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X-Linked Adrenoleukodystrophy

Synonym: X-ALD. Includes: Adrenomyeloneuropathy (AMN)

, PhD, , BA, and , MD.

Author Information
, PhD
Department of Neurogenetics
Kennedy Krieger Institute
Baltimore, Maryland
, BA
Department of Neurogenetics
Kennedy Krieger Institute
Baltimore, Maryland
, MD
Department of Neurogenetics
Kennedy Krieger Institute
Baltimore, Maryland

Initial Posting: ; Last Update: April 19, 2012.

Summary

Disease characteristics. X-linked adrenoleukodystrophy (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, behavior, vision, hearing, and motor function follow the initial symptoms and often lead to total disability within two years.
  • Adrenomyeloneuropathy (AMN) manifests most commonly in the late twenties as progressive paraparesis, 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 later.

Approximately 20% of females who are carriers develop neurologic manifestations that resemble AMN but have later onset (age ≥35 years) and milder disease than do affected males.

Diagnosis/testing. The diagnosis of X-ALD is based on clinical findings. MRI is always abnormal in males with neurologic symptoms and often provides the first diagnostic lead. Plasma concentration of very long chain fatty acids (VLCFA) is abnormal in 99% of males with X-ALD. Increased concentration of VLCFA in plasma and/or cultured skin fibroblasts is present in approximately 85% of affected females; 20% of known carriers have normal plasma concentration of VLCFA. ABCD1 is the only gene known to be associated with X-ALD.

Management. Treatment of manifestations: Corticosteroid replacement therapy is essential for those with adrenal insufficiency. Affected boys benefit from the general supportive care of parents and psychological and educational support. Physical therapy, management of urologic complications, and family and vocational counseling are of value for men with AMN.

Surveillance: For males with X-ALD, periodic reevaluation of adrenocortical function.

Evaluation of relatives at risk: Early identification of asymptomatic or minimally symptomatic at-risk males permits timely treatment of adrenal insufficiency.

Genetic counseling. X-ALD is inherited in an X-linked manner. About 93% of index cases have inherited the ABCD1 pathogenic variant from one parent; at most, 7% of individuals with X-ALD have a de novo mutation. Affected males transmit the ABCD1 pathogenic variant to all of their daughters and none of their sons. Carrier females have a 50% chance of transmitting the ABCD1 pathogenic variant in each pregnancy. Males who inherit the pathogenic variant will be affected; females who inherit it are carriers and will usually not be seriously affected. The phenotypic expression and prognosis of an affected male is unpredictably variable. Carrier testing of at-risk female relatives and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutation in the family is known.

Diagnosis

Clinical Diagnosis

The diagnosis of X-linked adrenoleukodystrophy (X-ALD) should be considered in four clinical settings:

  • Boys with symptoms of attention deficit disorder (ADD) who also show signs of dementia, progressive behavioral disturbance, vision loss, difficulty in understanding spoken language, worsening handwriting, incoordination, or other neurologic disturbances
  • Young or middle-aged men with progressive gait disorders, leg stiffness or weakness, abnormalities of sphincter control, and sexual dysfunction, with or without adrenal insufficiency or cognitive or behavioral deficits
  • All males with primary adrenocortical insufficiency, with or without evidence of neurologic abnormality
  • Adult women with progressive paraparesis, abnormalities of sphincter control, and sensory disturbances mainly affecting the legs. It may be difficult to establish the diagnosis of X-ALD in a female with a negative family history. Diagnosis is based on clinical features (most commonly progressive spastic paraparesis) and a panel of laboratory tests.

Neuroimaging. Brain MRI is always abnormal in neurologically symptomatic males with cerebral disease and often provides the first diagnostic lead. In approximately 85% of affected individuals, MRI shows a characteristic pattern of symmetric enhanced T2 signal in the parieto-occipital region with contrast enhancement at the advancing margin.

Testing

Very long chain fatty acids (VLCFA). Three parameters are analyzed:

  • Concentration of C26:0
  • Ratio of C24:0 to C22:0
  • Ratio of C26:0 to C22:0

Table 1 summarizes mean results for normal controls, affected males, and carrier females. The VLCFA assay is performed in a limited number of laboratories worldwide.

  • Males. The plasma concentration of very long chain fatty acids (VLCFA) is abnormal in males with X-ALD, irrespective of age. All three parameters are elevated in the majority of males, though some variation is observed. The discriminant function reported in Moser et al [1999] fully separates normal control males from affected males.
  • Females. Increased concentration of VLCFA in plasma and/or cultured skin fibroblasts is present in approximately 85% of females; 20% of known carriers have normal plasma concentration of VLCFA. The discriminant function reported in Moser et al [1999] is not able to distinguish all carriers from the normal control range. Note: The discriminant function published by Moser et al [1999] is applicable to the specific method used at that time. A different discriminant function would need to be derived for other methods of extraction and analysis.

Table 1. Plasma Very Long Chain Fatty Acid (VLCFA) Values in X-ALD

VLCFANormalMales with X-ALDObligate Female Carriers
C26:0µg/mL 10.23+0.091.30+0.450.68+0.29
C24:0/C22:0 20.84+0.101.71+0.231.30+0.19
C26:0/C22:0 20.01+0.0040.07+0.030.04+0.02

Steinberg et al [2008]

1. The concentration of C26:0 is reported as µg/mL; some laboratories report this as µmol/L.

2. Lorenzo's oil, a mixture of erucic and oleic acids, is used therapeutically to normalize VLCFA levels. Thus erucic acid (C22:1) levels are routinely reported when measuring plasma VLCFA. Certain oils used in cooking, such as mustard seed oil, have naturally high levels of erucic acid and thus can lead to an elevation similar to that observed with Lorenzo’s oil therapy.

Molecular Genetic Testing

Gene. ABCD1 is the only gene in which mutation is known to cause X-ALD.

Clinical testing

Table 2. Summary of Molecular Genetic Testing Used in X-ALD

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
MalesHeterozygous Females
ABCD1Sequence analysisSequence variants 499% 5, 6, 793% 8
Deletion/duplication analysis 9(Multi)exonic or whole-gene deletions/duplications~6% 10~6% 7

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Lack of amplification by PCRs prior to sequence analysis can suggest a putative deletion of one or more exons or the entire X-linked gene in a male; confirmation may require additional testing by deletion/duplication analysis. See footnote 9.

6. Includes the mutation detection frequency using deletion/duplication analysis

7. Mutation detection in hemizygous males and obligate heterozygotes: 399/423 had mutations detected by sequence analysis; 19/423 had mutations identified by deletion/duplication testing; in one of the five remaining individuals with no identifiable mutation, Southern blot analysis suggested a duplication or rearrangement [Steinberg, Moser, and Raymond; personal observation].

8. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.

9. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

10. Males initially suspected on sequence analysis of having a deletion in whom the deletion is subsequently confirmed by deletion/duplication analysis

Testing Strategy

To confirm/establish the diagnosis in a proband

  • Measurement of VLCFA is sufficient to establish the diagnosis of X-ALD in the majority of males.
  • Rarely, molecular genetic testing is required to confirm the diagnosis when measurement of VLCFA is inconclusive.

Identification of female carriers requires either (1) prior identification of the disease-causing mutation in the family or (2) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and if no mutation is identified, then by methods to detect gross structural abnormalities.

Note: Carriers are heterozygotes for this X-linked disorder and may develop clinical findings related to the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) using sequence analysis or deletion/duplication analysis for at-risk pregnancies require prior identification of the disease-causing mutation in the family. Prenatal diagnosis using biochemical testing requires prior biochemical confirmation of the diagnosis in the family.

Clinical Description

Natural History

The range of phenotypic expression in X-linked adrenoleukodystrophy (X-ALD) is wide and cannot be predicted through levels of VLCFA or family history. Widely varying phenotypes often co-occur in a single kindred or sibship [Moser et al 2001]. Many individuals with X-ALD remain asymptomatic until middle age or even later.

Symptom set 1. Childhood cerebral forms (~35% of affected individuals). Presentation occurs most commonly between age four and eight years, with a peak at age seven years. It virtually never occurs before age three years.

Affected boys present with behavioral or learning deficits, often diagnosed as attention deficit disorder or hyperactivity, which may respond to stimulant medication. These behaviors may persist for months or longer. They are followed by symptoms suggestive of a more serious underlying disorder that may include "spacing out" in school (inattention, deterioration in handwriting skills, and diminishing school performance); difficulty in understanding speech (though sound perception is normal); difficulty in reading, spatial orientation, and comprehension of written material; clumsiness; visual disturbances and occasionally diplopia; and aggressive or disinhibited behavior.

Brain MRI examination performed at this time can be strikingly abnormal even when symptoms are relatively mild.

In some boys, seizures may be the first manifestation.

While variable, the rate of progression may be rapid, with total disability in six months to two years followed by death at varying ages.

Most individuals have impaired adrenocortical function at the time that neurologic disturbances are first noted.

Symptom set 2. Adrenomyeloneuropathy (AMN) (~40%-45% of affected individuals). The typical presentation is a man in his twenties or middle age who develops progressive stiffness and weakness in the legs, abnormalities of sphincter control, and sexual dysfunction. All symptoms are progressive over decades.

Approximately 40%-45% of individuals with AMN show some degree of brain involvement on MRI or clinical examination. In 10%-20% of individuals with AMN, brain involvement becomes severely progressive and leads to serious cognitive and behavioral disturbances that may progress to total disability and death.

Approximately 70% of men with AMN have impaired adrenocortical function at the time that neurologic symptoms are first noted.

Symptom set 3. Addison disease only (~10% of affected individuals). Males present with signs of adrenal insufficiency between age two years and adulthood, most commonly by age 7.5 years. Presenting signs include unexplained vomiting and weakness or coma, leading to the diagnosis of Addison disease. Increased skin pigmentation resulting from excessive ACTH secretion is variably present.

Most males who present initially with adrenocortical insufficiency only develop evidence of AMN by middle age.

Overall, adrenal function is abnormal in 90% of neurologically symptomatic boys and in 70% of men with adrenomyeloneuropathy. It is usually normal in carrier females. The most sensitive indicators of adrenal dysfunction are elevated plasma ACTH and impaired rise of plasma cortisol in response to ACTH challenge. Adrenal antibodies are not present.

Presentations seen in approximately 5%-10% of affected males

  • Symptom set 4. Headache, increased intracranial pressure, hemiparesis or visual field defect, aphasia or other signs of localized brain disease. Onset is usually between age four and ten years but may occur in adolescence or, rarely, in adults.
  • Symptom set 5. Progressive behavioral disturbance, dementia, and paralysis in an adult
  • Symptom set 6. Progressive incoordination and ataxia in a child or adult
  • Symptom set 7. Neurogenic bladder and bowel abnormalities and occasionally impotence without other neurologic or endocrine disturbance in at-risk males who have a positive family history
  • Symptom set 8. No evidence of neurologic or endocrine dysfunction

Female carriers. Approximately 20% of female carriers develop mild to moderate spastic paraparesis in middle age or later. Adrenal function is usually normal.

Genotype-Phenotype Correlations

The phenotype cannot be predicted by VLCFA plasma concentration or by the nature of the mutation. The same mutation can be associated with each of the known phenotypes. Mild phenotypes may be associated with large deletions that abolish formation of the gene product, and severe phenotypes occur with missense mutations in which abundant immunoreactive protein product is produced [Moser & Moser 1999, Takano et al 1999, Pan et al 2005].

Segregation analysis suggests the action of an autosomal modifier gene; the presence of such a gene has not been proven. Some current, ongoing SNP association studies suggest that multiple loci, rather than a single modifier gene, likely contribute to phenotype [Semmler et al 2009, Brose et al 2012].

Penetrance

The biochemical phenotype of elevated plasma concentration of VLCFA has nearly 100% penetrance in males.

Although the variation in clinical phenotypes is great, neurologic manifestations are present in nearly all males by adulthood.

Nomenclature

Siemerling-Creuzfeldt disease is the eponym for X-ALD.

Historically, the eponym Schilder's disease referred to several clinical entities that included X-ALD and on occasion, families may have been given this diagnosis. Unfortunately, it is still sometimes used to refer to sudanophilic cerebral sclerosis and certain forms of multiple sclerosis, which may lead to diagnostic confusion.

Prevalence

The prevalence is estimated at between 1:20,000 and 1:50,000. The minimum frequency of hemizygotes (i.e., affected males) identified in the United States is estimated at 1:21,000 and that of hemizygotes plus heterozygotes (i.e., carrier females) at 1:16,800 [Bezman et al 2001].

The prevalence appears to be approximately the same in all ethnic groups.

Differential Diagnosis

Conditions that may share clinical features with X-linked adrenoleukodystrophy (X-ALD) include the following:

  • Symptom set 1 (childhood cerebral form). Attention deficit disorder; epilepsy, other types of Addison disease; brain tumor; other types of leukodystrophy including arylsulfatase deficiency (metachromatic leukodystrophy) and Krabbe disease (globoid cell leukodystrophy); subacute sclerosing encephalitis, multiple sclerosis, Lyme disease, and other dementing disorders including juvenile neuronal ceroid-lipofuscinosis (Batten disease)
  • Symptom set 2 (adrenomyeloneuropathy). Multiple sclerosis, progressive spastic paraparesis (see Hereditary Spastic Paraparesis Overview), amyotrophic lateral sclerosis, vitamin B12 deficiency, spinal cord tumor, cervical spondylosis
  • Symptom set 3 (Addison disease only). Allgrove syndrome (achalasia, alacrima, autonomic disturbance, and Addison disease). Males with apparently isolated primary adrenal insufficiency (i.e., no evidence for other systemic involvement) should be evaluated with plasma VLCFA because X-ALD is the most common genetic cause of Addison disease [Aubourg & Chaussain 2003]. The occurrence of Addison disease in female carriers for X-ALD is rare.
  • Symptom set 4. Brain tumor, MELAS, CADASIL
  • Symptom set 5. Alzheimer disease (see Alzheimer Disease Overview), alcoholic or toxic encephalopathy, solvent vapor exposure, psychosis
  • Symptom set 6. Olivopontocerebellar degeneration and other progressive ataxias (see Ataxia Overview).
  • Symptom set 7. Other causes of neurogenic bladder/bowel or impotence

See also Leukodystrophy Overview.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with X-linked adrenoleukodystrophy (X-ALD), the following evaluations are recommended:

  • Neurologic examination
  • Brain MRI
  • Adrenal function tests [Dubey et al 2005]
  • Genetics consultation

Treatment of Manifestations

When adrenal insufficiency is identified in an affected male, corticosteroid replacement therapy is essential and can be lifesaving. (Corticosteroid replacement therapy has no effect on nervous system involvement.)

Affected boys benefit from the general supportive care of parents, as well as psychological and educational support.

Physical therapy, management of urologic complications, and family and vocational counseling are of value for men with adrenomyeloneuropathy, many of whom maintain successful personal and professional lives [Silveri et al 2004].

Prevention of Primary Manifestations

Bone marrow transplantation (BMT) is an option for boys and adolescents in early stages of symptom set 1 who have evidence of brain involvement on MRI.

Because BMT has 20% risk of morbidity and mortality, it is recommended only for individuals with evidence of brain involvement by MRI but minimal neuropsychologic findings (performance IQ >80) and normal clinical neurologic examination.

BMT is not recommended for individuals with severe neurologic and neuropsychologic dysfunction (i.e., performance IQ <80) [Shapiro et al 2000, Baumann et al 2003, Loes et al 2003, Peters et al 2004, Mahmood et al 2005, Resnick et al 2005].

Surveillance

Adrenal function should be reevaluated periodically in males with X-ALD whose initial evaluation revealed normal adrenal cortical function [Dubey et al 2005].

Males with X-ALD should undergo brain MRI every six months through childhood and then yearly to monitor for the development of cerebral disease [Peters et al 2004] because MRI abnormalities occur well in advance of clinical disease [Loes et al 2003] and the evidence clearly shows that bone marrow transplantation has the best outcome when performed on an asymptomatic individual [Shapiro et al 2000, Peters et al 2004, Mahmood et al 2007].

Evaluation of Relatives at Risk

Early identification of asymptomatic or minimally symptomatic at-risk males permits timely treatment of adrenal insufficiency [Mahmood et al 2005].

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

In a single-arm study of presymptomatic boys with a normal MRI, reduction of hexacosanoic acid (C26:0) by Lorenzo's oil was associated with a reduced risk of developing MRI abnormalities and, therefore, childhood cerebral disease. The authors emphasized that the benefits of therapy required the reduction of C26:0 and that the amount of reduction correlated with lowered risk. Despite this reduction, some individuals still developed childhood cerebral disease. It is emphasized that the study was an open trial without a placebo group; thus, the results should be interpreted with some caution. The use of Lorenzo's oil remains an investigational therapy [Moser et al 2005].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

X-linked adrenoleukodystrophy (X-ALD) is inherited in an X-linked manner.

Risk to Family Members

Parents of a male or female proband

  • Approximately 95% of individuals representing index cases have inherited the ABCD1 pathogenic variant from one parent; at minimum, 4.1% of individuals with X-ALD have a de novo mutation [Wang et al 2011]. Evidence of germline or somatic/germline mosaicism is present in fewer than 1% of parents. Note: The estimated residual risk to parents of the 4.1% of probands with an apparent de novo mutation of having germline mosaicism is at least 13%.
  • It is appropriate to measure plasma VLCFA concentration in the mothers of both affected males and carrier females and in the fathers of carrier females. When the pathogenic variant has been identified in an affected family member, molecular genetic testing of ABCD1 can be used in the evaluation of the parents.

Sibs of a proband

  • The risk to sibs depends on the genetic status of the parents, which can be clarified by pedigree analysis, measurement of plasma concentration of VLCFA, and molecular genetic testing.
  • If the proband's mother is a carrier, the chance of transmitting the pathogenic variant in each pregnancy is 50%. Male sibs who inherit the pathogenic variant will be affected; female sibs who inherit it will be carriers and will usually not be seriously affected.
  • If the proband's father has a pathogenic variant in ABCD, all of the female sibs will be carriers, and none of the male sibs will be affected.
  • If neither parent is a carrier, the risk to sibs of a proband is low.

Offspring of a proband

  • Affected males transmit the ABCD1 pathogenic variant to all of their daughters and none of their sons.
  • Carrier females have a 50% chance of transmitting the ABCD1 pathogenic variant in each pregnancy. Males who inherit the pathogenic variant will be affected; females who inherit it are carriers and will usually not be seriously affected.

Other family members of a proband. Depending on their gender, family relationship, and the carrier status of the proband's parents, the proband's aunts and uncles and their offspring may be at risk of being carriers or of being affected.

Evaluation of at-risk family members is important for management and genetic counseling but is often implemented insufficiently. Several factors may contribute to insufficient evaluation:

  • Establishing the diagnosis in an affected individual with severe disability may be devastating to a family. Immediate concerns may overshadow the timely testing of family members.
  • Third party payors may not cover the cost of testing at-risk family members.
  • Some at-risk family members may choose not to be tested because they fear that a positive result could impair their ability to obtain or retain medical insurance coverage.
  • Individuals may have incomplete knowledge about at-risk family members and may not wish to inform them about the risk.

Carrier Detection

Testing of at-risk female relatives for carrier status is a two-step process:

1.

Measurement of plasma concentration of VLCFA is performed first; if abnormal, the female is a carrier.

2.

Because 20% of female carriers have normal plasma concentration of VLCFA, molecular genetic testing should be used to test those females with a normal concentration if the ABCD1 pathogenic variant has been identified in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Phenotypic variability. It is important for couples at risk to be aware that widely varying phenotypes often coexist in the same kindred or sibship. Thus, families who have experienced the relatively mild phenotypes need to be advised that affected offspring may display the severe phenotype.

At-risk, asymptomatic or symptomatic but undiagnosed family members. It is appropriate for at-risk males in a family to be identified and to be informed of their risk for X-ALD, while respecting principles of patient confidentiality. Identification of males with X-ALD through measurement of plasma concentration of VLCFA before symptoms occur or early in the course of the disease can allow for diagnosis and management of adrenal insufficiency before life-threatening complications occur. Such testing can also allow for correct diagnosis of early (and often nonspecific) neurologic, behavioral, and/or cognitive signs and symptoms.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. Prenatal testing is possible for pregnancies of women who are carriers in whom the risk of having an affected male is 25% (or 50% if the fetus is known to be male). The usual procedure is to determine fetal sex by performing chromosome analysis on fetal cells obtained by chorionic villus sampling (usually performed at ~10-12 weeks' gestation) or by amniocentesis (usually performed at ~15-18 weeks' gestation). If the karyotype is 46,XY and if the pathogenic variant has been identified in a family member, DNA from fetal cells can be analyzed for the known pathogenic variant.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Biochemical testing. If molecular genetic testing is not possible, very long chain fatty acids (VLCFA) can be measured in cultured amniocytes or cultured chorionic villus cells [Wanders et al 1998, Moser et al 1999]. False negative test results with the latter approach have been reported but may have been related to technical factors. Very long chain fatty acid measurement should be performed only by a laboratory with significant experience.

Preimplantation genetic diagnosis (PGD) may be an option for some families in whom the pathogenic variant has been identified or for those who would choose to implant only female embryos to avoid the possibility of an affected male.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Adrenoleukodystrophy Foundation
    241 Camden Street
    Slidell LA 70461
    Phone: 985-718-4728
    Email: information@adlfoundation.org
  • Australian Leukodystrophy Support Group, Inc.
    Nerve Centre
    54 Railway Road
    Blackburn Victoria 3130
    Australia
    Phone: 1800-141-400 (toll free); +61 3 98452831
    Fax: +61 3 95834379
    Email: mail@alds.org.au
  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)
  • NCBI Genes and Disease
  • Myelin Project
    1400 Wallace Boulevard
    Suite 258
    Amarillo TX 79106
    Phone: 800-869-3546 (toll-free); 806-356-4693
    Fax: 806-356-4694
    Email: margaret.weis@myelin.org
  • United Leukodystrophy Foundation (ULF)
    2304 Highland Drive
    Sycamore IL 60178
    Phone: 800-728-5483 (toll-free)
    Fax: 815-895-2432
    Email: office@ulf.org
  • Myelin Disorders Bioregistry Project
    Email: myelindisorders@cnmc.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. X-Linked Adrenoleukodystrophy: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for X-Linked Adrenoleukodystrophy (View All in OMIM)

300100ADRENOLEUKODYSTROPHY; ALD
300371ATP-BINDING CASSETTE, SUBFAMILY D, MEMBER 1; ABCD1

Gene structure. ABCD1 contains ten exons and spans 20 kb of genomic DNA. The 3616-bp transcript has 2,235 bp of coding sequence. Exon 1 is the largest, encompassing 900 bp. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. The comprehensive X-linked adrenoleukodystrophy database lists 595 non-recurrent pathogenic variants [Kemp et al 2001]. Non-recurrent pathogenic variants account for approximately half of the disease-causing variants reported, which include missense mutations (~62%), frameshift mutations (~22%), nonsense mutations (~10%), in-frame deletions/insertions (~3%), and large deletions (~3%).

Note: The proportion of individuals with large deletions reported is half of what the authors have found (6.4%) (Table 2) and is likely an underestimate because not all laboratories perform dosage testing.

The most common recurring pathogenic variant is c.1415_1416delAG in exon 5. This variant has been reported in 7% of families and has been observed with approximately the same frequency in all ethnic groups.

Missense mutations have been found in all parts of the gene but are most common in the membrane domain or the ATP-binding domain, emphasizing the importance of these two domains for the function of ALDP. In the series of 423 hemizygotes and obligate heterozygotes from the authors' experience, 62% of the detected sequence variations predicted missense mutations. Two thirds were previously reported in association with X-ALD. Furthermore, 29% of all patients had one of 15 mutations, including c.1415_1416delAG [Steinberg, personal observation].

Table 3. Selected ABCD1 Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change
(Alias 1, 2)
Reference Sequences
c.1415_1416delAG
(c.1801_1802delAG)
p.Gln472ArgfsTer83
(fsGlu471)
NM_000033​.2
NP_000024​.2

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. Nomenclature used in the literature

Normal gene product. The adrenoleukodystrophy protein (ALDP) contains 745 amino acids and is located in the peroxisomal membrane. It is a member of the ATP-binding cassette (ABC) protein transporter family. It is a characteristic feature of the family of ABC transporters that they function as dimers of two related halves. ALDP represents only one of these halves and is referred to as a half-transporter. Binding of two half-transporters creates a functional transporter whereby the two membrane domains form a channel through which the substrate is transported. Each of the ABC half-transporters contains a hydrophobic membrane domain with six membrane-spanning segments. The combination of the individual components may determine the specificity of the transporter. ALDP has been shown to be able to form a homodimer. ALDP homodimers are believed to be responsible for the transport of very long chain fatty acids across the peroxisome membrane from the cytosol [van Roermund et al 2008]

Abnormal gene product. The gene product is absent in 70% of affected individuals and, for reasons that are not well understood, may be absent even in individuals who have missense mutations. The principal biochemical abnormality is the accumulation of saturated, very long chain fatty acids, particularly hexacosanoic (C26:0) and tetracosanoic (C24:0) fatty acids, as a result of the impaired capacity to degrade these substances, a function that normally takes place in the peroxisome. It is not yet known how the defect in ALDP leads to the accumulation of very long chain fatty acids, but the protein appears to be required for the transport of these fatty acids into the peroxisome.

References

Literature Cited

  1. Aubourg P, Chaussain JL. Adrenoleukodystrophy: the most frequent genetic cause of Addison's disease. Horm Res. 2003;59 Suppl 1:104–5. [PubMed: 12638520]
  2. Baumann M, Korenke GC, Weddige-Diedrichs A, Wilichowski E, Hunneman DH, Wilken B, Brockmann K, Klingebiel T, Niethammer D, Kühl J, Ebell W, Hanefeld F. Haematopoietic stem cell transplantation in 12 patients with cerebral X-linked adrenoleukodystrophy. Eur J Pediatr. 2003;162:6–14. [PubMed: 12486501]
  3. Bezman L, Moser AB, Raymond GV, Rinaldo P, Watkins PA, Smith KD, Kass NE, Moser HW. Adrenoleukodystrophy: incidence, new mutation rate, and results of extended family screening. Ann Neurol. 2001;49:512–7. [PubMed: 11310629]
  4. Brose RD, Avramopoulos D, Smith KD. SOD2 as a potential modifier of X-linked adrenoleukodystrophy clinical phenotypes. J Neurol. 2012;259:1440–7. [PubMed: 22218650]
  5. Corzo D, Gibson W, Johnson K, Mitchell G, LePage G, Cox GF, Casey R, Zeiss C, Tyson H, Cutting GR, Raymond GV, Smith KD, Watkins PA, Moser AB, Moser HW, Steinberg SJ. Contiguous deletion of the X-linked adrenoleukodystrophy gene (ABCD1) and DXS1357E: a novel neonatal phenotype similar to peroxisomal biogenesis disorders. Am J Hum Genet. 2002;70:1520–31. [PMC free article: PMC419992] [PubMed: 11992258]
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  7. Kemp S, Pujol A, Waterham HR, van Geel BM, Boehm CD, Raymond GV, Cutting GR, Wanders RJ, Moser HW. ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: role in diagnosis and clinical correlations. Hum Mutat. 2001;18:499–515. [PubMed: 11748843]
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Suggested Reading

  1. Moser HW, Raymond GV, Dubey P. Adrenoleukodystrophy: new approaches to a neurodegenerative disease. JAMA. 2005;294:3131–4. [PubMed: 16380594]
  2. Moser HW, Smith KD, Watkins PA, Powers J, Moser AB. X-linked adrenoleukodystrophy. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 131. Available at www​.ommbid.com. Accessed 2-11-14.

Chapter Notes

Acknowledgments

The authors' work is supported by the National Institutes of Health and the Food and Drug Administration.

Author History

Corinne D Boehm, MS; Johns Hopkins Hospital (1999-2002)
Ann B Moser, BA (1999-present)
Hugo W Moser, MD; Johns Hopkins University School of Medicine (1999-2007*)
Gerald Raymond, MD (2006-present)
Steven J Steinberg, PhD (2002-present)

*Hugo W Moser, MD was Professor of Neurology and Pediatrics at Johns Hopkins University School of Medicine and former Director of the Kennedy Krieger Institute in Baltimore. He was a world-renowned expert in the field of neurogenetics. He was best known for his leadership role in understanding, diagnosing, and treating adrenoleukodystrophy (ALD). Dr. Moser died of cancer on January 20, 2007 at age 82. He is greatly missed by his family, friends, colleagues, and patients.

Revision History

  • 19 April 2012 (me) Comprehensive update posted live
  • 2 June 2009 (me) Comprehensive update posted live
  • 27 July 2006 (me) Comprehensive update posted to live Web site
  • 15 April 2004 (me) Comprehensive update posted to live Web site
  • 26 August 2002 (ss) Author revisions
  • 26 February 2002 (me) Comprehensive update posted to live Web site
  • 26 March 1999 (pb) Review posted to live Web site
  • 2 February 1999 (hm) Original submission
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