National Center for Advancing and Translational Sciences Genetic and Rare Diseases Information Center, a program of the National Center for Advancing and Translational Sciences

X-linked cerebral adrenoleukodystrophy


Other Names:
Adrenoleukodystrophy childhood cerebral form; ALD childhood cerebral form; Childhood cerebral ALD; Adrenoleukodystrophy childhood cerebral form; ALD childhood cerebral form; Childhood cerebral ALD; Adrenoleukodystrophy X-linked cerebral form; X-CALD See More
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This disease is grouped under:
The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.
orphanet

Orpha Number: 139396

Definition
A subtype of X-linked adrenoleukodystrophy (X-ALD), a peroxisomal disease characterized by severe inflammatory demyelination in the brain, and often associated with adrenal insufficiency.

Epidemiology
X-CALD manifests in 70% of male and 2% of female cases of X-ALD, whose estimated birth incidence (male and female) is 1/20,000.

Clinical description
X-CALD may occur in healthy boys (2.5-10 years old, 50% of cases), in symptomatic male adrenomyeloneuropathy (AMN, see this term) cases (35%), in adult males as the initial manifestation of X-ALD (~12%) and most rarely in adult women (2%). Adrenocortical insufficiency (AI, 65% of cases) is often latent, lacking melanoderma, presenting as fatigue, nausea or even acute primary adrenal insufficiency (see this term). AI sometimes precedes neurologic symptoms that are limited to mild cognitive dysfunction mimicking attention deficit disorder (ADD) in children. An active phase follows: emotional lability, cognitive decline and either visuospatial impairment or frontal syndrome are rapidly accompanied by deficits such as hemiplegia or quadriparesis, cerebellar ataxia, impaired central auditory discrimination, visual field defects, cortical blindness and often seizures. Patients may lose the ability to understand language and to walk within weeks. Some patients (10%) remain in a chronic or arrested X-CALD and often develop marked visual-spatial and cognitive deficits. Disturbances resembling schizophrenia or psychosis may occur, particularly in adolescents and adults.

Etiology
X-CALD is due to mutations of ABCD1 (Xq28,) encoding ALDP, a peroxisomal transmembrane protein involved in the transport of very long chain fatty acid CoA-esters (VLCFA) into the peroxisome; perturbing VLCFA homeostasis in glial cells contributes to myelin destabilization. This leads to severe neuroinflammation with impairment of the neuro-vascular unit followed by rapid functional decline.

Diagnostic methods
Genetic testing must be preceded in men by testing for high plasma concentrations of VLCFA. Initially, brain MRI reveals characteristic abnormal white matter signals, often in the splenium or genu of the corpus callosum. Then, the extent of demyelinating lesions progresses, as revealed by peripheral injection of gadolinium.

Differential diagnosis
Initial symptoms in boys may ressemble ADD. AI symptoms may resemble congenital or acquired forms of Addison disease (see this term).

Antenatal diagnosis
Gestational chorionic villus sampling (10-13 weeks), amniocentesis (15-18 weeks) and pre-implantation genetic testing are feasible

Genetic counseling
Transmission is X-linked, with less than 8% de novo<.i> mutations. Genetic testing of parents and male extended family is mandatory to permit early detection by brain MRI and to propose therapeutic intervention. Systematic testing of women at risk to be carriers is also warranted to propose genetic counseling.

Management and treatment
Brain MRI is the sole means to detect demyelination prior to symptomatic onset and must be performed every 6 months from 3-12 years, and then annually up to 50 years for all X-ALD males. Allogeneic hematopoietic stem cell transplant (HSCT) remains the only therapeutic intervention that can halt cerebral demyelination, but only when performed at a very early stage. Appropriate donors (HLA-identical non-affected siblings, HLA-matched unrelated donors or cord blood) must be identified rapidly. Autologous HSCT, genetically corrected ex vivo, had a similar efficacy to allogeneic HSCT in the first 4 treated patients. AI and hypogonadism are not cured by HSCT. Plasma testosterone, cortisol, mineralocorticoids, ACTH levels and ACTH stimulation reponses must be tested regularly. Replacement therapy may be required.

Prognosis
Left untreated, all but 10% of patients are bedridden, blind, lacking speech and require fulltime care, dying within 2-5 years. Arrested X-CALD may enter a phase of rapid neurological deterioration at any time.

Visit the Orphanet disease page for more resources.
Last updated: 3/1/2013

If you need medical advice, you can look for doctors or other healthcare professionals who have experience with this disease. You may find these specialists through advocacy organizations, clinical trials, or articles published in medical journals. You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments.

If you can’t find a specialist in your local area, try contacting national or international specialists. They may be able to refer you to someone they know through conferences or research efforts. Some specialists may be willing to consult with you or your local doctors over the phone or by email if you can't travel to them for care.

You can find more tips in our guide, How to Find a Disease Specialist. We also encourage you to explore the rest of this page to find resources that can help you find specialists.

Healthcare Resources

Research helps us better understand diseases and can lead to advances in diagnosis and treatment. This section provides resources to help you learn about medical research and ways to get involved.

Patient Registry

  • A registry supports research by collecting of information about patients that share something in common, such as being diagnosed with X-linked cerebral adrenoleukodystrophy. The type of data collected can vary from registry to registry and is based on the goals and purpose of that registry. Some registries collect contact information while others collect more detailed medical information. Learn more about registries.

    Registries for X-linked cerebral adrenoleukodystrophy:
    Myelin Disorders Bioregistry Project
     

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

Organizations Providing General Support

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

  • Genetics Home Reference (GHR) contains information on X-linked cerebral adrenoleukodystrophy. This website is maintained by the National Library of Medicine.

In-Depth Information

  • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
  • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.

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