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Disease Profile

X-linked cerebral adrenoleukodystrophy

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of onset

All ages

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ICD-10

E71.3

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

Adrenoleukodystrophy childhood cerebral form; ALD childhood cerebral form; Childhood cerebral ALD;

Categories

Congenital and Genetic Diseases; Endocrine Diseases; Male Reproductive Diseases;

Summary

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.

Symptoms

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Decreased circulating cortisol level
Low blood cortisol level
0008163
Diffuse demyelination of the cerebral white matter
0007162
Mental deterioration
Cognitive decline
Cognitive decline, progressive
Intellectual deterioration
Progressive cognitive decline

[ more ]

0001268
Myelopathy
0002196
Very long chain fatty acid accumulation
0008167
30%-79% of people have these symptoms
Abnormal circulating fatty-acid concentration
0004359
Abnormality of the brainstem white matter
0012501
Abnormality of the periventricular white matter
0002518
Global brain atrophy
Generalized brain degeneration
0002283
Peripheral axonal neuropathy
0003477
Sensorimotor neuropathy
Nerve damage causing decreased feeling and movement
0007141
5%-29% of people have these symptoms
Ankle clonus
Abnormal rhythmic movements of ankle
0011448
Astereognosia
0010527
Confusion
Disorientation
Easily confused
Mental disorientation

[ more ]

0001289
Difficulty walking
Difficulty in walking
0002355
Dysarthria
Difficulty articulating speech
0001260
Dysmetria
Lack of coordination of movement
0001310
Dysphagia
Poor swallowing
Swallowing difficulties
Swallowing difficulty

[ more ]

0002015
Facial myokymia
Involuntary facial quivering
0000317
Generalized hyperreflexia
0007034
Hamstring contractures
0003089
Hearing impairment
Deafness
Hearing defect

[ more ]

0000365
Hemiparesis
Weakness of one side of body
0001269
Hoffmann sign
0031993
Hyperactivity
More active than typical
0000752
Impaired visuospatial constructive cognition
0010794
Limb myoclonus
0045084
Lower limb spasticity
0002061
Male hypogonadism
Decreased function of male gonad
0000026
Memory impairment
Forgetfulness
Memory loss
Memory problems
Poor memory

[ more ]

0002354
Nasogastric tube feeding
0040288
Oculomotor apraxia
0000657
Seizure
0001250
Short attention span
Poor attention span
Problem paying attention

[ more ]

0000736
Spastic tetraparesis
0001285
Visual agnosia
0030222
1%-4% of people have these symptoms
Blindness
0000618
Inability to walk
0002540
Vegetative state
0031358

Organizations

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

      Learn more

      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.