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X-linked adrenoleukodystrophy and adrenomyeloneuropathy

X-linked adrenoleukodystrophy and adrenomyeloneuropathy
Authors:
Ronald JA Wanders, PhD
Florian S Eichler, MD
Section Editors:
Marc C Patterson, MD, FRACP
Sihoun Hahn, MD, PhD
Deputy Editors:
John F Dashe, MD, PhD
Carrie Armsby, MD, MPH
Literature review current through: Oct 2022. | This topic last updated: Feb 17, 2022.

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. ALD consists of a spectrum of phenotypes (including adrenomyeloneuropathy [AMN]) that vary in the age and severity of clinical presentation (table 1) [1,2]. These conditions are known as the ALD/AMN complex.

The pathophysiology, clinical manifestations, and treatment of ALD/AMN will be reviewed here. Other peroxisomal disorders are discussed separately. (See "Peroxisomal disorders".)

EPIDEMIOLOGY — ALD/AMN is the most common peroxisomal disorder [3]. 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 [4].

GENETICS — ALD/AMN is an X-linked disorder. It is caused by mutations in the adenosine triphosphate (ATP)-binding cassette (ABC), subfamily D, member 1 gene (ABCD1), located at Xq28, that encodes an ABC transporter [5-9]. The ABC transporter helps form the channel through which very long-chain fatty acids move into the peroxisome, probably as coenzyme A esters [10].

The phenotype does not correlate with the type of mutation, and different phenotypes can be seen within the same family.

PATHOGENESIS — ABCD1 mutations may 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/AMN [11]. However, plasma VLCFA levels do not predict phenotype and cell-specific functions of ABCD1 may play a role in the pathogenesis independent of VLCFA [12].

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 latter undergo atrophy in AMN). ALD protein is scarcely present in the corticospinal tract and corpus callosum [13].

Central nervous system – In cerebral forms of ALD, central nervous system pathology is characterized by diverse immune responses involving cellular and humoral mechanisms as well as cytokines and complement [14]. The profound mononuclear response is distinct from that seen in multiple sclerosis and is characterized by microglial activation followed by apoptosis [15].

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 [16,17]. 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 brain [18]. However, another in vitro study using muscle tissue from individuals with ALD and brain tissue from a mouse model of X-ALD did not find evidence of mitochondrial dysfunction [19].

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 [12].

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 [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 failure occurs along with irreversible degenerative neurologic defects. Adrenal failure may predate, occur simultaneously with, or follow the onset of the neurologic deterioration [21].

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

NEUROPATHOLOGY — In the central nervous system, ALD is characterized by inflammatory demyelination, resulting in confluent and bilaterally symmetric loss of myelin in the cerebral and cerebellar white matter [22,23]. 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 [24]:

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 X-linked 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 acids (VLCFA)-containing lipids, such as gangliosides or proteolipids, acting as antigens [25]. In vitro studies suggest that the VLCFA accumulation that occurs in the absence of ABDC1 function promotes inflammation [26]. 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 adrenomyeloneuropathy, both inflammatory and noninflammatory demyelination lesions occur [22]. 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 [27]. Mitochondrial pathology [28] and oxidative stress [16] also contribute to pathogenesis. When peripheral nerves are affected in ALD/AMN, 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.

CLINICAL FEATURES — Abnormalities primarily affect the central nervous system, adrenal cortex, and Leydig cells in the testes. Affected males have one of three main phenotypes and can present from childhood through adulthood (table 1) [29]. Female carriers often develop symptoms of myelopathy and peripheral neuropathy in adulthood. The clinical course in females is milder, and the onset is later (after age 35 years) than in affected males.

Childhood cerebral forms — Childhood ALD presents between three and ten years of age (peak seven years), representing approximately 35 percent of all phenotypes in the ALD/AMN complex (table 1) [30]. Childhood ALD rarely presents after 15 years of age and almost never occurs before age three years.

Boys typically present with learning disabilities and behavior problems that are often diagnosed initially as attention deficit hyperactivity disorder, and may respond to stimulant medication [1]. This is followed by neurologic deterioration that includes increasing cognitive and behavioral abnormalities, blindness, and the development of quadriparesis [31]. Approximately 20 percent of affected boys have seizures, which may be the first manifestation in some. Spontaneously arrested ALD, characterized by absence of symptom progression and lack of lesion growth or enhancement on sequential brain magnetic resonance imaging (MRI), occurs in approximately 10 to 15 percent of ALD cases [32-34]. These patients may be asymptomatic at diagnosis. A minority of patients with arrested ALD eventually convert to progressive ALD, so continued vigilance and monitoring is necessary; younger patients may have a higher risk converting to progressive disease [35]. (See "Attention deficit hyperactivity disorder in children and adolescents: Clinical features and diagnosis", section on 'Clinical features' and "Specific learning disabilities in children: Clinical features", section on 'Risk factors'.)

Most affected individuals have adrenal insufficiency. Some have hyperpigmented skin due to increased adrenocorticotropic hormone (ACTH) secretion. (See "Causes of primary adrenal insufficiency in children".)

Adrenomyeloneuropathy — AMN typically presents in adult males between 20 and 40 years of age (average 28 years) and comprises approximately 40 to 45 percent of ALD/AMN complex (table 1) [30,31]. In one study of 46 males with ALD (ages 16 to 71), the frequency of myelopathy increased with age from 31 percent in patients younger than 30 years to 95 percent in patients older than 50 years [36].

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. Numbness and pain from polyneuropathy are also common in males with AMN. Gonadal dysfunction may precede motor abnormalities. The majority have adrenal insufficiency. AMN may also present as a progressive cerebellar disorder. (See "Causes of primary adrenal insufficiency in children" and "Diagnosis of adrenal insufficiency in adults".)

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 AMN [37]. In other observational studies, auditory brainstem evoked responses correlated more with AMN than ALD, while auditory function was generally normal [38,39].

Cerebral involvement at the time of diagnosis of AMN is rare, occurring in only 6 percent of patients [40]. However, in long-term follow-up studies, 20 to 60 percent of patients with AMN developed symptoms of cerebral involvement (eg, cognitive decline, behavioral abnormalities, visual loss, impaired auditory discrimination, or seizures) and/or cerebral demyelination on brain MRI [40,41]. Patients with cerebral involvement have more rapidly progressive illness. (See 'Prognosis' below.)

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 [42-44]. 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 to 40 years [44]. Most affected patients had clinical signs attributable to adrenal insufficiency at the time of diagnosis. The majority of patients who present with the isolated adrenal insufficiency phenotype develop myelopathy by middle age.

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 [45]. (See "Causes of primary adrenal insufficiency in children".)

Prompt evaluation for ALD is warranted in boys presenting with primary adrenal insufficiency, particularly if antiadrenal antibodies are negative. Early diagnosis of ALD may improve outcomes from hematopoietic cell transplantation (HCT) [46]. (See "Clinical manifestations and diagnosis of adrenal insufficiency in children", section on 'Evaluate for cause' and 'Hematopoietic cell transplantation' below.)

Other presentations — Atypical presentations occur in approximately 5 to 10 percent of affected males. These include [30]:

Headache and intracranial pressure with signs of localized brain disease (eg, hemiparesis, visual field defect, or aphasia) in boys between 4 and 10 years of age (or, less commonly, in adolescents or adults)

Progressive paralysis, dementia, and behavior disturbance in an adult

Progressive incoordination and ataxia in a child or adult

Erectile dysfunction without other findings in a male with a family history of ALD

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

Asymptomatic

Females with ALD — Females who are heterozygous for a pathogenic ABCD1 mutation often develop symptoms during adulthood (table 1) [47,48]. Affected individuals typically present with an AMN-like phenotype, consisting of peripheral neuropathy and myelopathy, often with a gait disorder and fecal incontinence and sometimes with mild spastic paraparesis [31,48]. 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 [48]. Adrenal insufficiency and cerebral involvement are 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 [48], although prior reports reached the opposite conclusion [47].

DIAGNOSIS

Diagnostic approach — The possibility of ALD/AMN may be raised by the above clinical signs or symptoms (including isolated adrenal insufficiency), a family history of ALD/AMN, or a positive newborn screen. The diagnostic approach is as follows:

In males, the very long-chain fatty acid (VLCFA) panel is highly sensitive for detecting ALD/AMN and is the appropriate first step in the diagnosis. If the VLCFA levels are elevated, or if the ratios of VLCFA are abnormal, genetic testing should be performed to confirm the diagnosis. (See 'Very long-chain fatty acid levels' below and 'Genetic testing' below.)

In females, the VLCFA panel based on free fatty acids is less sensitive (15 percent of carriers have normal results). There is evidence that biochemical testing employing C26:0-lysophosphatidylcholine (C26:0-LPC) may be more consistent and reliable compared with VLCFA analysis [49]. Overall, genetic testing is the definitive test for suspected female carriers. (See 'Genetic testing' below.)

All individuals with confirmed ALD/AMN complex, including symptomatic female heterozygotes, should undergo testing of adrenal function and neuroimaging to determine the extent of cerebral involvement. (See 'Adrenocorticotropic hormone stimulation' below and 'Neuroimaging' below.)

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 DNA-based methods. Using assisted reproductive technology, preimplantation genetic diagnosis can be accomplished in embryos using multiple displacement amplification [50]. 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 X-linked ALD was added to the Recommended Uniform Screening Panel in 2016 [51,52]. Information on implementation by individual states is available on the ALD database website [53]. The general principles and procedures of newborn screening are described in detail separately. (See "Newborn screening".)

Newborn screening for ALD is performed using high-throughput tandem mass spectrometry analysis of C26:0-LPC. Alternative approaches have been proposed [54]. Newborn screening for X-linked ALD also detects peroxisomal biogenesis disorders and female carriers of a defective ABCD1 gene. (See "Peroxisomal disorders".)

Infants with a positive screening test should undergo follow-up confirmatory testing with VLCFA analysis and ABCD1 mutation analysis as soon as possible. VLCFA levels and the type of genetic variation do not predict clinical phenotype. Thus, once the diagnosis of X-linked ALD is confirmed, periodic monitoring should be performed to assess for adrenal insufficiency and/or cerebral involvement. Surveillance protocols vary in different regions [54]. (See 'Adrenocorticotropic hormone stimulation' below and 'Neuroimaging' below.)

The benefits of early diagnosis of childhood cerebral ALD are that it facilitates timely initiation of adrenal hormone replacement therapy and permits definitive treatment (ie, hematopoietic cell transplantation [HCT]) to be undertaken prior to development of irreversible cerebral injury. (See 'Hematopoietic cell transplantation' below.)

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 [52,54-56]. 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.

Laboratory testing — Laboratory testing begins with measuring VLCFA levels. If elevated VLCFA levels are detected, confirmatory genetic testing is performed. In addition, adrenal function should be evaluated by adrenocorticotropic hormone (ACTH) stimulation testing.

Very long-chain fatty acid levels — The plasma concentration of VLCFAs is elevated in nearly all males with the disorder [57]. VLCFA concentration is increased in plasma or fibroblasts in approximately 85 percent of female carriers. Testing typically includes three VLCFA parameters [57]:

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)

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 heterozygotes; in one study, 92 percent of heterozygotes were identified by combined plasma and leukocyte analyses [58]. 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 X-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 [59]. Additional information on genetic testing, including a list of accepted laboratories providing this testing, is available through the genetic testing registry.

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. At times, it can be difficult to demonstrate that a novel sequence variant is pathogenic when VLCFA levels are normal [60]. 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.

Adrenocorticotropic hormone stimulation — Adrenal function should be evaluated by measurement of plasma ACTH level and the rise in plasma cortisol level following ACTH stimulation. Testing is abnormal in 90 percent of boys with neurologic signs, and in 70 percent of men with AMN [30]. ACTH levels are often increased already during the first year of life [45]. 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 "Initial testing for adrenal insufficiency: Basal cortisol and the ACTH stimulation test" and "Clinical manifestations and diagnosis of adrenal insufficiency in children", section on 'Adrenocorticotropic hormone stimulation test'.)

Neuroimaging — All individuals with confirmed ALD/AMN complex should undergo neuroimaging with brain magnetic resonance imaging (MRI) at the time of diagnosis. In symptomatic males with cerebral forms of ALD, MRI is always abnormal, demonstrating demyelination in cerebral white matter. By contrast, brain MRI is often normal in patients with AMN. Presymptomatic boys with childhood ALD who initially have normal MRI should undergo follow-up imaging every 6 to 12 months. 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 'Hematopoietic cell transplantation' below.)

MRI abnormalities can range from mild to severe. Lesions are usually bilateral, though unilateral involvement can be seen [61]. The occipitoparietal region is typically affected (image 1) and the frontal lobe is involved up to 15 percent of cases [62,63]. Contrast enhancement on T1-weighted MRIs strongly correlates with likelihood of disease progression [64].

Proton MR spectroscopy detects white matter abnormalities that may not be apparent on conventional MR imaging and may predict disease progression [65,66]. In one report, this technique was evaluated in 25 individuals with X-linked ALD, ages 2 to 43 years [66]. MRI and proton MR spectroscopy were performed at baseline, and follow-up MRI was performed at an average of 3.5 years. 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 AMN, axonal changes may be seen on brain magnetic resonance spectroscopy [67] and diffusion tensor based imaging [68]. Magnetization transfer MRI may be effective in determining the extent of spinal cord involvement in AMN [69]. Functional MRI and proton MR spectroscopy may reveal prominent changes in the brain not apparent on conventional cranial MRI [70]. Using quantitative MRI-derived measures, it is possible to identify and quantify structural changes in the upper spinal cord and brain which correspond to the known pathology in AMN [71].

Studies of magnetic resonance perfusion imaging suggest that changes in local brain perfusion might be one of the earliest signs of lesion development [72]. 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 MR imaging, relative cerebral blood volume in brain white matter may help predict clinical outcomes following hematopoietic stem cell transplantation [73,74].

Electrophysiology testing — Additional testing may include the following:

Visual evoked responses can be monitored serially to assess disease progression in asymptomatic males without radiologic abnormalities [75]

Auditory-evoked potentials can help detect hearing loss

Somatosensory-evoked potentials are used for evaluation of myelopathy in adults with AMN

Electromyography and nerve conduction studies can be helpful for diagnosis of polyneuropathy (see "Overview of polyneuropathy", section on 'Diagnostic evaluation')

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

Childhood cerebral ALD – The early signs and symptoms of childhood ALD (eg, poor school performance, behavior 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 magnetic resonance imaging (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: Clinical features" and "Specific learning disabilities 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). The clinical course and family history can help distinguish ALD from these disorders, though ultimately very long-chain fatty acids (VLCFA) levels and genetic testing are required to make 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".)

Adrenomyeloneuropathy (AMN) – 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 AMN 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, 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). (See "Causes of primary adrenal insufficiency (Addison's disease)" and "Causes of primary adrenal insufficiency in children".)

TREATMENT — Treatment options are targeted to specific phenotypes (table 1) [76]. Hematopoietic cell transplantation (HCT) is the treatment of choice for boys with early stages of cerebral ALD. Adrenal insufficiency, if present, is treated with corticosteroid replacement. Treatment of patients with advanced cerebral ALD and those with pure adrenomyeloneuropathy (AMN) is supportive. Other interventions such as dietary modifications (including Lorenzo's oil), statin medications, and other agents have not demonstrated clinical efficacy in limited observational studies and clinical trials. (See 'Ineffective and unproven therapies' below.)

Childhood cerebral adrenoleukodystrophy

Asymptomatic patients with normal MRI — For asymptomatic boys with ALD who have normal magnetic resonance imaging (MRI), management consists of close monitoring as described in the previous sections (see 'Neuroimaging' above and 'Adrenocorticotropic hormone stimulation' above). Most of these patients are detected through newborn screening or testing performed due to an affected family member.

Routine MRI surveillance allows for early detection of onset of cerebral involvement and may facilitate optimal early treatment with HCT. HCT should not be undertaken in boys without MRI evidence of cerebral involvement, because approximately one-half of this group will remain free of cerebral disease [76].

Early cerebral adrenoleukodystrophy — Early cerebral ALD includes patients with evidence of central nervous system involvement on MRI who are asymptomatic or have only mild symptoms (eg, behavior changes, cognitive deficits, vision or hearing impairment). Allogenic HCT is the preferred treatment for early childhood cerebral ALD. Hematopoietic stem cell gene therapy may be an option for patients who do not have a suitable donor. (See 'Hematopoietic cell transplantation' below and 'Gene therapy' below.)

In addition to HCT, some children may benefit from symptomatic treatments directed at their specific symptoms (eg, psychotropic medications for behavioral difficulties or psychiatric symptoms).

Other interventions such as dietary modifications (including Lorenzo's oil), statin medications, and other agents have not demonstrated clinical efficacy in limited observational studies and clinical trials. (See 'Ineffective and unproven therapies' below.)

Hematopoietic cell transplantation — Allogenic HCT has emerged as the treatment of choice for individuals with early stages of cerebral involvement in ALD [76-78]. Stem cells can be harvested from a variety of hematologic sources, including peripheral blood, bone marrow, and umbilical cord blood. (See "Sources of hematopoietic stem cells" and "Donor selection for hematopoietic cell transplantation".)

The most appropriate candidates for HCT are boys with evidence of central nervous system involvement on MRI who are early in their disease course (ie, mild or no signs and symptoms) [30].

HCT does not appear to affect the course of adrenal dysfunction in patients with ALD, so patients require ongoing monitoring for adrenal dysfunction, and treatment, if necessary [79]. (See 'Adrenal insufficiency' below.)

The efficacy of HCT in childhood cerebral ALD is supported by several observational studies [80-83]. In the largest study, which reported the outcomes in 94 boys with cerebral ALD who underwent HCT between 1982 and 1999, the overall estimated five-year survival was 56 percent [81]. The leading causes of death were progression of cerebral ALD in 21 patients and graft-versus host disease in 5 patients. Five-year survival was 92 percent among the subgroup of patients in which transplant was performed in the early stage of the illness (n = 25; defined as having no or only one neurologic deficit [not including cognitive or behavioral symptoms], and mild abnormalities on brain MRI [MRI severity score <9 on a 34-point scale]).

A subsequent retrospective report compared outcomes in 30 nontransplanted patients with early-stage cerebral ALD who were matched by neurologic disability and MRI severity scores with 19 transplanted early-stage cerebral ALD patients [82]. Five-year survival was considerably higher in the transplanted patients compared with the nontransplanted group (95 versus 54 percent, respectively).

In another single institution report of 60 boys with cerebral ALD who underwent HCT between 2000 and 2009, the overall estimated five-year survival was 75 percent [83]. Survival was lower among subjects with more severe neuroradiographic findings and clinical evidence of neurologic dysfunction (60 and 66 percent, respectively) compared with those without symptoms and with mild radiographic findings (91 and 89 percent, respectively). Post-transplantation progression of neurologic dysfunction also depended on the severity of MRI findings and symptoms prior to treatment. The cumulative incidence of HCT-related mortality at day 100 was 8 percent in this study.

The use of HCT in adult patients is discussed below. (See 'Adrenomyeloneuropathy' below.)

Gene therapy — Gene therapy may be an option for patients with cerebral ALD who do not have a matched related donor for HCT [84,85]. In a single-arm open-label study, 17 boys with early stage cerebral ALD were enrolled to undergo transplantation with autologous CD34+ cells transfected with Lenti-D (a lentiviral vector containing manufactured ABCD1 complementary DNA) [85]. Of the 17 boys enrolled in the study, 15 (88 percent) survived to 24 months post-transplantation with no major functional disabilities. Two patients died: one from disease progression that began during pre-transplantation conditioning, and one was withdrawn from the study and died from complications of subsequent allogeneic HCT. In the 15 surviving patients, none had evidence of graft failure or graft-versus-host disease.

These results suggest that transplantation with autologous hematopoietic stem cells transfected with Lenti-D (elivaldogene autotemcel; eli-cel) may have comparable efficacy for treatment of early cerebral ALD compared with conventional allogeneic HCT and it may be safer. However, given the relatively short follow-up of these patients, these results should be regarded as preliminary. A subsequent clinical trial (NCT03852498 [86]) was placed on hold by the FDA in August 2021 after a patient developed myelodysplastic syndrome [87], and important uncertainties remain. Data on long-term stability of the transduced cells are not yet available. The risk for genotoxic effects with lentiviral vectors is not fully characterized, though it appears to be low. Importantly, this treatment has not yet received regulatory approval.

Similar to allogeneic transplantation, hematopoietic stem-cell gene therapy is not expected to have an effect on the phenotypes of AMN or adrenal insufficiency.

Studies with adeno-associated virus-mediated gene correction have shown biochemical correction in animal models of the disease [88]. No studies have been conducted in humans.

Advanced cerebral adrenoleukodystrophy — Management of patients with advanced cerebral involvement is primarily supportive. HCT should not be undertaken in patients with advanced disease, since the available evidence suggests that HCT does not improve clinical outcomes in these individuals. (See 'Hematopoietic cell transplantation' above.)

Management often requires a team of providers from different specialties, including neurology, genetics, physiatry, endocrinology, speech therapy, ophthalmology, and audiology. The prognosis for patients with advanced cerebral ALD is generally poor and involvement of a palliative care team is usually appropriate. (See 'Prognosis' below and "Pediatric palliative care".)

Patients with advanced cerebral ALD experience problems similar to those in other neurodegenerative disorders and management principles are similar. These issues are discussed in greater detail in separate topic reviews. They include:

Learning disabilities (see "Specific learning disabilities in children: Educational management")

Aggressive behavior (see "Management of neuropsychiatric symptoms of dementia")

Vision problems (see "Vision screening and assessment in infants and children")

Feeding difficulties (dysphagia, vomiting, aspiration) (see "Aspiration due to swallowing dysfunction in children")

Poor coordination and ataxia (see "Overview of cerebellar ataxia in adults", section on 'Chronic progressive ataxias' and "Overview of the hereditary ataxias")

Seizures (see "Seizures and epilepsy in children: Initial treatment and monitoring")

In addition, most patients with advanced disease have adrenal insufficiency and require replacement therapy. (See 'Adrenal insufficiency' below.)

Adrenomyeloneuropathy — Treatment options for adults with AMN are primarily symptomatic [89]. AMN without cerebral involvement does not appear to benefit from HCT. Other interventions such as dietary modifications (including Lorenzo's oil), statin medications, and other pharmacologic agents have not demonstrated clinical efficacy in patients with AMN. (See 'Ineffective and unproven therapies' below.)

Pure AMN – Treatment of patients with pure AMN is supportive and is similar to other types of myelopathy. Interventions are aimed at preventing and treating complications of spinal cord disease (eg, spasticity, bladder dysfunction, sexual dysfunction, pressure ulcers). (See "Chronic complications of spinal cord injury and disease".)

Treatment of polyneuropathy is similar as with other causes and is discussed separately. (See "Overview of polyneuropathy", section on 'Management'.)

AMN without cerebral involvement does not appear to benefit from HCT. HCT does not slow progression of AMN and may exacerbate myelopathy symptoms. In a series of 14 adult males with cerebral AMN who underwent HCT, 86 percent experienced motor disability exacerbations during the first six months following HCT [90]. Most patients also experienced new or aggravated bladder dysfunction during the transplant period. In another report of five boys who underwent HCT in childhood for cerebral ALD, three developed symptoms of AMN in adulthood [91]. Ex vivo gene therapy (which is also based on hematopoietic stem cells) is also unlikely to benefit AMN.

AMN with cerebral involvement – Based on extremely limited data, HCT may be an option for some adult patients with AMN who have mild cerebral involvement. As is the case with childhood ALD, adult patients with advanced neurologic disease are generally not considered candidates for HCT.

Support for the use of HCT in adults with cerebral AMN comes largely from indirect evidence demonstrating benefits of HCT in boys with early cerebral ALD (see 'Hematopoietic cell transplantation' above). Data on HCT in adults with cerebral AMN are limited. In a retrospective study of 14 adult males with cerebral AMN who were treated with HCT in four European centers, median age at detection of cerebral disease was 33 years; five patients had established severe motor disability prior to HCT [90]. Overall survival was 57 percent at a median follow-up of 65 months. Severe motor dysfunction prior to HCT and/or bilateral involvement of the internal capsule on brain MRI were associated with poor survival (20 percent). Death was directly transplant-related in three patients; due to primary disease progression in advanced ALD in one patient; and due to secondary disease progression in the setting of multiorgan failure or non-engraftment in two patients. All eight survivors demonstrated radiographic arrest of cerebral demyelination and none developed severe neurocognitive decline; however, most (five of eight) had deterioration of motor function.

Further studies are needed to clarify the role of HCT in adults with cerebral AMN.

Adrenal insufficiency — Corticosteroid replacement therapy is essential for patients with adrenal insufficiency. However, it has no effect on neurologic abnormalities in ALD. Adrenal function should be evaluated yearly in affected males without adrenal insufficiency. (See 'Adrenocorticotropic hormone stimulation' above and "Clinical manifestations and diagnosis of adrenal insufficiency in children".)

Corticosteroid replacement therapy is summarized in the table (table 6). Additional details of the treatment of adrenal insufficiency, including hormone replacement therapy, treatment during stress conditions, and management of adrenal crisis, are provided in a separate topic review. (See "Treatment of adrenal insufficiency in children".)

Ineffective and unproven therapies

Dietary modifications and Lorenzo's oil — Based on the limited available evidence, dietary interventions (including Lorenzo's oil) do not appear to be effective in preventing or slowing disease progression in ALD/AMN. Until new data become available, we suggest not routinely using these interventions. In the United States, expanded access to Lorenzo's oil ended in May of 2017 and Lorenzo's oil is no longer available.

Despite the lack of proven efficacy, some families and caregivers may be highly motivated to try Lorenzo's oil and some providers in areas outside of the United States may offer Lorenzo's oil to presymptomatic boys with ALD. If Lorenzo's oil is used, platelet counts and liver function tests should be monitored regularly. In addition, as previously discussed, patients should be closely monitored for onset of cerebral involvement since HCT is the preferred treatment for early cerebral ALD. (See 'Neuroimaging' above and 'Hematopoietic cell transplantation' above.)

Lorenzo's oil – Lorenzo's oil is a mixture of glycerol trioleate and glycerol trierucate that reduces the synthesis of very long-chain fatty acid (VLCFA) by competitive inhibition of the enzyme responsible for elongation of saturated fatty acids [92]. There was initial enthusiasm due to the ability of Lorenzo's oil to impact biochemistry. However, subsequent small clinical trials found that these biochemical improvements did not result in clinical improvement or slowing of disease progression in treated patients [93-95].

In two studies, administration of Lorenzo's oil to individuals with AMN normalized plasma concentration of VLCFA but did not stop disease progression in those with neurologic abnormalities [93,94]. Lorenzo's oil has also not had an impact on preexisting endocrine dysfunction of the adrenal cortex and testis [92].

In a single-arm open-label study of 89 asymptomatic boys (mean age 4.8 years at study entry) with ALD treated with Lorenzo's oil and moderate fat restriction and followed for a mean of 6.9 years, 24 percent developed MRI abnormalities and 11 percent developed clinically apparent neurologic abnormalities consistent with childhood cerebral ALD [95]. The lack of concurrent controls limits the ability to draw conclusions regarding the efficacy of treatment, though this rate of development of neurologic involvement appeared less than in historical controls [96]. Another limitation of the study is the relatively large number of participants who were either lost to follow-up (13 percent) or censored because they underwent HCT (16 percent). In a separate report of this cohort, Lorenzo's oil did not appear to have an effect on measures of oxidative stress and peroxidation [97].

Adverse effects of Lorenzo's oil reported in these studies included thrombocytopenia, elevated liver enzymes, gastrointestinal complaints, and gingivitis [93,94].

A placebo-controlled trial of Lorenzo's oil in AMN, was stopped early due to adverse effects and results of the trial are not available [98].

Restricting intake of fatty foods – Restriction of dietary VLCFA can be accomplished by reducing the intake of fatty foods. However, this approach will not decrease the VLCFA concentration, because endogenous synthesis continues [31].

Statins and other agents — Pharmacologic agents that have been proposed as potential therapeutic agents for ALD/AMN include statins and sodium phenyl acetate. We suggest not using these agents for treatment of ALD/AMN.

In a small observational study, lovastatin reduced plasma VLCFA levels in 12 affected individuals [99]. However, in a subsequent prospective randomized trial in 14 patients, the decrease in plasma VLCFA levels was small and transient, suggesting it is probably a nonspecific result of a concurrent decrease in plasma low-density lipid (LDL) cholesterol [100]. Lovastatin did not reduce VLCFA levels in peripheral blood lymphocytes. The investigators concluded that the available data do not support use of lovastatin as a therapy to lower VLCFA levels in patients with ALD/AMN and that additional clinical trials with clinical end points are unwarranted.

Animal and ex vivo studies have suggested a potential therapeutic role for phenyl acetate (and its prodrug phenylbutyrate) [101-103]. The mechanism involves upregulation of ABCD2 (ALD-related gene), thereby generating more ALD-related protein. There are no available clinical data on these agents in patients with ALD/AMN.

PROGNOSIS — ALD/AMN is a progressive disorder. The prognosis depends on the phenotype [21]:

Childhood cerebral ALD – The rate of disease progression in childhood cerebral ALD is variable and appears related to the degree of brain inflammation and contrast enhancement on brain magnetic resonance imaging (MRI) [64]. Without treatment, rapid progression is common, with total disability in six months to two years, and death within 5 to 10 years of diagnosis. For boys who undergo successful hematopoietic cell transplant (HCT) at an early stage of disease, five-year survival >90 percent [81]. However, HCT is not curative and myelopathy symptoms may develop in adulthood [91].

Adrenomyeloneuropathy (AMN) – Progression of myelopathy occurs over years to decades. Most male patients lose the ability to ambulate unassisted by age 50 [21]. Neurogenic bladder is also nearly universal by this age. As previously discussed, there are no available disease-modifying therapies to slow or prevent progression of AMN. Up to 60 percent of patients with AMN develop cerebral involvement and have a more rapidly progressive illness [41]. Cerebral involvement is typically associated with serious cognitive and behavioral disturbances progressing to total disability and early death [40].

Adrenal insufficiency only – Most patients who present with the isolated adrenal insufficiency phenotype develop progressive myelopathy by middle age.

Female carriers – Almost 90 percent in female carriers develop myelopathy symptoms by age 60 [48]. Progression is slower than in men. Adrenal insufficiency and cerebral involvement are very rare.

SUMMARY AND RECOMMENDATIONS

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 phenotypes (including adrenomyeloneuropathy [AMN]) that vary in the age and severity of clinical presentation (table 1). Together, these conditions are known as the ALD/AMN complex. (See 'Introduction' above and 'Genetics' above and 'Pathogenesis' above.)

Affected males have one of three main phenotypes and can present from childhood through adulthood (table 1):

Childhood cerebral ALD – 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 magnetic resonance imaging (MRI); a minority of these patients undergo stepwise progression or conversion to progressive childhood cerebral ALD. (See 'Childhood cerebral forms' above.)

AMN – AMN 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. AMN may also present as a progressive cerebellar disorder. (See 'Adrenomyeloneuropathy' 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 the majority of affected patients, adrenal insufficiency presents before age of 10 years, but it can present later. Most patients with isolated adrenal insufficiency go on to develop AMN by mid-adulthood. (See 'Adrenal insufficiency' above.)

Female carriers often develop myelopathy 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 X-linked ALD/AMN is available in some states in the United States. If the newborn screen is positive, follow-up confirmation testing should be completed as soon as possible. (See 'Newborn screening' above.)

Laboratory testing for ALD begins with measuring VLCFA levels. The plasma concentration of VLCFAs is elevated in nearly all males with the ALD/AMN complex. 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.)

All individuals with confirmed ALD/AMN complex should undergo neuroimaging with brain magnetic resonance imaging (MRI) at the time of diagnosis. In symptomatic males with forms of ALD other than pure AMN, MRI is always abnormal, demonstrating demyelination in cerebral white matter. By contrast, brain MRI is often normal in patients with pure AMN. Presymptomatic boys with childhood ALD who initially have normal MRI should undergo follow-up imaging every 6 to 12 months. (See 'Neuroimaging' above.)

Treatment options for ALD/AMN are targeted to specific phenotypes (table 1):

Childhood cerebral ALD (see 'Childhood cerebral adrenoleukodystrophy' above):

-For most boys with childhood cerebral ALD who are early in their disease course, we suggest allogenic hematopoietic cell transplantation (HCT) rather than supportive care alone (Grade 2C). HCT should not be undertaken in patients with advanced neurologic disease as it does not appear to improve clinical outcomes in this setting. Similarly, HCT should not be undertaken in presymptomatic boys who lack MRI evidence of cerebral involvement. (See 'Hematopoietic cell transplantation' above.)

-HCT does not appear to affect the course of adrenal dysfunction in patients with ALD, so patients require ongoing monitoring for adrenal dysfunction, and treatment, if necessary. (See 'Adrenal insufficiency' above and "Treatment of adrenal insufficiency in children".)

AMN (see 'Adrenomyeloneuropathy' above):

-Cerebral AMN – HCT may be an option for some adult patients with AMN who have mild cerebral involvement. The available data on HCT in this setting are extremely limited. As is the case with childhood ALD, adult patients with advanced neurologic disease are generally not considered candidates for HCT.

-Pure AMN – AMN without cerebral involvement does not appear to benefit from HCT. Treatment of these patients is supportive and is similar to other types of myelopathy. Interventions are aimed at preventing and treating complications of spinal cord disease (eg, spasticity, bladder dysfunction, sexual dysfunction, pressure ulcers). (See "Chronic complications of spinal cord injury and disease".)

Adrenal insufficiency – Individuals with adrenal insufficiency, with or without other manifestations of ALD or AMN, require lifelong corticosteroid replacement therapy. (See "Treatment of adrenal insufficiency in children" and "Treatment of adrenal insufficiency in adults".)

For all patients with ALD/AMN complex, we suggest not routinely using dietary modifications (including Lorenzo's oil) or statin medications to lower VLCFA levels (Grade 2C). These interventions have not demonstrated clinical efficacy in limited observational studies and clinical trials. (See 'Ineffective and unproven therapies' above.)

ALD is a progressive disorder. The prognosis depends on the phenotype. (See 'Prognosis' above.)

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Topic 6200 Version 37.0

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