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X-linked adrenoleukodystrophy

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Disease definition

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


Classification level: Disorder

  • ALD
  • X-ALD
  • X-linked ALD

Prevalence: -

Inheritance: X-linked dominant

Age of onset: Adolescent, Adult, Childhood, Elderly

ICD-10: E71.3

ICD-11: 5C57.1

OMIM: 300100 302700

UMLS: C0162309

MeSH: D000326

GARD: 5758

MedDRA: 10051260


X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder with an estimated birth prevalence of 1/17,000 (male and female). It has been reported throughout the world.

Clinical description

X-ALD affects males and females, although symptoms and disease progression differ. The age of onset is highly variable and the rate of progression is unpredictable. Male patients usually present in childhood with signs and symptoms of adrenal failure (80% of male patients develop adrenal failure before the age of 18) or with a rapidly progressive leukodystrophy (40% of male patients before the age of 18, with a lifetime prevalence of 60%). Leukodystrophy is initially clinically silent, but eventually neuropsychiatric symptoms develop, followed by focal deficits like hemiparesis and auditory agnosia, and occasionally epileptic seizures. In early adulthood male patients develop a progressive myelopathy (and peripheral neuropathy) with a gait disorder and incontinence. Progression is slow (over years). Penetrance of this myelopathy is complete, although age of onset and progression are highly variable (some patients require a walking aid whilst others remain ambulatory). Female patients virtually never develop adrenal failure or leukodystrophy. About 90% develop a myelopathy and peripheral neuropathy, but at a later age (after 40 years of age) and with slower progression (over decades) than in males.


X-ALD is caused by variants of ABCD1 (Xq28), with about 900 different mutations reported. There is no geno-phenotype correlation. The encoded protein peroxisomal transmembrane protein is involved in the transport of very long-chain fatty acid CoA-esters (VLCFA) from the cytosol into the peroxisome. Although the exact pathophysiology is poorly understood, perturbed VLCFA homeostasis in glial cells may contribute to the destabilization of the myelin sheath and impairment of axonal function.

Diagnostic methods

If there is clinical suspicion, the diagnosis is established by determining plasma VLCFA (C26:0 and C26:0/C22:0 ratio) which is increased in all male patients; up to 15% of female patients have normal VLCFA. Recently, C26:0-lysophosphatidylcholine in bloodspots or plasma has been validated as diagnostic marker, and is elevated in all male and virtually all female patients. The diagnosis can be confirmed by ABCD1 mutation analysis. If necessary, functional assays in cultured skin fibroblasts are available. In case of leukodystrophy, the MRI pattern is virtually pathognomonic. Adrenal failure can be established with an ACTH stimulation test. Newborn screening for X-ALD has been recently implemented in certain regions.

Differential diagnosis

Testing for X-ALD is recommended in all males presenting with adrenal failure (especially in cases of isolated glucocorticoid deficiency). In adult men or women presenting with a chronic myelopathy, the differential diagnosis is large and includes both acquired and genetic disorders. There is no relevant differential diagnosis for presentation with leukodystrophy.

Antenatal diagnosis

In case of a positive family history and a fetus at risk, genetic prenatal diagnosis is possible.

Genetic counseling

The disorder is X-linked. Male patients transmit the disorder to all of their daughters, but never to a son. Female patients transmit the disorder to 50% of their sons and daughters. In case a patient is diagnosed, family screening and counseling is recommended.

Management and treatment

Adrenal insufficiency in X-ALD is treated by hydrocortisone (and if needed fludrocortisone) by an endocrinologist. For the progressive myelopathy there is currently no disease modifying treatment available. 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.


Pre-symptomatic diagnosis permits monitoring for the occurrence of adrenal failure and the onset of cerebral ALD. If appropriate treatment is initiated, severe morbidity and mortality can be prevented. There is currently no treatment to prevent the occurrence or progression of the myelopathy. However, with appropriate supportive care life expectancy is near normal.

Last update: July 2021 - Expert reviewer(s): Dr M. [Marc] ENGELEN | ERN-RND*

* European Reference Network

A summary on this disease is available in Français (2021) Logo ERN Español (2021) Logo ERN Deutsch (2013) Italiano (2013) Português (2021) Logo ERN Nederlands (2021) Logo ERN Suomi (2013.pdf) Polski (2013.pdf)
Detailed information
General public
Article for general public
Svenska (2018) - Socialstyrelsen
Clinical practice guidelines
English (2014) - J Intern Med Logo ERN
Disease review articles
Review article
English (2012) - Orphanet J Rare Dis
Clinical genetics review
English (2023) - GeneReviews
Genetic testing
Guidance for genetic testing
English (2011) - Eur J Hum Genet

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