X-linked adrenoleukodystrophy

What is X-Linked Adrenoleukodystrophy?

X-linked adrenoleukodystrophy (X-ALD), caused by harmful changes in the ABCD1 gene, is a genetic condition that primarily affects the nervous system and adrenal glands. Neurologic problems result from deterioration (demyelination) of the insulating covering (myelin) of the nerves in the brain and spinal cord. This causes a decline in intellectual and motor function and ultimately reduces lifespan. X-ALD is also associated with adrenal insufficiency, which results in the decreased production of certain hormones causing abnormalities in blood pressure, heart rate, and ability to have children. X-ALD is an X-linked disease. This means that the ABCD1 gene is on the X-chromosome. Individuals assigned male at birth have one copy of the X-chromosome, while individuals assigned female at birth have two copies. Because males only have one copy of the ABCD1 gene, a harmful change in the ABCD1 gene typically causes more severe symptoms in males.

There are three major forms of X-ALD that occur in males:

Childhood cerebral form

The childhood form is the most severe. By age four, children will typically start to experience learning and/or behavior problems that progress over time. Symptoms include intellectual disability and problems with speech, vision, hearing, and motor function. The rate of symptom progression is variable but can result in significant disability within a few years after symptoms start.

Adrenomyeloneuropathy type (AMN)

This type of X-ALD most often presents in early adulthood. Initial symptoms may include difficulty walking, speech difficulties, loss of muscle movement coordination, impaired sexual function, and behavior changes. An absence of some hormones (adrenal insufficiency) may also lead to weakness, weight loss, skin changes, vomiting, and coma.

Addison disease only

This is the mildest form of X-ALD. Individuals with this form often present with symptoms associated with adrenal insufficiency only. The onset of this form varies but typically occurs by eight years of age. The Addison disease only form may progress into symptoms of the AMN type during adulthood. The adrenal function typically remains normal in female carriers.

X-ALD is highly variable, and different forms of X-ALD can be observed within the same family.

Female carriers

Up to 65% of females with a harmful change in ABCD1 may develop symptoms similar to the AMN form of the condition. The onset of symptoms in females typically occurs in adulthood and has a slower progression than in males, but will typically be present by age 65.

How common is X-Linked Adrenoleukodystrophy?

Collectively, all forms of X-ALD are estimated to occur in approximately 1 in 16,800 males worldwide.

How is X-Linked Adrenoleukodystrophy treated?

Currently, there is no cure for X-ALD. However, treatments are available to address many of the symptoms. A multidisciplinary team of healthcare professionals, including neurologists, physical therapists, urologists, ophthalmologists, audiologists, endocrinologists, and other healthcare specialists, will need to be involved in the treatment and ongoing management of individuals with X-ALD. Corticosteroid replacement therapy treats symptoms caused by adrenal insufficiency but does not relieve neurologic symptoms. Hematopoietic stem cell transplantation (HSCT) is often recommended for younger males in the early stages of the disease; this treatment can often stop the progression of neurological symptoms. Recently, the FDA approved a gene therapy (elivaldogene autotemcel) for treating males ages four to seventeen. This treatment can significantly slow the progression of the disease.

What is the prognosis for a person with X-Linked Adrenoleukodystrophy?

The life expectancy of individuals with this type depends on the severity of the signs and symptoms, how quickly the disorder progresses, and how early treatment is started. Individuals with the cerebral form of X-linked adrenoleukodystrophy usually survive only a few years after symptoms begin but may survive longer with intensive medical support. The prognosis for individuals with the AMN type and Addison disease only type vary; in some cases, neurologic damage may lead to early death.