystrophy (X-ALD) is a genetic disease linked to the X-chromosome. Onset can occur in childhood, adolescence or adulthood. X-ALD is characterized by progressive demyelination of the central and peripheral nervous system associated to adrenal insufficiency and to the build-up of very-long-chain fatty acids (VLCFAs). Incidence is estimated at 1 in 17 000 births.

Note: X-ALD should be clearly differentiated from neonatal adrenoleukodystrophy, a variant of Zellweger syndrome.

 

Source: Orphanet, X-ALD Database, Gene Reviews (NIH), ALD Connect

Learn more:

In man :

  • Inflammatory cerebral demyelinating forms (ages: 5-12)
  • Non-inflammatory chronic cerebral demyelinating forms (ages: 10-15)
  • Adrenomyeloneuropathy (ages: 20-60)
  • Adrenomyeloneuropathy complicated by an inflammatory cerebral demyelination (ages: 20-45)
  • Adrenal insufficiency (Addison's disease) (ages: 5-40)
  • Testicular insufficiency (ages > 20)

In woman :

  • Adrenomyeloneuropathy (ages: 40-50)

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Cerebral demyelinating forms

They affect boys between the age of 5 and 12 years old and 35% of men between 20 and 40 years old. Female carriers are not affected.

1. Cerebral demyelinating forms in children

They show a three steps progression:

  • A latent phase with appearance of demyelinating lesions progressing slowly;
  • A second phase where appear concomitantly clinical signs, a marked and rapid progression of the demyelinating lesions that become inflammatory ;
  • A stabilisation with severe motor and mental impairment leading to a bed-ridden, even vegetative state and possibly death.

Clinical symptoms vary according to the location of the demyelinating lesions. Generally, the earlier the disease onset starts the quicker it progresses.

2. Cerebral demyelinating forms in adults

Although these forms progress like the childhood cerebral forms, the latent initial phase is much longer (5 to 10 years). All adults suffering from cerebral demyelination also show also signs of spinal cord injury.

3. Chronic cerebral forms

Less than 5% of cerebral demyelinating forms do not progress to an inflammatory stage. The demyelinating lesions show very progressively. Patients do not develop visual or motor impairments except when an AMN form appears at adulthood.

Adrenomyeloneuropathy (AMN)

This form affects 60% of men with a mutated ABCD1 gene and 50% of ALD female carriers. The first AMN symptoms appear between the ages of 20 and 50, with a peak between the ages 20 and 30 in men. AMN is characterized by a progressive spastic paralysis associated to  imbalance and urinary problems and leading to moderate to severe motor impairment within 10 to 15 years.

In female carriers, the first symptoms usually appear after the age of forty. The spastic paralysis can progress either rapidly within 5 years to become a significant motor disability (walk with a walking stick) or slowly over 15 to 20 years with no remission. In general, in female carriers with AMN symptoms develop a progressive disease that is less severe than in men but with more frequent and severe pain.

35% of AMN men develop cerebral demyelination (see above) in a secondary stage of the disease. This risk becomes major between the ages of 20 and 30. Female carriers never develop cerebral lesions.

Adrenal insufficiency (Addison's disease)

Approximately 70% of ALD patients will suffer from adrenal insufficiency at some point in their lives. It can start prior (sometimes for several decades) or during the course of one of the ALD forms. It can be detected starting at ages of 3 or 4 by observation of marked brown hyperpigmented areas on  the face, neck and back of the hands, on scars or in fingers, of worsening fatigue, digestive problems, nausea or loss of appetite.

In AMN female carriers, adrenal insufficiency is rare.

Testicular insufficiency

Men often show biological signs of testicular insufficiency without the appearance of clinical symptoms. Female carriers have no ovarian function impairment.

Genetics

ALD is caused by a mutation in the ABCD1 gene, located on the X chromosome (at position Xq28). Identified in 1993 by professors Aubourg and Mandel and their respective teams, the ABCD1 gene encodes for a peroxisomal protein, named ALDP, belonging to the family of ABC transporters. ALDP is believed to import VLCFAs or their derivatives into the fatty acids." >peroxisomes where they are broken down by oxidation.

ALD patients' fibroblasts show a reduced VLCFA oxidation, but also an increase in processing long-chain fatty acids into VLCFAs which probably contributes to VLCFA excess in body tissue.

The pathophysiology of peripheral damage, cerebral demyelination, and adrenal insufficiency is still uncertain. It is suspected that there is a connection between abnormal VLCFA accumulation, demyelination, adrenal insufficiency and the inflammatory response but the underlying mechanisms remain unclear.

Diagnosis

Diagnosis is based on measurement of plasma VLCFA levels. This test allows identifying 100% of affected boys and men and 80 to 95% of female carriers. A woman can therefore be a carrier but still present normal plasma VLCFA levels.

Mutation testing for the ABCD1 gene or study of the ALD protein is only useful at the diagnostic level for the reliable identification of women that are potentially carriers.

Genetic counseling

More than 1400 different mutations have been identified. With a few exceptions, each ALD family carries its own unique mutation of the ABCD1 gene. A genetic consultation will allow to:

  • Identify boys who are still neurologically asymptomatic and to be able to offer them a bone marrow transplant early in the disease course. It requires to perform a cerebral MRI every 6 months from 4 to 12 years old, and then yearly until the age of 45;
  • Identify ALD patients with adrenal insufficiency which could cause sudden death
  • Identify females that might be carriers and give them the option of a prenatal diagnosis. Female carriers have a 50% risk of having a son with the disease and a 50% risk of having a daughter who is a carrier.

ALD adult males will not transmit the disease to their sons. Their daughters will however be systematically carriers.

Allogeneic bone marrow transplantation (BMT)

BMT is the only treatment which, if performed in the very early stages of the disease, can stabilize and even allow a decline in cerebral demyelinating lesions. It is ineffective and can even be harmful if performed at a later stage. Transplant is only possible if a compatible donor or umbilical cord blood is found. This procedure carries a high mortality rate of 15 to 20%.

Treatment options for AMN

It is based on a symptomatic care: active and passive physical therapy, treatment of urinary problems, spasticity, pain and fatigue.

Treatment of adrenal insufficiency

This extremely simple treatment is based on the prescription of hydrocortisone or fludrocortisone, which is taken orally on a daily basis. This treatment is critical and should not ever be discontinued.

Lorenzo's oil

This diet is based on low VLCFA regimen and treatment with an oil rich in erucic and oleic acids ('Lorenzo's oil'). It enables normalization of plasma VLCFA levels within three months. This treatment has no effect on cerebral forms of ALD and AMN. It could reduce the risk of developing cerebral damage if treatment is started before the age of six.

Treatment of cerebral forms in a late stage

Treatment is essentially palliative but crucial to improve the quality of life of the affected children and adults like pain and spasticity management, treatment of orthopedic complications, and the use of a gastric feeding tube to ensure adequate nutrition.

Psychological care

Psychological care should be offered not only to the patient, but also to siblings, parents, spouse and often for other members of the affected family.