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X-Linked Adrenoleukodystrophy

Synonym: X-ALD

, MD, , BA, and , MD.

Author Information

Initial Posting: ; Last Update: February 15, 2018.

Summary

Clinical 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 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.

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

Diagnosis/testing.

The diagnosis of X-ALD is established in a male proband with suggestive clinical findings and elevated very long chain fatty acids (VLCFA). MRI is always abnormal in boys with cerebral disease and often provides the first diagnostic lead. The diagnosis of X-ALD is usually established in a female proband with detection of a heterozygous ABCD1 pathogenic variant and elevated VLCFA.

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 (currently suggested at 6-month intervals) and MRIs for detection of early cerebral disease (yearly until age 3 years and then at 6-month intervals until age 10 years).

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 95% of persons representing index cases have inherited the ABCD1 pathogenic variant from one parent; at least 4.1% of individuals with X-ALD have a de novo pathogenic variant. 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. Heterozygote (carrier) detection for at-risk female relatives and prenatal testing or preimplantation diagnosis for pregnancies at increased risk are possible if the pathogenic variant in the family is known.

GeneReview Scope

X-Linked Adrenoleukodystrophy: Included Phenotypes 1
  • Childhood cerebral form
  • Adrenomyeloneuropathy (AMN)
  • Addison disease only

For synonyms and outdated names see Nomenclature.

1.

For other genetic causes of these phenotypes see Differential Diagnosis.

Diagnosis

Suggestive Findings

The diagnosis of X-linked adrenoleukodystrophy (X-ALD) should be suspected in an individual in one of four clinical settings and in infants with a positive newborn screen result.

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.

Newborn screening. In February 2016, newborn screening for X-ALD was added to the recommended uniform screening panel in the United States. At present several states have added it to their newborn blood spot screening. New York state began screening in 2012 and all newborns are screened using a three-tiered algorithm: the first two tiers involve biochemical testing (i.e., tandem mass spectrometry [MS/MS] of C26:0; in all those with an out-of-range result, C26:0 LPC is measured using HPLC-MS/MS) [Vogel et al 2015] (see Table 1). The third tier is molecular genetic testing to confirm the diagnosis (see Establishing the Diagnosis, Molecular genetic testing). Other states have chosen varying strategies.

Establishing the Diagnosis

Male proband. The diagnosis of X-ALD is established in a male proband with suggestive clinical findings and elevated very long chain fatty acids (VLCFA). Measurement of VLCFA is sufficient to establish the diagnosis of X-ALD in the majority of affected males. Rarely, when measurement of VLCFA is inconclusive, detection of a hemizygous ABCD1 pathogenic variant on molecular genetic testing is required to confirm the diagnosis (see Table 2).

Female proband. The diagnosis of X-ALD is usually established in a female proband by detection of a heterozygous ABCD1 pathogenic variant and elevated VLCFA.

A female with childhood-onset X-ALD caused by biallelic pathogenic variants in ABCD1 involving a maternally inherited pathogenic variant in ABCD1 in combination with a paternally derived deletion of chromosome Xq27 has been reported [Hershkovitz et al 2002].

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
C26:0 µg/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
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

Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

  • Single-gene testing. Sequence analysis of ABCD1 is performed first followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
  • A multigene panel that includes ABCD1 and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
    Note: Analysis of ABCD1 by next-generation sequencing is complicated by the presence of pseudogenes ABCD1P1, ABCD1P2, ABCD1P3, ABCD1P4, and ABCD1P5.
  • More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Note: The clinical consequence of pathogenic or suspected pathogenic variants in ABCD1 may be determined by clinical correlation with very long chain fatty acid analysis [Schackmann et al 2016].

Table 2.

Molecular Genetic Testing Used in X-ALD

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
ABCD1Sequence analysis 3, 497% 5
Gene-targeted deletion/duplication analysis 63% 5
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.

5.

In hemizygous males and obligate heterozygotes: 399/423 had pathogenic variants, likely pathogenic variants, or variants of uncertain significance detected by sequence analysis; 19/423 had pathogenic variants identified by gene-targeted deletion/duplication analysis; in one of the five remaining individuals with no identifiable pathogenic variant, Southern blot analysis suggested a duplication or rearrangement [Steinberg, Moser, and Raymond, personal observation; adrenoleukodystrophy.info].

6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

Clinical Characteristics

Clinical Description

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]. Some individuals with X-ALD remain asymptomatic until their adult years.

Presentations Most Commonly Seen in Affected Males

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, and are followed by symptoms suggestive of a more serious underlying disorder including: "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%). 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%). 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 do not develop evidence of AMN until 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 ~5%-10% of Affected Males

Symptom set 4 includes 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 includes progressive behavioral disturbance, dementia, and paralysis in an adult.

Symptom set 6 includes progressive incoordination and ataxia in a child or adult.

Symptom set 7 includes 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 shows no evidence of neurologic or endocrine dysfunction.

Female Carriers

More than 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 ABCD1 pathogenic variant, as the same pathogenic variant 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 pathogenic variants in which abundant immunoreactive protein product is produced [Moser & Moser 1999, Takano et al 1999, Pan et al 2005].

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 including X-ALD; on occasion, families may have been given this diagnosis. Schilder's disease is still sometimes (incorrectly) 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 and other types of Addison disease; brain tumor; other types of leukodystrophy including arylsulfatase A 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 Paraplegia Overview), amyotrophic lateral sclerosis, vitamin B12 deficiency, spinal cord tumor, and cervical spondylosis
  • Symptom set 3 (Addison disease only). Allgrove syndrome (achalasia, alacrima, autonomic disturbance, and Addison disease; OMIM 231550). 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 Hereditary Ataxia Overview)
  • Symptom set 7. Other causes of neurogenic bladder/bowel or impotence

See also Leukodystrophy Overview.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with X-linked adrenoleukodystrophy (X-ALD), the following evaluations are recommended if they have not already been completed:

  • Neurologic examination
  • Brain MRI
  • Adrenal function tests [Dubey et al 2005]
  • Consultation with a clinical geneticist and/or genetic counselor

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 with cerebral disease 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

Hematopoietic stem cell transplantation (HSCT) is an option for boys and adolescents in early stages of symptom set 1 who have evidence of brain involvement on MRI.

In X-ALD, HSCT has been associated with a 20% risk for morbidity and mortality and is recommended only for individuals with evidence of brain involvement by MRI and minimal neuropsychologic findings (performance IQ >80) with a normal clinical neurologic examination.

HSCT 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]. With the institution of newborn screening, specific professional guidelines are being developed, but it is suggested that this be at least every six months.

Males with X-ALD should undergo brain MRI. It is presently recommended that this should start at age 12 months and be repeated yearly till age three. From age three to ten years, MRI should be performed every six months to monitor for early evidence of childhood cerebral disease [Peters et al 2004] because MRI abnormalities occur well in advance of clinical disease [Loes et al 2003]. Evidence clearly shows that HSCT has the best outcome when performed on an asymptomatic individual [Shapiro et al 2000, Peters et al 2004, Mahmood et al 2007]. Beyond age ten years the frequency of MRI should be yearly because of the development of cerebral changes in some males even in adulthood.

Evaluation of Relatives at Risk

It is appropriate to evaluate the older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from timely treatment of adrenal insufficiency before life-threatening complications occur [Mahmood et al 2005]. Such testing can also allow for correct diagnosis of early (and often nonspecific) neurologic, behavioral, and/or cognitive signs and symptoms.

If born in the United States, males affected with X-ALD may be diagnosed by universal newborn screening soon after birth. If newborn screening data are not available for at-risk sibs, several diagnostic approaches can be considered.

  • If the ABCD1 pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives.
  • If the ABCD1 pathogenic variant in the family is not known, very long chain fatty acid analysis may be used with the limitations previously discussed to clarify the disease status of at-risk relatives.

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 effectiveness of therapy depended on 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].

A trial of ex vivo gene therapy is ongoing [Eichler et al 2017]. This multicenter trial is using transfected hematopoietic stem cells to compare the efficacy of this approach to traditional allogeneic HSCT. Based on recent preliminary results the authors report that Lenti-D gene therapy may be a safe and effective alternative to allogeneic stem-cell transplantation in boys with early-stage cerebral disease.

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for 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 proband

Sibs of a proband

Offspring of a proband

  • Affected males transmit the ABCD1 pathogenic variant to all of their daughters (who will be heterozygotes and will usually not be seriously affected) and none of their sons.
  • Heterozygous 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 the pathogenic variant will be heterozygotes and will usually not be seriously affected.
  • Note: Widely varying phenotypes often coexist in the same family. Thus, a proband who has experienced a relatively mild phenotype may have offspring who display the severe phenotype.

Other family members. Depending on their gender, family relationship, and the genetic 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 (see Related Genetic Counseling Issues).

Heterozygote (Carrier) Detection

Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the ABCD1 pathogenic variant has been identified in the proband.

Note: Very long chain fatty acid analysis is not recommended as a screening method for females known to be at risk (see Establishing the Diagnosis).

Related Genetic Counseling Issues

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 – or molecular genetic testing if the familial ABCD1 pathogenic variant is known – 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. (See Management, Evaluation of Relatives at Risk.)

Evaluation of at-risk family members is important for management and genetic counseling but is often incompletely implemented. 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.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Molecular genetic testing

  • Once the ABCD1 pathogenic variant has been identified in an affected family member, molecular genetic prenatal testing for a pregnancy at increased risk is possible.
  • Preimplantation genetic diagnosis may be an option for some families in whom the ABCD1 pathogenic variant has been identified or for those who would choose to implant only female embryos to avoid the possibility of an affected male.

Biochemical testing. If molecular genetic testing is not available, very long chain fatty acids can be measured in cultured amniocytes or cultured chorionic villus cells [Wanders et al 1998, Moser et al 1999]. Prenatal diagnosis using biochemical testing requires prior biochemical confirmation of the diagnosis in the family.

Note: (1) False negative test results using biochemical testing have been reported but may have been related to technical factors. (2) Very long chain fatty acid measurement should be performed only by a laboratory with significant experience.

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
  • ALD Connect
    Phone: 617-643-4218
    Email: admin@aldconnect.org
  • Leukodystrophy Australia
    P O Box 2550
    Mount Waverley Victoria 3149
    Australia
    Phone: 1800-141-400 (toll free)
    Email: info@leuko.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
    P.O. Box 39
    Pacific Palisades CA 90272
    Phone: 800-869-3546 (toll-free)
    Fax: 310-230-4298
    Email: margaret.weis@myelin.org
  • United Leukodystrophy Foundation (ULF)
    224 North Second Street
    Suite 2
    DeKalb IL 60115
    Phone: 800-728-5483 (toll-free); 815-748-3211
    Fax: 815-748-0844
    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 from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) 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 3,616-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.

Pathogenic variants. The comprehensive X-linked adrenoleukodystrophy database lists 770 non-recurrent pathogenic and likely pathogenic variants, as well as rare variants of uncertain significance identified in affected males or obligate heterozygotes [Kemp et al 2001]. Non-recurrent pathogenic variants account for approximately half of the disease-causing variants reported, which include missense pathogenic variants (~61%), frameshifts (~17%), nonsense pathogenic variants (~10%), in-frame deletions/insertions (~4%), and large deletions (~3%).

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 variants 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 variants predicted missense variants. Two thirds were previously reported in association with X-ALD. Furthermore, 29% of all patients had one of 15 pathogenic variants, including c.1415_1416delAG [SJ Steinberg, personal observation].

Table 3.

Selected ABCD1 Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Predicted Protein 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 authors. 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 (varnomen​.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 pathogenic variants. 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

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Suggested Reading

  • Moser HW, Raymond GV, Dubey P. Adrenoleukodystrophy: new approaches to a neurodegenerative disease. JAMA. 2005;294:3131–4. [PubMed: 16380594]
  • Moser HW, Smith KD, Watkins PA, Powers J, Moser AB. X-linked adrenoleukodystrophy. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 131. New York, NY: McGraw-Hill.

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)
Ali Fatemi, MD (2018-present)
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; Johns Hopkins University School of Medicine (2002-2018)

*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

  • 15 February 2018 (ha) Comprehensive update posted live
  • 9 April 2015 (me) Comprehensive update posted live
  • 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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