X-Linked Adrenoleukodystrophy

[X-ALD. Includes: Adrenomyeloneuropathy (AMN)]

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

• Middle-aged or older 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 T-2 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

• 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.

ALD protein. In approximately 70% of carriers, the ALD protein (ALDP) is immunonegative. If ALDP is known to be immunonegative and the familial mutation is not known, this test can be used in females for carrier detection.

Note: Extreme skewing of X-chromosome inactivation occurs on rare occasion and can result in false negative results [Moser et al 1999].

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 concentration

• Impaired rise of plasma cortisol concentration in response to administered ACTH

Note: Adrenal antibodies are not present.

Molecular Genetic Testing

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Gene. ABCD1 is the only gene known to be associated with X-ALD.

Clinical testing

• Sequence analysis. PCR and sequence analysis of the coding region and flanking intronic regions identified mutations in 290/310 (93%) hemizygous males or obligate heterozygote females [Moser, Moser, Steinberg; personal observation].

• Deletion/duplication analysis identifies deletions/duplications not detectable by sequence analysis of genomic DNA; a variety of methods including Southern blot, quantitative PCR, real-time PCR, multiplex ligation dependent probe amplification (MLPA), and array GH may be used.
  
  Some individuals have gene rearrangements that require deletion/duplication analysis for detection:

  • Seventeen of the 20 individuals (in the series of 310 individuals) without an ABCD1 mutation identified by sequence analysis had a deletion detected by Southern blot analysis [Moser, Moser, Steinberg; personal observation].

  • In one of the three remaining individuals, Southern blot analysis suggested a duplication or rearrangement.

Table 2 summarizes molecular genetic testing for this disorder.

Table 2. Molecular Genetic Testing Used in X-ALD

Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency Test Method		Test Availability
			Affected males	Carrier females
ABCD1	Sequence analysis	Sequence alterations 1	99% 2	93%	Clinical
		Large deletions		0% 3
	Deletion/ duplication testing 4	Large deletions and rearrangements	Not needed 5	~6% 2

1. Small intragenic deletions/insertions, nonsense and splice site mutations

2. Mutation detection in hemizygous males and obligate heterozygotes: 290/310 have mutations detected by sequence analysis and 17/310 have mutations identified by deletion/duplication testing.

3. Sequence analysis of genomic DNA cannot detect exonic, multiexonic, or whole-gene deletions on the X chromosome in carrier females.

4. Testing that detects deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, real-time PCR, multiplex ligation dependent probe amplification (MLPA), or array GH may be used.

5. Sequence analysis can detect putative exonic, multiexonic, and whole-gene deletions on the X chromosome in affected males based on lack of amplification by PCR. Confirmation of a deletion in an affected male generally requires deletion/duplication testing.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

Confirming 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) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Genetically Related (Allelic) Disorders

CADDS. Three males with a contiguous deletion syndrome involving the 5' end of ABCD1, termed CADDS (contiguous ABCD1 DXS1357E deletion syndrome), have been described [Corzo et al 2002]. The phenotype of CADDS is earlier in onset and distinct from that resulting from mutations involving ABCD1 alone. All three boys had neonatal cholestasis, hypotonia, and developmental delay. None had craniofacial abnormalities. All three died before age one year. The finding that implicated ABCD1 in this new syndrome was immunocytochemical analysis of cultured cells that demonstrated morphologically normal peroxisomes lacking the membrane protein encoded by ABCD1. Two of the three mothers were found to be deletion carriers.

CADDS contrasts with X-ALD, in which the earliest onset of neurologic symptoms is age 2.75 years and liver disease is not observed. Plasma very long chain fatty acid (VLCFA) concentrations were elevated in CADDS; however, in contrast to the autosomal recessive peroxisome biogenesis disorders, Zellweger syndrome spectrum (PBD, ZSS), all other peroxisomal metabolic pathways tested were normal.

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 that 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 develop evidence of AMN only by middle age.

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, but 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.

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; it should now be used solely to refer to sudanophilic cerebral sclerosis.

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) 1:16,800 [Bezman et al 2001].

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

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]

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].

Testing 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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

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

• About 93% of individuals representing index cases have inherited the ABCD1 mutation from one parent; at most, 7% of individuals with X-ALD have de novo mutations.

• 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 disease-causing mutation has been identified in an affected family member, molecular genetic testing of the ABCD1 gene 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 disease-causing mutation in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers and will usually not be seriously affected.

• If the proband's father has a disease-causing mutation in the ABCD1 gene, 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 mutation to all of their daughters and none of their sons.

• Carrier females have a 50% chance of transmitting the ABCD1 mutation in each pregnancy. Males who inherit the mutation will be affected; females who inherit the mutation 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 disease-causing ABCD1 mutation has been identified in the family.

Related Genetic Counseling Issues

See Management, Testing of Relatives at Risk for information on testing 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 affected or carriers.

DNA banking. 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. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.

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 (CVS) at approximately ten to 12 weeks' gestation or by amniocentesis usually performed at approximately 15 to 18 weeks' gestation. If the karyotype is 46,XY and if the disease-causing mutation has been identified in a family member, DNA from fetal cells can be analyzed for the known disease-causing mutation.

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.

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

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified or for those who would choose to implant only female embryos to avoid the possibility of an affected male. For laboratories offering PGD, see .

Literature Cited

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Suggested Reading

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 will be greatly missed by his family, friends, colleagues, and patients.

Revision History

• 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