Adrenoleukodystrophy

A genetic disorder affecting the adrenal glands and nervous system

Adrenoleukodystrophy (ALD) is a rare genetic disorder characterized by the progressive dysfunction of the adrenal glands and the nervous system. It is an X-linked disorder, primarily affecting males, and is caused by mutations in the ABCD1 gene.

Genetics

Adrenoleukodystrophy is caused by mutations in the ABCD1 gene, which is located on the X chromosome. This gene encodes a protein that is involved in the transport of very long-chain fatty acids (VLCFAs) into peroxisomes, where they are broken down. Mutations in ABCD1 lead to the accumulation of VLCFAs in tissues, particularly affecting the adrenal cortex and the white matter of the brain.

Diagram of the ABCD1 gene location on the X chromosome

Pathophysiology

The accumulation of VLCFAs in the body disrupts normal cellular function. In the adrenal glands, this leads to adrenal insufficiency, also known as Addison's disease. In the nervous system, the buildup of VLCFAs causes demyelination, which is the loss of the protective myelin sheath surrounding nerve cells. This demyelination results in progressive neurological symptoms.

Clinical Presentation

The clinical presentation of adrenoleukodystrophy can vary widely, but it is often categorized into several forms:

• Childhood cerebral ALD: This is the most severe form, typically presenting between the ages of 4 and 10. It is characterized by rapid neurological decline, including behavioral changes, vision and hearing loss, and motor dysfunction.

• Adrenomyeloneuropathy (AMN): This adult-onset form presents with progressive stiffness and weakness in the legs, bladder dysfunction, and sexual dysfunction. It usually begins in the third or fourth decade of life.

• Addison-only phenotype: Some individuals present with adrenal insufficiency without significant neurological symptoms.

Diagnosis

Diagnosis of adrenoleukodystrophy is based on clinical presentation, biochemical testing, and genetic analysis. Elevated levels of VLCFAs in the blood are indicative of the disorder. Genetic testing can confirm mutations in the ABCD1 gene.

Management

There is currently no cure for adrenoleukodystrophy, but management focuses on symptomatic treatment and supportive care. Hormone replacement therapy is used to treat adrenal insufficiency. In some cases, hematopoietic stem cell transplantation may be considered, particularly in early-stage childhood cerebral ALD.

Prognosis

The prognosis of adrenoleukodystrophy varies depending on the form and severity of the disease. Childhood cerebral ALD has a poor prognosis, with rapid progression and early mortality. Adrenomyeloneuropathy progresses more slowly, but can lead to significant disability.

Related pages

• X-linked recessive inheritance
• Peroxisome
• Demyelinating disease
• Addison's disease

Gallery

• 

  MRI of a patient with adrenoleukodystrophy showing white matter changes

• 

  Adrenoleukodystrophy

• 

  ABCD1 gene