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Clinical features, evaluation, and diagnosis of X-linked adrenoleukodystrophy

Clinical features, evaluation, and diagnosis of X-linked adrenoleukodystrophy
Literature review current through: Jan 2024.
This topic last updated: Aug 30, 2023.

INTRODUCTION — X-linked adrenoleukodystrophy (ALD; MIM #300100) is a peroxisomal disorder of beta-oxidation that results in accumulation of very long-chain fatty acids (VLCFAs) in all tissues. Patients with ALD are asymptomatic at birth, but during life, adrenal insufficiency, leukodystrophy, and myeloneuropathy occur. Specific disease manifestations and disease severity are highly variable among patients (table 1) [1].

The pathophysiology, clinical manifestations, evaluation, and diagnosis of ALD will be reviewed here. Treatment and prognosis are reviewed separately. (See "Management and prognosis of X-linked adrenoleukodystrophy".)

Other peroxisomal disorders are discussed elsewhere. (See "Peroxisomal disorders".)

TERMINOLOGY — Traditionally, patients with ALD were classified as having distinct phenotypes like "Addison-only," "adrenomyeloneuropathy" (AMN), or "cerebral ALD" (CALD), often subclassified as "childhood cerebral ALD," "adolescent cerebral ALD," or "adult cerebral ALD." Overlap phenotypes ("AMN cerebral") were also often used. However, these descriptions suggest a rather static disorder wherein an individual develops one of these phenotypes.

It is more correct to describe ALD as a progressive neurometabolic disorder with symptoms that accumulate during life. Symptoms can be classified into specific clinical syndromes: leukodystrophy, myeloneuropathy, and adrenal insufficiency. This system will be adopted for this topic review.

GENETICS — ALD is an X-linked disorder. It is caused by mutations in the adenosine triphosphate (ATP)-binding cassette (ABC), subfamily D, member 1 (ABCD1) gene, located at Xq28, which encodes an ABC transporter [2-6]. Four to 5 percent of individuals with ALD have a de novo pathogenic variant [7]. The ABC transporter helps form the channel through which very long-chain fatty acids (VLCFAs) move into the peroxisome, probably as coenzyme A esters [8].

There is no known genotype-phenotype correlation for pathogenic variants in the ABCD1 gene. Disease severity and clinical manifestations vary, even within families with the same ABCD1 variant.

PATHOGENESIS — ABCD1 pathogenic variants prevent normal transport of very long-chain fatty acids (VLCFAs) into peroxisomes, thereby preventing beta-oxidation and breakdown of VLCFAs. Accumulation of abnormal VLCFAs in affected organs (central nervous system, Leydig cells of the testes, and the adrenal cortex) is presumed to underlie the pathologic process of ALD [9]. However, total plasma VLCFA levels do not predict phenotype, and cell-specific functions of ABCD1 may play a role in the pathogenesis independent of VLCFAs [10].

The distribution of the ALD protein maps to regions of high metabolic activity (heart, skeletal muscle, and liver) and to critical neural regions, including subcortical and cerebellar white matter, hypothalamus, adrenocorticotropic hormone (ACTH)-producing cells in the pituitary, and dorsal root ganglia (the last undergo atrophy in ALD). ALD protein is scarcely present in the corticospinal tract and corpus callosum [11].

Central nervous system – In ALD patients with a leukodystrophy, central nervous system pathology is characterized by diverse immune responses involving cellular and humoral mechanisms as well as cytokines and complement [12]. The profound mononuclear response is distinct from that seen in multiple sclerosis and is characterized by microglial activation followed by apoptosis [13].

The precise mechanisms for the inflammatory response and cerebral injury are uncertain. Contributing factors may include:

Oxidative stress and damage – Oxidative stress and damage (lipid peroxidation) play an important role in the pathogenesis [14,15]. It has been suggested that VLCFA toxicity leads to mitochondrial dysfunction and abnormal calcium regulation, as supported by in vitro studies in neurons and glia from rat brains [16]. However, another in vitro study using muscle tissue from individuals with ALD and brain tissue from a mouse model of ALD did not find evidence of mitochondrial dysfunction [17].

Altered blood-brain barrier permeability – In one in vitro study, changes in blood-brain barrier permeability due to lack of ABCD1 occurred prior to elevations in VLCFA [10].

Head trauma – Head trauma may be an initiating trigger and a possible mechanism for the associated immune response, as suggested in a small case series [18-20].

Adrenal gland – In the adrenal gland, abnormal VLCFAs may directly alter cellular function by inhibiting the effects of ACTH on the adrenocortical cells, or indirectly by initiating an autoimmune response. In almost all instances, adrenocortical insufficiency occurs along with irreversible degenerative neurologic defects. Adrenal insufficiency may predate, occur simultaneously with, or follow the onset of the neurologic deterioration [1].

Comparison of this pathophysiology to that of other peroxisomal disorders is discussed separately. (See "Peroxisomal disorders".)

NEUROPATHOLOGY — The leukodystrophy of ALD (cerebral ALD) is characterized by inflammatory demyelination, resulting in confluent and bilaterally symmetric loss of myelin in the cerebral and cerebellar white matter [21,22]. The splenium of the corpus callosum and the occipitoparietal regions are usually affected first, with asymmetric progression of the lesions toward the frontal or temporal lobes. In general, arcuate fibers are spared, except in chronic cases. Axonal loss may be considerable, but myelin loss is usually greater. Lesions may sometimes involve the brainstem, especially the pons. The spinal cord is usually spared, except for bilateral corticospinal tract degeneration.

The inflammatory demyelination in ALD appears to occur in the following specific sequence [23]:

Enlargement of the extraneural space

Vacuolization and myelin swelling with reactive astrocytes and macrophage infiltration

Perivascular lymphocytic and increased permeability of the blood brain barrier

Loss of myelin with lipophage formation

Loss of oligodendroglia and axons

Dystrophic mineralization

The lymphocytes in acute demyelinative lesions of patients with childhood cerebral ALD are mainly CD8 cytotoxic T cells. There is cytolysis of oligodendrocytes. In addition, CD1 molecules have been noted, suggesting that CD1-mediated lipid antigen presentation may occur with very long-chain fatty acid (VLCFA)-containing lipids, such as gangliosides or proteolipids, acting as antigens [24]. In vitro studies suggest that the VLCFA accumulation that occurs in the absence of ABDC1 function promotes inflammation [25]. However, most studies that suggest that VLCFAs are toxic employ supraphysiologic doses in vitro or in vivo that are never encountered in humans with ALD.

In the myeloneuropathy of ALD, both inflammatory and noninflammatory demyelination lesions occur [21]. Affected individuals also develop a degenerative axonopathy that involves the ascending and descending tracts of the spinal cord, especially in fasciculus gracilis and the lateral corticospinal tracts. The histologic pattern is Wallerian degeneration [26]. Mitochondrial pathology [27] and oxidative stress [14] also contribute to pathogenesis. When peripheral nerves are affected in myeloneuropathy, characteristic lamellar and lamellar-lipid inclusions are seen in Schwann cell cytoplasm or within endoneurial macrophages. Central nervous system macrophages, but not oligodendrocytes, may also have inclusions. Spicular or trilaminar inclusions may also occur in the central nervous system.

EPIDEMIOLOGY — Although ALD is a rare disease, it is the most common peroxisomal disorder [28]. Newborn screening in the United States found a birth incidence in males of 1 in 14,700 [29]. In a report that included data from the two laboratories that perform most of the assays for the disorder, the minimum frequency in the United States for the male population was estimated at 1 in 21,000 for hemizygotes and 1 in 16,800 for hemizygotes plus heterozygotes [30,31].

CLINICAL FEATURES

Range of manifestations — ALD causes both neurologic and endocrine manifestations. More than half of male patients develop a progressive leukodystrophy ("cerebral ALD"), and virtually all patients develop slowly progressive myeloneuropathy (spinal cord disease and peripheral neuropathy) in adulthood and adrenal insufficiency.

Thinning of scalp hair occurs frequently in males and females with ALD and can be an important clue to the diagnosis, though the finding alone is nonspecific.

In female patients, myeloneuropathy is common, while leukodystrophy and adrenal insufficiency are rare. (See 'Females with ALD' below.)

Now that newborn screening has been implemented in several areas of the world, an increasing population of presymptomatic patients is recognized. (See 'Newborn screening' below.)

Leukodystrophy — The onset of leukodystrophy occurs mainly between 3 and 10 years of age (peak incidence 7 years), with approximately 40 percent of male patients developing a leukodystrophy before the age of 18 years (table 1) [32]. The lifetime prevalence is approximately 60 percent [33].

Manifestations – Boys with leukodystrophy typically present with learning disabilities and behavior problems that are often diagnosed initially as attention deficit hyperactivity disorder, and may respond to stimulant medication [34]. This is followed by neurologic deterioration that includes increasing cognitive and behavioral abnormalities, blindness, and the development of quadriparesis [35]. Approximately 20 percent of affected boys have seizures, which may be the first manifestation in some.

In symptomatic males with leukodystrophy, magnetic resonance imaging (MRI) is always abnormal, demonstrating confluent demyelinating cerebral white matter lesions. (See 'Neuroimaging' below.)

MRI abnormalities can range from mild to severe. Lesions are usually bilateral, though unilateral involvement can be seen [36]. The occipitoparietal region is typically affected (image 1 and image 2) and the frontal lobe is involved in up to 15 percent of cases [37,38]. Contrast enhancement on T1-weighted MRIs strongly correlates with likelihood of disease progression [39].

Arrested ALD – Spontaneously arrested ALD is characterized by absence of symptom progression and lack of lesion growth or enhancement on sequential brain MRI. This occurs in approximately 10 to 15 percent of ALD cases [40-42]. These patients may be asymptomatic at diagnosis.

Patients with arrested ALD may remain stable for years but can eventually convert again to progressive ALD, so continued vigilance and monitoring are necessary; younger patients may have a higher risk of converting to progressive disease [43]. (See "Attention deficit hyperactivity disorder in children and adolescents: Clinical features and diagnosis", section on 'Clinical features' and "Specific learning disorders in children: Clinical features", section on 'Risk factors'.)

Most individuals with leukodystrophy also have adrenal insufficiency; of these, some have hyperpigmented skin due to increased adrenocorticotropic hormone (ACTH) secretion. (See 'Adrenal insufficiency' below.)

Myeloneuropathy — Spinal cord disease and peripheral neuropathy (myeloneuropathy) typically present in adult males between 20 and 40 years of age (average 28 years) (table 1) [32,35]. The incidence of myeloneuropathy increases with age and eventually affects virtually all patients [44]. In one study of 46 males with ALD (ages 16 to 71 years), the frequency of myeloneuropathy increased with age from 31 percent in patients younger than 30 years to 95 percent in patients older than 50 years [45]. Note that myeloneuropathy is the primary manifestation of ALD in female patients; females are at increased risk for developing myeloneuropathy with increasing age. (See 'Females with ALD' below.)

Manifestations – The primary symptoms and signs of myeloneuropathy are progressive stiffness and weakness of the legs (spastic paraparesis), sensory ataxia due to dorsal column dysfunction, abnormal sphincter control, neurogenic bladder, and sexual dysfunction. Numbness and pain from polyneuropathy are also common in males with myeloneuropathy.

Progression of myeloneuropathy is slow. A prospective observational study found that significant worsening quantified by the expanded disability status scale (EDSS) occurred over two years; change in EDSS over one year of follow-up was not significant [45].

In those with advanced myeloneuropathy, atrophy of the cervical spinal cord is apparent on MRI [46]. There are no signal abnormalities on T2-weighted MRI sequences; abnormalities other than atrophy on routine MRI are not compatible with ALD. In a cross-sectional study, physiologic and radiologic (magnetic resonance fractional anisotropy) assessments confirmed the presence of sensorimotor abnormalities in the dorsal columns extending into the brainstem and correlated with overall severity in myeloneuropathy [47].

Associated adrenal and cerebral involvement – Most patients with myeloneuropathy also have adrenal insufficiency [44]. (See 'Adrenal insufficiency' below.)

Cerebral involvement at the time of diagnosis of myeloneuropathy is uncommon [48]. However, in long-term follow-up studies, 20 to 60 percent of patients with myeloneuropathy developed symptoms of cerebral involvement (eg, cognitive decline, behavioral abnormalities, visual loss, impaired auditory discrimination, or seizures) and/or cerebral demyelination on brain MRI [33,48]. Patients with cerebral involvement have more rapidly progressive illness. (See "Management and prognosis of X-linked adrenoleukodystrophy", section on 'Prognosis'.)

Adrenal insufficiency — Primary adrenal insufficiency is the initial manifestation of ALD in 30 to 40 percent of patients [44,49,50]. In a case series of 159 male patients with ALD managed at two major referral centers, 47 percent developed adrenal insufficiency by age 10 years and an additional 29 percent developed adrenal insufficiency between the ages of 10 and 40 years [44].

Manifestations – Signs and symptoms of adrenal insufficiency may include fatigue, nonspecific gastrointestinal symptoms, vomiting, weakness, and morning headaches. Some individuals have hyperpigmented skin due to increased ACTH secretion. Fasting hypoglycemia may also be noted. Biochemical evidence of adrenal insufficiency can be present for up to two years before the development of clinical signs [51]. (See "Causes of primary adrenal insufficiency in children".)

Unlike autoimmune adrenal insufficiency, the adrenal insufficiency of ALD is usually characterized by glucocorticoid deficiency only, while mineralocorticoid function is preserved [44].

Prompt evaluation for ALD is warranted in boys presenting with primary adrenal insufficiency, particularly if antiadrenal antibodies are negative. Early diagnosis may improve outcomes from hematopoietic cell transplantation (HCT) [52]. (See "Clinical manifestations and diagnosis of adrenal insufficiency in children", section on 'Evaluate for cause' and "Management and prognosis of X-linked adrenoleukodystrophy", section on 'Allogeneic HCT'.)

Associated myeloneuropathy – Most patients who present with isolated adrenal insufficiency develop myeloneuropathy by middle age [44].

Females with ALD — Females with a pathogenic ABCD1 variant often develop symptoms during adulthood (table 1) [53,54]. Affected individuals typically have myeloneuropathy manifesting as a gait disorder and often (fecal) incontinence [35,54]. The frequency of symptoms increases from less than 20 percent in females under 40 years of age to almost 90 percent in females older than 60 years [54].

Adrenal insufficiency and cerebral involvement are very rare in females. Based on the most rigorous analysis, there does not appear to be correlation between the pattern of X chromosome inactivation (also known as lyonization) and the risk for clinical symptoms [54], although prior reports reached the opposite conclusion [53].

EVALUATION AND DIAGNOSIS

Prenatal diagnosis — Prenatal testing is available for subsequent pregnancies of females with affected children or other positive family history. Prenatal diagnostic methods have shifted from biochemical to deoxyribonucleic acid (DNA)-based methods. Using assisted reproductive technology, preimplantation genetic diagnosis can be accomplished in embryos using multiple displacement amplification [55]. Issues related to preimplantation genetic diagnosis are discussed in greater detail separately. (See "Preimplantation genetic testing".)

Newborn screening — In the United States, newborn screening for ALD was added to the Recommended Uniform Screening Panel in 2016 [56,57]. Information on implementation by individual states is available on the ALD database website [58]. In several other countries (Taiwan, the Netherlands, Italy) newborn screening is implemented or is in a pilot phase. Newborn screening in the Netherlands is sex-specific and identifies only boys with ALD [31]. The general principles and procedures of newborn screening are described in detail separately. (See "Overview of newborn screening".)

Methods – Newborn screening for ALD is performed using high-throughput tandem mass spectrometry analysis of C26:0-lysophosphatidylcholine (C26:0-LPC). Alternative approaches have been proposed [59]. Newborn screening for ALD also detects peroxisomal biogenesis disorders and female carriers of a defective ABCD1 gene. The screening protocol in the Netherlands is different and does not identify other disorders with increased C26:0-LPC (such as Zellweger spectrum disorders and Aicardi-Goutieres syndrome) [31]. (See "Peroxisomal disorders".)

Follow-up for positive screen – Infants with a positive screening test should undergo follow-up confirmatory testing with very long-chain fatty acid (VLCFA) analysis and ABCD1 mutation analysis as soon as possible. Total VLCFA levels (C26:0 and C26:0/C22:0 ratio) and the specific ABCD1 variant do not predict disease severity. Thus, once the diagnosis of ALD is confirmed, periodic monitoring should be performed to assess for leukodystrophy and adrenal insufficiency. Recommendations for follow-up are reviewed separately (figure 1). (See "Management and prognosis of X-linked adrenoleukodystrophy", section on 'Surveillance'.)

A positive newborn screen in a female should prompt evaluation of at-risk male relatives.

Benefits and limitations – The benefits of early diagnosis of leukodystrophy are that it facilitates early treatment (ie, hematopoietic cell transplantation [HCT]) before the onset of overt neurologic symptoms. (See "Management and prognosis of X-linked adrenoleukodystrophy".)

There are few data available on the harms of screening. Reports on the ALD newborn screening experience have described some unique challenges of this approach, particularly with identifying individuals who have genetic variants of uncertain significance [57,59-61]. For female carriers detected through newborn screening, results of genetic testing can be difficult to interpret if there are no other affected family members available for testing. Some variants found in genetic testing may not cause ALD symptoms.

When to suspect ALD — Several clinical scenarios should raise consideration of ALD [32,62]:

A positive family history of ALD

A positive newborn screen

A patient with clinical symptoms or signs suggestive of ALD:

In males of any age, the presence of confluent white matter abnormalities on brain MRI in a pattern suggestive of leukodystrophy, including those without cognitive and neurologic symptoms

In adult men and women, symptoms or signs of chronic myeloneuropathy (eg, gait dysfunction, spastic paraparesis, sphincter dysfunction) with a normal brain MRI

In males of any age, primary adrenal insufficiency without autoimmune antibodies (eg, steroid-21-hydroxlyase autoantibodies)

Diagnostic approach in males — In symptomatic males, the VLCFA panel is highly sensitive for detecting ALD and is the appropriate first step in the diagnosis. VLCFAs are usually determined as total plasma C26:0 and C26:0/C22:0 ratio. However, C26:0-LPC probably has advantages (less false positives due to nonfasted blood samples) [63]. (See 'Very long-chain fatty acid levels' below.)

If the VLCFA levels are elevated or if the ratios of VLCFA are abnormal, genetic testing should be performed to confirm the diagnosis. (See 'Genetic testing' below.)

In asymptomatic males or those identified by newborn screening, genetic testing is first-tier; biochemical testing is not necessary when a clear pathogenic ABCD1 variant has been identified [62]. In cases of unclear pathogenicity, VLCFA levels are very useful for making the diagnosis.

All males with confirmed ALD should undergo testing of adrenal function and neuroimaging to determine the extent of cerebral involvement. (See 'Adrenal function' below and 'Neuroimaging' below and "Management and prognosis of X-linked adrenoleukodystrophy", section on 'Surveillance'.)

Diagnostic approach in females — Genetic testing is the definitive test for suspected female carriers, including females with myeloneuropathy when ALD is being considered, and those at risk based upon family history. (See 'Genetic testing' below.)

In females, the VLCFA panel based on total free fatty acids in plasma (C26:0 and C26:0/C22:0 ratio) is less sensitive (15 percent of carriers have normal results). Biochemical testing employing C26:0-LPC is more consistent and reliable compared with VLCFA analysis [63,64]. (See 'Very long-chain fatty acid levels' below.)

In females with ALD, routine testing of adrenal function and neuroimaging is not recommended [62].

Laboratory testing

Very long-chain fatty acid levels — The preferred diagnostic test for ALD is C26:0-LPC [62]. It can be determined from dried blood spots or plasma in newborns and in patients with suspected ALD. It seems to have even better test characteristics than total C26:0 and also identifies virtually all females with ALD [62-65].

If C26:0-LPC is not available, testing typically includes fasting plasma levels of three VLCFA parameters [66]:

C26:0 level

Ratio of C26:0 to docosanoic acid (C26:0/C22:0)

Ratio of C26:0 to tetracosanoic acid (C26:0/C24:0)

The plasma concentration of VLCFAs is elevated in nearly all males with the disorder [66]. VLCFA concentration is increased in plasma or fibroblasts in approximately 85 percent of patients.

Alternatively, VLCFA levels may be determined in blood leukocytes using gas chromatography-mass spectrometry. Combining this test with measurement of plasma VLCFA improves sensitivity for identifying female patients; in one study, 92 percent of female patients were identified by combined plasma and leukocyte analyses [67]. VLCFA levels are also elevated in some other peroxisomal disorders. (See "Peroxisomal disorders".)

Genetic testing — Although the combination of typical clinical features and markedly elevated VLCFA levels is sufficient to establish a preliminary diagnosis of ALD in most affected males, the diagnosis should be confirmed by genetic testing. Genetic testing ensures certainty of the diagnosis and facilitates genetic counseling.

Testing consists of mutation analysis of the ABCD1 gene [68]. Additional information on genetic testing, including a list of accepted laboratories providing this testing, is available through the genetic testing registry. A database of annotated ABCD1 variants is available at The ABCD1 Variant Database.

Genetic testing is particularly important in cases with borderline VLCFA levels or atypical features.

In females, genetic testing is necessary, as only 85 percent of females have elevated plasma VLCFAs. However, C26:0-LPC is elevated in virtually all female patients, even those with normal C26:0 levels [64].

Variant of uncertain significance (VUS) – At times, it can be difficult to demonstrate that a novel genetic sequence variant is pathogenic when VLCFA levels are normal [69]. In such cases, generating clonal cell lines that express potentially pathogenic alleles, followed by biochemical analysis, can be helpful and represents an important adjunct to standard testing.

Due to newborn screening and the use of (trio) whole exome sequencing, there is increased identification of individuals with a VUS in the ABCD1 gene who have only slightly elevated levels of VLCFAs in plasma (above control levels but below the range usually encountered in patients with ALD) [70]. In cases where the individual is asymptomatic and has no positive family history of ALD, functional testing (beta-oxidation assays in cultured skin fibroblasts) may be able to classify the variant as likely pathogenic (impaired peroxisomal beta-oxidation capacity) or benign (normal peroxisomal beta-oxidation capacity) [70]. Also, extended family screening to identify symptomatic individuals might be needed to classify variants in the ABCD1 gene in some cases if biochemical testing yields ambiguous results.

Adrenal function — Adrenal function should be evaluated in males by measurement of plasma adrenocorticotropic hormone (ACTH) level and the rise in plasma cortisol level following ACTH stimulation. If initial adrenal testing is normal, follow-up testing should be performed every 6 to 12 months in affected males. Females usually have normal adrenal function. (See "Management and prognosis of X-linked adrenoleukodystrophy", section on 'Surveillance for adrenal insufficiency'.)

Electrodiagnostic tests — Electromyography and nerve conduction studies can be helpful for diagnosis of polyneuropathy. (See "Overview of polyneuropathy", section on 'Diagnostic evaluation'.)

Neuroimaging — All neurologically asymptomatic males with confirmed ALD should undergo surveillance neuroimaging with brain MRI beginning at age two (figure 1) [62]. (See "Management and prognosis of X-linked adrenoleukodystrophy", section on 'MRI surveillance for leukodystrophy'.)

MRI – In symptomatic males with leukodystrophy, brain MRI is always abnormal, demonstrating demyelination in cerebral white matter (image 2). By contrast, brain MRI is often normal in patients with only myeloneuropathy and/or adrenal insufficiency. Since MRI changes precede neurologic signs, routine MRI surveillance allows for early detection of onset of cerebral involvement and may facilitate optimal early treatment with HCT (ie, at an early stage of disease). (See "Management and prognosis of X-linked adrenoleukodystrophy", section on 'MRI surveillance for leukodystrophy'.)

Other imaging techniques – Proton MR spectroscopy detects white matter abnormalities that may not be apparent on conventional MRI and may predict disease progression [71,72]. In one report, this technique was evaluated in 25 individuals with ALD, ages 2 to 43 years [72]. MRI and proton MR spectroscopy were performed at baseline, and follow-up MRI was performed at an average of 3.5 years after the baseline imaging. Based on the MRI findings, participants were classified as noncerebral, cerebral nonprogressive, or cerebral progressive. A concentration ratio of N-acetylaspartate to choline of ≤5 predicted disease progression with a sensitivity and specificity of 100 and 83 percent, respectively, and a positive and negative predictive value of 66 and 100 percent, respectively.

Although the conventional brain MRI is often normal in individuals with myeloneuropathy, axonal changes may be seen on brain MR spectroscopy [73] and diffusion tensor imaging [74]. Magnetization transfer MRI may be effective in determining the extent of spinal cord involvement in myeloneuropathy [75]. Functional MRI and proton MR spectroscopy may reveal prominent changes in the brain not apparent on conventional cranial MRI [76]. Using quantitative MRI-derived measures, it is possible to identify and quantify structural changes in the upper spinal cord and brain that correspond to the known pathology in myeloneuropathy [77].

Studies of magnetic resonance perfusion imaging suggest that changes in local brain perfusion might be one of the earliest signs of lesion development [78]. Decreased brain magnetic resonance perfusion precedes leakage of the blood-brain barrier, as demonstrated by contrast enhancement in cerebral ALD. Together with gadolinium enhancement intensity on brain MRI, relative cerebral blood volume in brain white matter may help predict clinical outcomes following HCT [79,80].

Assessment after diagnosis — Patients diagnosed with ALD should be monitored for disease manifestations (leukodystrophy, myeloneuropathy, adrenal insufficiency) (figure 1), as reviewed in detail elsewhere. (See "Management and prognosis of X-linked adrenoleukodystrophy", section on 'Surveillance'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis is based on the phenotype:

Leukodystrophy in ALD – The early signs and symptoms of leukodystrophy (eg, poor school performance, behavioral problems) may be mistaken for a learning disorder, attention deficit hyperactivity disorder, autism spectrum disorder, or other psychiatric or developmental disorders. These disorders are not typically associated with focal neurologic deficits, visual impairment, or seizures. If such findings are present, neuroimaging with MRI may be warranted and will distinguish ALD from these psychiatric and developmental disorders. (See "Attention deficit hyperactivity disorder in children and adolescents: Clinical features and diagnosis" and "Autism spectrum disorder in children and adolescents: Clinical features" and "Specific learning disorders in children: Clinical features".)

The differential diagnosis for the MRI findings of ALD includes acute disseminated encephalomyelitis, multiple sclerosis, and other leukodystrophies (eg, Krabbe disease, metachromatic leukodystrophy); however, the pattern of lesions on the MRI of the brain allows one to easily distinguish between these different disorders and is virtually pathognomonic [81]. The clinical course and family history also help one to distinguish ALD from other disorders, though ultimately very long-chain fatty acid (VLCFA) levels and genetic testing are required to confirm the diagnosis. (See "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis" and "Pathogenesis, clinical features, and diagnosis of pediatric multiple sclerosis" and "Krabbe disease" and "Metachromatic leukodystrophy".)

Myeloneuropathy – Other causes of spinal cord dysfunction include multiple sclerosis, amyotrophic lateral sclerosis, vitamin B12 deficiency, and progressive spastic paraparesis, including hereditary spastic paraparesis (table 2). These disorders are discussed in detail separately. (See "Evaluation and diagnosis of multiple sclerosis in adults" and "Disorders affecting the spinal cord".)

Some patients with myeloneuropathy may present with predominant features of polyneuropathy rather than spinal cord dysfunction. Polyneuropathy has a wide variety of causes, ranging from the common (eg, diabetes mellitus, alcohol abuse, human immunodeficiency virus [HIV] infection) to the rare (eg, Charcot-Marie-Tooth disease). It often occurs as a side effect of medication (table 3) or as a manifestation of systemic disease (table 4). The rate of progression of the polyneuropathy in conjunction with its character (axonal or demyelinating) can help identify its etiology. An approach to identifying the etiology in patients presenting predominantly with polyneuropathy is provided separately. (See "Overview of polyneuropathy".)

Adrenal insufficiency – Other causes of primary adrenal insufficiency are summarized in the table and are discussed in detail separately (table 5). The typical manifestation of adrenal insufficiency in ALD is glucocorticoid deficiency with normal mineralocorticoid function, unlike the pattern seen in most other causes of primary adrenal insufficiency, which are usually associated with both glucocorticoid and mineralocorticoid deficiency [44]. (See "Causes of primary adrenal insufficiency (Addison disease)" and "Causes of primary adrenal insufficiency in children".)

SUMMARY AND RECOMMENDATIONS

Disease description – Adrenoleukodystrophy (ALD) is a peroxisomal disorder of beta-oxidation that results in accumulation of very long-chain fatty acids (VLCFAs) in all tissues. It is an X-linked genetic disorder caused by mutations in the ABCD1 gene. ALD consists of a spectrum of clinical syndromes (including leukodystrophy, myeloneuropathy, and adrenal insufficiency) that vary in the age and severity of clinical presentation (table 1). (See 'Introduction' above and 'Genetics' above and 'Pathogenesis' above.)

ALD in males – Affected males have (combinations of) several clinical syndromes and can present from childhood through adulthood (table 1):

Leukodystrophy – Affected boys typically present between four and eight years of age with learning disabilities and behavior problems, followed by neurologic deterioration that includes increasing cognitive and behavioral abnormalities, blindness, and the development of quadriparesis. Approximately 20 percent of affected individuals have seizures. Approximately 10 to 15 percent have arrested ALD, characterized by absence of symptom progression and lack of lesion growth or enhancement on brain MRI; a minority of these patients undergo stepwise progression or conversion to progressive childhood leukodystrophy. (See 'Leukodystrophy' above.)

Myeloneuropathy – Myeloneuropathy typically presents in adult males between 20 and 40 years of age. The primary manifestation is spinal cord dysfunction with progressive stiffness and weakness of the legs (spastic paraparesis), abnormal sphincter control, neurogenic bladder, and sexual dysfunction. Polyneuropathy is also a common feature, presenting with numbness or painful paresthesias, which contribute to gait abnormalities. Most individuals have adrenal insufficiency. Myeloneuropathy may also present as a progressive cerebellar disorder. (See 'Myeloneuropathy' above.)

Adrenal insufficiency – Primary adrenal insufficiency is the initial manifestation of ALD in 30 to 40 percent of patients and remains the only sign of ALD in approximately 8 to 10 percent. In most affected patients, adrenal insufficiency presents before the age of 10 years, but it can present later. Most patients with isolated adrenal insufficiency go on to develop myeloneuropathy by mid-adulthood. (See 'Adrenal insufficiency' above.)

Females – Female patients often develop myeloneuropathy and polyneuropathy symptoms during adulthood (table 1). The frequency of symptoms rises from <20 percent in females under 40 years of age to almost 90 percent in females older than 60 years. (See 'Females with ALD' above.)

Newborn screening – For ALD, newborn screening is available in some states in the United States and several other countries. If the newborn screen is positive, follow-up confirmation testing should be completed as soon as possible. (See 'Newborn screening' above.)

Laboratory testing – Measuring VLCFA levels is the first step. The plasma concentration of VLCFAs is elevated in nearly all males with the ALD. If elevated VLCFA levels are detected, confirmatory genetic testing is performed. In addition, adrenal function testing should be performed at the time of diagnosis and re-evaluated yearly. (See 'Laboratory testing' above.)

Imaging – All male individuals with confirmed ALD complex should undergo neuroimaging with brain MRI at the time of diagnosis. Brain MRI is normal before onset of leukodystrophy but is abnormal in symptomatic males with leukodystrophy, demonstrating demyelination in cerebral white matter (image 2). In patients with myeloneuropathy, MRI of the spinal cord is normal (although atrophy of the cervical spinal cord becomes apparent in advanced disease). Presymptomatic boys with childhood ALD who initially have normal MRI should undergo follow-up imaging every 6 to 12 months. (See 'Neuroimaging' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Florian S Eichler, MD, who contributed to earlier versions of this topic review.

  1. Kemp S, Huffnagel IC, Linthorst GE, et al. Adrenoleukodystrophy - neuroendocrine pathogenesis and redefinition of natural history. Nat Rev Endocrinol 2016; 12:606.
  2. Mosser J, Douar AM, Sarde CO, et al. Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. Nature 1993; 361:726.
  3. Mosser J, Lutz Y, Stoeckel ME, et al. The gene responsible for adrenoleukodystrophy encodes a peroxisomal membrane protein. Hum Mol Genet 1994; 3:265.
  4. Migeon BR, Moser HW, Moser AB, et al. Adrenoleukodystrophy: evidence for X linkage, inactivation, and selection favoring the mutant allele in heterozygous cells. Proc Natl Acad Sci U S A 1981; 78:5066.
  5. Holzinger A, Kammerer S, Berger J, Roscher AA. cDNA cloning and mRNA expression of the human adrenoleukodystrophy related protein (ALDRP), a peroxisomal ABC transporter. Biochem Biophys Res Commun 1997; 239:261.
  6. McGuinness MC, Lu JF, Zhang HP, et al. Role of ALDP (ABCD1) and mitochondria in X-linked adrenoleukodystrophy. Mol Cell Biol 2003; 23:744.
  7. Wang Y, Busin R, Reeves C, et al. X-linked adrenoleukodystrophy: ABCD1 de novo mutations and mosaicism. Mol Genet Metab 2011; 104:160.
  8. van Roermund CW, Visser WF, Ijlst L, et al. The human peroxisomal ABC half transporter ALDP functions as a homodimer and accepts acyl-CoA esters. FASEB J 2008; 22:4201.
  9. Kemp S, Wanders R. Biochemical aspects of X-linked adrenoleukodystrophy. Brain Pathol 2010; 20:831.
  10. Musolino PL, Gong Y, Snyder JM, et al. Brain endothelial dysfunction in cerebral adrenoleukodystrophy. Brain 2015; 138:3206.
  11. Höftberger R, Kunze M, Weinhofer I, et al. Distribution and cellular localization of adrenoleukodystrophy protein in human tissues: implications for X-linked adrenoleukodystrophy. Neurobiol Dis 2007; 28:165.
  12. Hudspeth MP, Raymond GV. Immunopathogenesis of adrenoleukodystrophy: current understanding. J Neuroimmunol 2007; 182:5.
  13. Eichler FS, Ren JQ, Cossoy M, et al. Is microglial apoptosis an early pathogenic change in cerebral X-linked adrenoleukodystrophy? Ann Neurol 2008; 63:729.
  14. Powers JM, Pei Z, Heinzer AK, et al. Adreno-leukodystrophy: oxidative stress of mice and men. J Neuropathol Exp Neurol 2005; 64:1067.
  15. López-Erauskin J, Galino J, Bianchi P, et al. Oxidative stress modulates mitochondrial failure and cyclophilin D function in X-linked adrenoleukodystrophy. Brain 2012; 135:3584.
  16. Hein S, Schönfeld P, Kahlert S, Reiser G. Toxic effects of X-linked adrenoleukodystrophy-associated, very long chain fatty acids on glial cells and neurons from rat hippocampus in culture. Hum Mol Genet 2008; 17:1750.
  17. Oezen I, Rossmanith W, Forss-Petter S, et al. Accumulation of very long-chain fatty acids does not affect mitochondrial function in adrenoleukodystrophy protein deficiency. Hum Mol Genet 2005; 14:1127.
  18. Raymond GV, Seidman R, Monteith TS, et al. Head trauma can initiate the onset of adreno-leukodystrophy. J Neurol Sci 2010; 290:70.
  19. Bouquet F, Dehais C, Sanson M, et al. Dramatic worsening of adult-onset X-linked adrenoleukodystrophy after head trauma. Neurology 2015; 85:1991.
  20. Benzoni C, Aquino D, Di Bella D, et al. Severe worsening of adult-onset Alexander disease after minor head trauma: Report of two patients and review of the literature. J Clin Neurosci 2020; 75:221.
  21. Powers JM. Adreno-leukodystrophy (adreno-testiculo-leukomyelo-neuropathic-complex). Clin Neuropathol 1985; 4:181.
  22. Ferrer I, Aubourg P, Pujol A. General aspects and neuropathology of X-linked adrenoleukodystrophy. Brain Pathol 2010; 20:817.
  23. Powers JM, Liu Y, Moser AB, Moser HW. The inflammatory myelinopathy of adreno-leukodystrophy: cells, effector molecules, and pathogenetic implications. J Neuropathol Exp Neurol 1992; 51:630.
  24. Ito M, Blumberg BM, Mock DJ, et al. Potential environmental and host participants in the early white matter lesion of adreno-leukodystrophy: morphologic evidence for CD8 cytotoxic T cells, cytolysis of oligodendrocytes, and CD1-mediated lipid antigen presentation. J Neuropathol Exp Neurol 2001; 60:1004.
  25. Singh J, Khan M, Singh I. Silencing of Abcd1 and Abcd2 genes sensitizes astrocytes for inflammation: implication for X-adrenoleukodystrophy. J Lipid Res 2009; 50:135.
  26. Powers JM, DeCiero DP, Ito M, et al. Adrenomyeloneuropathy: a neuropathologic review featuring its noninflammatory myelopathy. J Neuropathol Exp Neurol 2000; 59:89.
  27. Powers JM, DeCiero DP, Cox C, et al. The dorsal root ganglia in adrenomyeloneuropathy: neuronal atrophy and abnormal mitochondria. J Neuropathol Exp Neurol 2001; 60:493.
  28. Moser HW, Moser AB. Peroxisomal disorders: overview. Ann N Y Acad Sci 1996; 804:427.
  29. Moser AB, Jones RO, Hubbard WC, et al. Newborn Screening for X-Linked Adrenoleukodystrophy. Int J Neonatal Screen 2016; 2.
  30. Bezman L, Moser AB, Raymond GV, et al. Adrenoleukodystrophy: incidence, new mutation rate, and results of extended family screening. Ann Neurol 2001; 49:512.
  31. Albersen M, van der Beek SL, Dijkstra IME, et al. Sex-specific newborn screening for X-linked adrenoleukodystrophy. J Inherit Metab Dis 2023; 46:116.
  32. Raymond GV, Moser AB, Fatemi, A. X-linked adrenoleukodystrophy. In GeneReviews. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1315/ (Accessed on May 30, 2023).
  33. de Beer M, Engelen M, van Geel BM. Frequent occurrence of cerebral demyelination in adrenomyeloneuropathy. Neurology 2014; 83:2227.
  34. Moser HW, Raymond GV, Dubey P. Adrenoleukodystrophy: new approaches to a neurodegenerative disease. JAMA 2005; 294:3131.
  35. Percy AK, Rutledge SL. Adrenoleukodystrophy and related disorders. Ment Retard Dev Disabil Res Rev 2001; 7:179.
  36. Young RS, Ramer JC, Towfighi J, et al. Adrenoleukodystrophy: unusual computed tomographic appearance. Arch Neurol 1982; 39:782.
  37. Esiri MM, Hyman NM, Horton WL, Lindenbaum RH. Adrenoleukodystrophy: clinical, pathological and biochemical findings in two brothers with the onset of cerebral disease in adult life. Neuropathol Appl Neurobiol 1984; 10:429.
  38. MacDonald JT, Stauffer AE, Heitoff K. Adrenoleukodystrophy: early frontal lobe involvement on computed tomography. J Comput Assist Tomogr 1984; 8:128.
  39. Melhem ER, Loes DJ, Georgiades CS, et al. X-linked adrenoleukodystrophy: the role of contrast-enhanced MR imaging in predicting disease progression. AJNR Am J Neuroradiol 2000; 21:839.
  40. Mallack EJ, van de Stadt S, Caruso PA, et al. Clinical and radiographic course of arrested cerebral adrenoleukodystrophy. Neurology 2020; 94:e2499.
  41. Liberato AP, Mallack EJ, Aziz-Bose R, et al. MRI brain lesions in asymptomatic boys with X-linked adrenoleukodystrophy. Neurology 2019; 92:e1698.
  42. Korenke GC, Pouwels PJ, Frahm J, et al. Arrested cerebral adrenoleukodystrophy: a clinical and proton magnetic resonance spectroscopy study in three patients. Pediatr Neurol 1996; 15:103.
  43. Carlson AM, Huffnagel IC, Verrips A, et al. Five men with arresting and relapsing cerebral adrenoleukodystrophy. J Neurol 2021; 268:936.
  44. Huffnagel IC, Laheji FK, Aziz-Bose R, et al. The Natural History of Adrenal Insufficiency in X-Linked Adrenoleukodystrophy: An International Collaboration. J Clin Endocrinol Metab 2019; 104:118.
  45. Huffnagel IC, van Ballegoij WJC, van Geel BM, et al. Progression of myelopathy in males with adrenoleukodystrophy: towards clinical trial readiness. Brain 2019; 142:334.
  46. van de Stadt SIW, van Ballegoij WJC, Labounek R, et al. Spinal cord atrophy as a measure of severity of myelopathy in adrenoleukodystrophy. J Inherit Metab Dis 2020; 43:852.
  47. Zackowski KM, Dubey P, Raymond GV, et al. Sensorimotor function and axonal integrity in adrenomyeloneuropathy. Arch Neurol 2006; 63:74.
  48. van Geel BM, Bezman L, Loes DJ, et al. Evolution of phenotypes in adult male patients with X-linked adrenoleukodystrophy. Ann Neurol 2001; 49:186.
  49. Moser HW, Moser AB, Smith KD, et al. Adrenoleukodystrophy: phenotypic variability and implications for therapy. J Inherit Metab Dis 1992; 15:645.
  50. Laureti S, Casucci G, Santeusanio F, et al. X-linked adrenoleukodystrophy is a frequent cause of idiopathic Addison's disease in young adult male patients. J Clin Endocrinol Metab 1996; 81:470.
  51. Dubey P, Raymond GV, Moser AB, et al. Adrenal insufficiency in asymptomatic adrenoleukodystrophy patients identified by very long-chain fatty acid screening. J Pediatr 2005; 146:528.
  52. Polgreen LE, Chahla S, Miller W, et al. Early diagnosis of cerebral X-linked adrenoleukodystrophy in boys with Addison's disease improves survival and neurological outcomes. Eur J Pediatr 2011; 170:1049.
  53. Maier EM, Kammerer S, Muntau AC, et al. Symptoms in carriers of adrenoleukodystrophy relate to skewed X inactivation. Ann Neurol 2002; 52:683.
  54. Engelen M, Barbier M, Dijkstra IM, et al. X-linked adrenoleukodystrophy in women: a cross-sectional cohort study. Brain 2014; 137:693.
  55. Lledó B, Bernabeu R, Ten J, et al. Preimplantation genetic diagnosis of X-linked adrenoleukodystrophy with gender determination using multiple displacement amplification. Fertil Steril 2007; 88:1327.
  56. http://www.hrsa.gov/advisorycommittees/mchbadvisory/heritabledisorders/recommendations/secretary-final-response-x-ald.pdf (Accessed on July 13, 2016).
  57. Kemper AR, Brosco J, Comeau AM, et al. Newborn screening for X-linked adrenoleukodystrophy: evidence summary and advisory committee recommendation. Genet Med 2017; 19:121.
  58. R Salzman and S Kemp. Newborn Screening for ALD, ALD database. Available at: http://www.x-ald.nl/clinical-diagnosis/newborn-screening/ (Accessed on August 09, 2017).
  59. Vogel BH, Bradley SE, Adams DJ, et al. Newborn screening for X-linked adrenoleukodystrophy in New York State: diagnostic protocol, surveillance protocol and treatment guidelines. Mol Genet Metab 2015; 114:599.
  60. Wiens K, Berry SA, Choi H, et al. A report on state-wide implementation of newborn screening for X-linked Adrenoleukodystrophy. Am J Med Genet A 2019; 179:1205.
  61. Lee S, Clinard K, Young SP, et al. Evaluation of X-Linked Adrenoleukodystrophy Newborn Screening in North Carolina. JAMA Netw Open 2020; 3:e1920356.
  62. Engelen M, van Ballegoij WJC, Mallack EJ, et al. International Recommendations for the Diagnosis and Management of Patients With Adrenoleukodystrophy: A Consensus-Based Approach. Neurology 2022; 99:940.
  63. Jaspers YRJ, Ferdinandusse S, Dijkstra IME, et al. Comparison of the Diagnostic Performance of C26:0-Lysophosphatidylcholine and Very Long-Chain Fatty Acids Analysis for Peroxisomal Disorders. Front Cell Dev Biol 2020; 8:690.
  64. Huffnagel IC, Dijkgraaf MGW, Janssens GE, et al. Disease progression in women with X-linked adrenoleukodystrophy is slow. Orphanet J Rare Dis 2019; 14:30.
  65. Huffnagel IC, van de Beek MC, Showers AL, et al. Comparison of C26:0-carnitine and C26:0-lysophosphatidylcholine as diagnostic markers in dried blood spots from newborns and patients with adrenoleukodystrophy. Mol Genet Metab 2017; 122:209.
  66. Moser AB, Kreiter N, Bezman L, et al. Plasma very long chain fatty acids in 3,000 peroxisome disease patients and 29,000 controls. Ann Neurol 1999; 45:100.
  67. Unterberger U, Regelsberger G, Sundt R, et al. Diagnosis of X-linked adrenoleukodystrophy in blood leukocytes. Clin Biochem 2007; 40:1037.
  68. Boehm CD, Cutting GR, Lachtermacher MB, et al. Accurate DNA-based diagnostic and carrier testing for X-linked adrenoleukodystrophy. Mol Genet Metab 1999; 66:128.
  69. Schackmann MJ, Ofman R, van Geel BM, et al. Pathogenicity of novel ABCD1 variants: The need for biochemical testing in the era of advanced genetics. Mol Genet Metab 2016; 118:123.
  70. van de Stadt SIW, Mooyer PAW, Dijkstra IME, et al. Biochemical Studies in Fibroblasts to Interpret Variants of Unknown Significance in the ABCD1 Gene. Genes (Basel) 2021; 12.
  71. Eichler FS, Itoh R, Barker PB, et al. Proton MR spectroscopic and diffusion tensor brain MR imaging in X-linked adrenoleukodystrophy: initial experience. Radiology 2002; 225:245.
  72. Eichler FS, Barker PB, Cox C, et al. Proton MR spectroscopic imaging predicts lesion progression on MRI in X-linked adrenoleukodystrophy. Neurology 2002; 58:901.
  73. Dubey P, Fatemi A, Barker PB, et al. Spectroscopic evidence of cerebral axonopathy in patients with "pure" adrenomyeloneuropathy. Neurology 2005; 64:304.
  74. Dubey P, Fatemi A, Huang H, et al. Diffusion tensor-based imaging reveals occult abnormalities in adrenomyeloneuropathy. Ann Neurol 2005; 58:758.
  75. Fatemi A, Smith SA, Dubey P, et al. Magnetization transfer MRI demonstrates spinal cord abnormalities in adrenomyeloneuropathy. Neurology 2005; 64:1739.
  76. Marino S, De Luca M, Dotti MT, et al. Prominent brain axonal damage and functional reorganization in "pure" adrenomyeloneuropathy. Neurology 2007; 69:1261.
  77. Castellano A, Papinutto N, Cadioli M, et al. Quantitative MRI of the spinal cord and brain in adrenomyeloneuropathy: in vivo assessment of structural changes. Brain 2016; 139:1735.
  78. Musolino PL, Rapalino O, Caruso P, et al. Hypoperfusion predicts lesion progression in cerebral X-linked adrenoleukodystrophy. Brain 2012; 135:2676.
  79. Miller WP, Mantovani LF, Muzic J, et al. Intensity of MRI Gadolinium Enhancement in Cerebral Adrenoleukodystrophy: A Biomarker for Inflammation and Predictor of Outcome following Transplantation in Higher Risk Patients. AJNR Am J Neuroradiol 2016; 37:367.
  80. McKinney AM, Benson J, Nascene DR, et al. Childhood Cerebral Adrenoleukodystrophy: MR Perfusion Measurements and Their Use in Predicting Clinical Outcome after Hematopoietic Stem Cell Transplantation. AJNR Am J Neuroradiol 2016; 37:1713.
  81. Schiffmann R, van der Knaap MS. Invited article: an MRI-based approach to the diagnosis of white matter disorders. Neurology 2009; 72:750.
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