X-Adrenoleukodystrophy (X-ALD) – ABCD1 gene

Also known as: Addison disease and cerebral sclerosis; Siemerling-creutzfeldt disease; Bronze Schilder disease; Melanodermic leukodystrophy

OMIM#300100 https://omim.org/entry/300100

1. The Disease:

A progressive peroxisomal disease, characterized by endocrine dysfunction (adrenal failure and sometimes testicular insufficiency), progressive myelopathy and peripheral neuropathy, and leukodystrophy.

2. The symptoms:

Age of onset is highly variable, but often in the first decade. Lack of early signs or symptoms does not exclude the diagnosis. X-ALD affects the nervous system white matter and the adrenal cortex. Three main phenotypes are seen in affected males:

The childhood cerebral form: manifests most commonly between ages four and eight years. It initially resembles attention-deficit disorder or hyperactivity; progressive impairment of cognition, behaviour, vision, hearing, and motor function follow the initial symptoms and often lead to total disability within six months to two years. Most individuals have impaired adrenocortical function at the time that neurologic disturbances are first noted.

Adrenomyeloneuropathy (AMN): manifests most commonly in an individual in his twenties or middle age as progressive stiffness and weakness of the legs, sphincter disturbances, sexual dysfunction, and often, impaired adrenocortical function; all symptoms are progressive over decades.

“Addison disease only”: presents with primary adrenocortical insufficiency between age two years and adulthood and most commonly by age 7.5 years, without evidence of neurologic abnormality; however, some degree of neurologic disability (most commonly AMN) usually develops by middle age.

3. Actions to take in case of early diagnosis:

Biochemical correlation is recommended with elevated very long chain fatty acids (VLCFA).

MRI is always abnormal in boys with cerebral disease and can help in symptomatic cases.

X-ALD is a lifelong disease requiring lifetime management and regular follow-up with a Paediatric Neurology Center Management is provided by multidisciplinary team.

Adrenal insufficiency in X-ALD is treated by hydrocortisone (and if needed fludrocortisone) by an endocrinologist.

The leukodystrophy is treatable with allogeneic hematopoietic cell transplant (HCT), although the outcome is only acceptable when treated in the early stages (Loes score < 9). Autologous HCT after ex vivo lentiviral gene therapy is pending approval in the U.S.A and Europe.

For the progressive myelopathy there is currently no disease modifying treatment available.

Genetic counselling is highly recommended for family planning and evaluation of at-risk family members such as siblings.

4. For more information:

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