What is X-linked adrenoleukodystrophy (X-ALD)?

From the Guidelines

X-linked adrenoleukodystrophy (X-ALD) is a genetic disorder that affects males and is characterized by a wide variation in clinical presentation.

Key Characteristics

• X-ALD is an X-linked condition, meaning it is inherited in an X-linked pattern [ 1 ]
• It is associated with elevated very long-chain fatty acids (VLCFA) in serum samples, which can be used as a diagnostic marker [ 1 ]
• The condition can present with a range of symptoms, including adrenal insufficiency and neurological abnormalities

Diagnosis and Screening

• Males should be screened for X-ALD by measuring VLCFA in a serum sample [ 1 ]
• A diagnosis of X-ALD should be considered in males with primary adrenal insufficiency or other suggestive symptoms [ 1 ]
• Other investigations, such as computer tomography scans and genetic testing, may also be necessary to confirm the diagnosis and rule out other causes of adrenal insufficiency [ 1 ]

From the Research

Definition and Overview of X-Linked Adrenoleukodystrophy (X-ALD)

X-linked adrenoleukodystrophy (X-ALD) is a genetic disorder characterized by the accumulation of very long chain fatty acids in tissues, leading to a range of clinical manifestations 2, 3, 4, 5. The disorder is caused by mutations in the ABCD1 gene, which encodes a peroxisomal membrane protein responsible for the transport of very long chain fatty acids into peroxisomes for degradation 4, 5.

Clinical Spectrum of X-ALD

The clinical spectrum of X-ALD is heterogeneous and can vary significantly between individuals. Common manifestations include:

• Adrenocortical insufficiency (Addison's disease) 2, 3, 4, 5
• Progressive myelopathy and peripheral neuropathy 2, 3, 4, 5
• Cerebral demyelinating disease (cerebral adrenoleukodystrophy) 2, 3, 4, 5
• Spastic paraparesis 4, 5
• Urinary symptoms, walking difficulty, and spasticity in female patients 6

Gender Differences in X-ALD

There are significant gender differences in the clinical presentation and progression of X-ALD:

• Male patients are more severely affected and typically develop adrenocortical insufficiency and cerebral demyelinating disease at a younger age 2, 3, 4, 5
• Female patients tend to develop myelopathy and peripheral neuropathy at a later age and are less likely to develop adrenocortical insufficiency or cerebral demyelinating disease 2, 3, 4, 5, 6

Diagnosis and Treatment of X-ALD

Diagnosis of X-ALD is based on the measurement of very long chain fatty acid levels in plasma and mutation analysis of the ABCD1 gene 4, 5. Treatment options include:

• Allogeneic bone marrow transplantation, which can provide a permanent cure if performed at an early stage of cerebral demyelination 5
• Dietary therapy, which may have a partial preventive effect in boys treated before 6 years of age 5
• Treatment of Addison's disease, which is mandatory but does not modify the course of neurological symptoms 5