X-Linked Adrenoleukodystrophy

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 genetic testing for pregnancies at increased risk are possible if the pathogenic variant in the family is known.

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.

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.

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.

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 EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.