Version May 2024
INTRODUCTION — X-linked adrenoleukodystrophy (ALD) 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 may develop adrenal failure, leukodystrophy, and/or myeloneuropathy (spinal cord disease and peripheral neuropathy). Disease manifestations and disease severity are highly variable among patients.
The treatment and prognosis of ALD will be reviewed here. Other aspects of ALD are reviewed separately. (See "Clinical features, evaluation, and diagnosis of X-linked adrenoleukodystrophy".)
SURVEILLANCE — Patients diagnosed with ALD should be monitored for disease manifestations (leukodystrophy, myeloneuropathy, adrenal insufficiency), as detailed in the sections that follow (figure 1).
MRI surveillance for leukodystrophy — All neurologically asymptomatic males with confirmed ALD should undergo surveillance neuroimaging with brain magnetic resonance imaging (MRI); over half of males will eventually develop a progressive leukodystrophy, the clinical effects of which may be mitigated by early treatment. (See "Clinical features, evaluation, and diagnosis of X-linked adrenoleukodystrophy", section on 'Leukodystrophy'.)
Routine surveillance in females is not recommended as leukodystrophy is rare in females [1]. (See "Clinical features, evaluation, and diagnosis of X-linked adrenoleukodystrophy", section on 'Females with ALD'.)
Based on the age distribution of developing an active, inflammatory brain lesion, 2022 consensus guidelines recommend the following brain MRI surveillance [1]:
●Age 2 years: Baseline MRI without contrast (earlier brain MRI can be difficult to interpret due to incomplete myelination)
●Age 2 to 12 years: MRI with contrast every six months
●Age 12+ years: MRI annually, with contrast if lesion detected
Patients with lesions detected at any time by MRI should be referred urgently to a specialist or center with expertise in ALD [2]. (See 'Early leukodystrophy' below.)
Surveillance for myeloneuropathy — The history and neurologic examination are the primary methods used to detect myeloneuropathy and polyneuropathy (myeloneuropathy). This can be done in conjunction with clinic visits or other testing (figure 1). Attention to the symptoms and signs of myeloneuropathy (eg, leg weakness, spasticity, gait ataxia, and sphincter dysfunction) is particularly important for patients who are 18 years of age and older, as onset is generally during adulthood for males and females. Virtually all males and most affected females develop myeloneuropathy. (See "Clinical features, evaluation, and diagnosis of X-linked adrenoleukodystrophy", section on 'Myeloneuropathy'.)
Surveillance for adrenal insufficiency — Male patients should be evaluated for adrenal function by measurement of plasma adrenocorticotropic hormone (ACTH) level and the rise in plasma cortisol level following ACTH stimulation. In addition, patients should also be evaluated for mineralocorticoid deficiency with plasma renin and serum electrolytes [1].
If initial adrenal testing is normal, follow-up testing should be performed every three to six months in males from six months to 10 years of age, and then yearly thereafter (figure 1). (See "Diagnosis of adrenal insufficiency in adults" and "Clinical manifestations and diagnosis of adrenal insufficiency in children", section on 'Adrenocorticotropic hormone stimulation test'.)
Monitoring males for adrenal insufficiency is recommended over the course of the lifetime. However, early-life monitoring is more challenging due to the unpredictable secretory patterns and poor reference ranges for ACTH and cortisol in the first two years of life [3,4].
Testing is or will become abnormal in 90 percent of boys with neurologic signs and in 80 percent of men with myeloneuropathy [5,6]. ACTH levels are often increased already during the first year of life [7].
Females usually have normal adrenal function, and surveillance is not necessary.
TREATMENT
Asymptomatic with normal MRI — For asymptomatic boys with ALD who have normal MRI of the brain, management consists of close monitoring with brain MRI surveillance (see 'MRI surveillance for leukodystrophy' above) and adrenal testing (see 'Surveillance for adrenal insufficiency' above), as described in the previous sections (figure 1).
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 hematopoietic cell transplantation (HCT) [2,8]. 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 [9].
Leukodystrophy
Early leukodystrophy — Early leukodystrophy includes patients with evidence of central nervous system involvement on MRI who are either asymptomatic or have only mild symptoms (eg, behavior changes, cognitive deficits, vision, or hearing impairment).
Approach to treatment
●Allogeneic HCT is the preferred treatment for patients with early leukodystrophy who have a matched donor (figure 1). (See 'Allogeneic HCT' below.)
●HCT using autologous hematopoietic stem cells transfected with Lenti-D (elivaldogene autotemcel) may be an option (where available) for patients who do not have a suitable donor. (See 'Autologous HCT with ex vivo gene therapy' below.)
However, there are no randomized controlled trials of HCT for ALD, and evidence obtained using historical control groups may be questionable given that patients are now being detected at an earlier stage via screening protocols. In addition, the long-term safety of gene therapy is unknown.
In all cases, the risks of engraftment problems and graft-versus-host disease (GVHD) associated with allogeneic HCT will need to be weighed against risks of myelodysplastic syndrome (MDS) associated with autologous HCT using ex vivo gene therapy. (See 'Allogeneic HCT' below and 'Autologous HCT with ex vivo gene therapy' below.)
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.)
Allogeneic HCT
●Use – Allogeneic HCT has emerged as the treatment of choice for individuals with early stages of cerebral involvement in ALD who have an appropriate matched related donor [9-11]. Stem cells can be harvested from a variety of hematologic sources, including peripheral blood, bone marrow, and umbilical cord blood. (See "Hematopoietic cell transplantation (HCT): Sources of hematopoietic stem/progenitor cells" and "Donor selection for hematopoietic cell transplantation".)
The most appropriate candidates for HCT are boys with evidence of cerebral involvement on MRI who are early in their disease course (ie, mild or no signs and symptoms) [5]. However, the optimal timing for HCT is uncertain. For example, HCT is generally offered to asymptomatic patients with any evidence of active disease on MRI, even if MRI findings are quite subtle. Nevertheless, it is not known whether some of these subtle findings might spontaneously arrest without treatment [12,13].
The role of HCT in patients with myeloneuropathy is discussed below. (See 'Myeloneuropathy' below.)
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 [14]. (See 'Adrenal insufficiency' below.)
●Efficacy – The efficacy of HCT in the leukodystrophy of ALD is supported by several observational studies [15-18]. A retrospective report published in 2007 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 [17]. Five-year survival was considerably higher in the transplanted patients compared with the nontransplanted group (95 versus 54 percent, respectively).
Other uncontrolled reports have found that HCT performed in the early stages of leukodystrophy for patients with mild disease is associated with higher survival rates compared with HCT performed in later stages for patients with more severe disease [16,18]. In a study of 94 boys with cerebral ALD who underwent HCT between 1982 and 1999, the overall estimated five-year survival was 56 percent [16]. Five-year survival was 92 percent among the subgroup of patients (n = 25) in which transplant was performed in the early stage of the illness, defined as having no or only one neurologic deficit (not including cognitive or behavioral symptoms) and mild abnormalities on brain MRI with a score ≤9 on a 34-point MRI severity scale (Loes scoring method), where 0 is normal and 34 is severely abnormal [19]. Although some studies suggest that neurologic outcome is good in those transplanted with a Loes score ≤9 [18,20], other studies have found severe, persistent cognitive deficits in those transplanted with a Loes score of 4.5 to 9 [21]. Therefore, a Loes score of 4.5 or lower may be preferable for selecting patients for HCT. The leading causes of death were progression of cerebral ALD in 21 patients and GVHD in 5 patients.
●Adverse effects – In addition to GVHD, HCT is associated with numerous short- and long-term complications that can affect many organ systems. (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease" and "Early complications of hematopoietic cell transplantation" and "Survival, quality of life, and late complications after hematopoietic cell transplantation in adults".)
Autologous HCT with ex vivo gene therapy
●Use – Autologous HCT using genetically modified cells may be an option for patients with early cerebral ALD, particularly those who do not have a matched related donor for allogeneic HCT [22-24]. This treatment is offered at a few specialized centers in the United States. Like allogenic HCT, autologous HCT using gene therapy is not expected to benefit myeloneuropathy or adrenal insufficiency.
Gene therapy with autologous hematopoietic stem cells transfected with Lenti-D (elivaldogene autotemcel, eli-cel, a lentiviral vector containing manufactured ABCD1 complementary deoxyribonucleic acid [DNA]) was granted accelerated approval by the US Food and Drug Administration (FDA) in September 2022 for the treatment of boys ages 4 to 17 years with early active cerebral ALD [25]. While the FDA approval is not restricted to children who lack a human leukocyte antigen (HLA)-matched donor, the studies that led to the approval mostly enrolled patients without an HLA-matched donor.
●Efficacy – As reviewed below, autologous HCT with elivaldogene autotemcel may have comparable efficacy for treatment of early cerebral ALD compared with conventional allogeneic HCT and may be safer, particularly when compared with HLA-mismatched allogeneic HCT. However, given the relatively short follow-up of these patients, these results should be regarded as preliminary.
The efficacy of autologous HCT with elivaldogene autotemcel was reported in a single-arm open-label study involving 17 boys with early-stage cerebral ALD who did not have an HLA-matched donor [23]. At 24 months post-transplantation, 88 percent of patients were alive with no major functional disabilities. Two patients died: one from disease progression that began during pretransplantation conditioning, and one who was withdrawn from the study and died from complications of subsequent allogeneic HCT. In the 15 surviving patients, none had evidence of GVHD.
The FDA approval was based on additional data from two uncontrolled prospective studies, the results of which are available only from the FDA label [24]; full details of these studies have not been published. They were both open-label single-arm studies involving a total of 67 children with early cerebral ALD (ie, mild abnormalities on MRI with or without clinical symptoms). At the time of FDA approval, there were only 11 patients who had complete follow-up data and had symptomatic disease. In a post hoc analysis limited to these 11 patients, disease progression appeared to be slower compared with a historical control group consisting of seven untreated patients [24]. At 24 months, 72 percent (95% CI 35-90 percent) of treated patients were alive without major functional disability compared with 43 percent (95% CI 10-73 percent) of patients in the historical untreated control group. Given the small number of patients included in the analysis, it is unclear whether this finding is statistically significant. In addition, the control group was older (median 9 versus 6 years) and had greater MRI involvement (median MRI severity score 5 versus 2.5) at baseline, which may explain, at least in part, any potential difference in disease progression.
A separate analysis available only in the FDA label reported the outcomes in patients treated with autologous HCT with elivaldogene autotemcel (n = 61) compared with historical controls who were treated with HLA-matched allogeneic HCT (n = 34) or HLA-mismatched allogeneic HCT (n = 17) [24]. Based on Kaplan-Meier curves, survival during the first nine months following treatment appeared to be better in patients treated with HLA-matched allogeneic HCT or autologous HCT using elivaldogene autotemcel compared with HLA-mismatched allogeneic HCT. However, the exact numbers are not provided, and it is unclear whether this finding was statistically significant. No patient treated with elivaldogene autotemcel developed acute or chronic GVHD during the first 24 months after treatment. A long-term follow-up study is ongoing.
●Adverse effects and complications – The FDA label for elivaldogene autotemcel carries a boxed warning about the risk of hematologic malignancy and life-threatening MDS [24,26]. 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.
HCT itself is associated with numerous short- and long-term complications that can affect many organ systems. (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease" and "Early complications of hematopoietic cell transplantation" and "Survival, quality of life, and late complications after hematopoietic cell transplantation in adults".)
Advanced leukodystrophy — Management of patients with advanced cerebral involvement is primarily supportive. HCT should not be undertaken in patients with advanced disease, since the limited available evidence suggests that HCT does not improve clinical outcomes in these individuals. (See 'Allogeneic HCT' 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".)
Symptomatic management of leukodystrophy — Patients with symptomatic leukodystrophy experience problems like those in other neurodegenerative disorders, and management principles are similar. These issues are discussed in greater detail in separate UpToDate topic reviews. They include:
●Learning disabilities (see "Specific learning disorders 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.)
Myeloneuropathy
●Supportive care – Treatment of patients with myeloneuropathy is supportive (figure 1) and is similar to that of other types of myelopathy [27]. Interventions are aimed at preventing and treating complications of myeloneuropathy (eg, spasticity, bladder dysfunction, sexual dysfunction, pressure ulcers). (See "Chronic complications of spinal cord injury and disease".)
Treatment of ALD-related polyneuropathy is similar to other causes of polyneuropathy and is discussed separately. (See "Overview of polyneuropathy", section on 'Management'.)
Interventions such as dietary modifications (including Lorenzo's oil), statin medications, and other pharmacologic agents have not demonstrated clinical efficacy in patients with myeloneuropathy. (See 'Ineffective and unproven therapies' below.)
●No role for HCT in myeloneuropathy without leukodystrophy – Myeloneuropathy without cerebral involvement does not appear to benefit from HCT [28].
Limited data suggest that HCT does not slow progression of myeloneuropathy in ALD [28] and may exacerbate myelopathy symptoms. In a series of 14 adult males with cerebral myeloneuropathy who underwent HCT, 86 percent experienced motor disability exacerbations during the first six months following HCT [29]. 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 myeloneuropathy in adulthood [28]. Autologous HCT with ex vivo gene therapy is also unlikely to benefit myeloneuropathy.
●Uncertain role for HCT in myeloneuropathy and leukodystrophy – Based on limited data, HCT may be an option for some adult patients with myeloneuropathy who develop leukodystrophy and are identified in an early stage. 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 leukodystrophy comes largely from indirect evidence demonstrating benefits of HCT in boys with early cerebral ALD. (See 'Allogeneic HCT' above.)
Data on HCT in adults with leukodystrophy are limited. In a retrospective study of 14 adult males with leukodystrophy 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 [29]. At a median follow-up of 65 months, overall survival was 57 percent. 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 myeloneuropathy.
●Investigational agents – Leriglitazone was evaluated in a randomized controlled trial of 116 ambulatory adult males with myeloneuropathy but no evidence of progressive leukodystrophy on MRI [30]. There was no benefit of leriglitazone compared with placebo on the primary outcome measure (six-minute walk test at week 96), although there was an effect on some secondary outcome measures (reduced body sway). Of note, leukodystrophy occurred in none of the treatment group compared with 5 percent in the placebo group. The possible preventive effect on the occurrence of leukodystrophy will be studied in an upcoming trial.
Adrenal insufficiency — Glucocorticoid replacement therapy (and in approximately 15 percent of cases also mineralocorticoid replacement) is essential for patients with adrenal insufficiency. However, it has no effect on neurologic abnormalities in ALD.
Additional details on 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" and "Treatment of adrenal insufficiency in adults".)
Individuals with ALD and adrenal insufficiency should also have ongoing monitoring for mineralocorticoid deficiency, which may appear years or decades later. (See "Treatment of adrenal insufficiency in children", section on 'Mineralocorticoids' and "Treatment of adrenal insufficiency in adults", section on 'Mineralocorticoid replacement for selected individuals'.)
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. 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 hematopoietic cell transplantation (HCT) is the preferred treatment for early cerebral ALD. (See "Clinical features, evaluation, and diagnosis of X-linked adrenoleukodystrophy", section on 'Neuroimaging' and 'Allogeneic HCT' 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 acids (VLCFAs) by competitive inhibition of the enzyme responsible for elongation of saturated fatty acids [31]. 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 [32-34].
In two studies, administration of Lorenzo's oil to individuals with myeloneuropathy normalized plasma concentration of VLCFAs but did not stop disease progression in those with neurologic abnormalities [32,33]. Lorenzo's oil has also not had an impact on pre-existing endocrine dysfunction of the adrenal cortex and testis [31].
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 [34]. 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 [35]. 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 [36].
Adverse effects of Lorenzo's oil reported in these studies included thrombocytopenia, elevated liver enzymes, gastrointestinal complaints, and gingivitis [32,33].
A placebo-controlled trial of Lorenzo's oil in myeloneuropathy was stopped early due to adverse effects, and results of the trial are not available [37].
●Restricting intake of fatty foods – Restriction of dietary VLCFAs can be accomplished by reducing the intake of fatty foods. However, this approach will not decrease the VLCFA concentration, because endogenous synthesis continues [38].
Statins and other agents — Pharmacologic agents that have been proposed as potential therapeutic agents for ALD include statins and sodium phenyl acetate. We suggest not using these agents for treatment of ALD.
In a small observational study, lovastatin reduced plasma VLCFA levels in 12 affected individuals [39]. 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 lipoprotein (LDL) cholesterol [40]. 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 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) [41-43]. 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.
PROGNOSIS — ALD is a progressive disorder. The prognosis is highly variable and depends on specific presentation [44]:
Leukodystrophy — The rate of disease progression in childhood leukodystrophy (cerebral ALD) is variable and appears to be related to the degree of brain inflammation and contrast enhancement on brain MRI [45]. In a report of 43 male patients with ALD, enhancement on initial T1-weighted MRI was present in 21 patients; at a mean follow-up of 14 months, disease progression demonstrated by MRI and neurologic scores was found in 18 (86 percent) [45]. For 22 patients with no enhancement on initial MRI, follow-up evaluations at a mean of 22 months demonstrated disease progression in only 4 of the 22 patients (18 percent).
Without treatment, rapid progression is most common, with total disability in six months to two years [46]. Spontaneous arrest of leukodystrophy, characterized by absence of symptom progression and lack of lesion growth or enhancement on brain MRI, occurs in a minority [12]. Patients with arrested ALD may remain stable for years but can eventually convert again to progressive ALD, so continued vigilance and monitoring is necessary. (See "Clinical features, evaluation, and diagnosis of X-linked adrenoleukodystrophy", section on 'Leukodystrophy'.)
For boys who undergo successful hematopoietic cell transplantation (HCT) at an early stage of disease, five-year survival is >90 percent [16]. However, HCT is not curative, and myelopathy symptoms may develop in adulthood [28]. (See 'Allogeneic HCT' above.)
Myeloneuropathy — Progression of myeloneuropathy occurs slowly over years to decades. Most male patients lose the ability to ambulate unassisted by age 50 years [44]. Neurogenic bladder is also nearly universal by this age. There are no available disease-modifying therapies to slow or prevent progression of myeloneuropathy.
Up to 60 percent of patients with myeloneuropathy eventually develop cerebral involvement and have a more rapidly progressive illness [47]. Cerebral involvement is typically associated with serious cognitive and behavioral disturbances progressing to total disability and early death [48].
Adrenal insufficiency only — Virtually all patients who present with isolated adrenal insufficiency develop progressive myelopathy by middle age.
Female patients — Almost 90 percent of female patients develop myelopathy symptoms by age 60 [49]. Progression is slower than in men [50]. Adrenal insufficiency and cerebral involvement are very rare.
SUMMARY AND RECOMMENDATIONS
●Surveillance – Patients diagnosed with X-linked adrenoleukodystrophy (ALD) should be monitored for disease manifestations (leukodystrophy, myeloneuropathy, adrenal insufficiency), as detailed above (figure 1). (See 'Surveillance' above.)
●Treatment – Treatment options for ALD are targeted to specific disease manifestations (table 1 and figure 1):
•Asymptomatic with normal brain MRI – For asymptomatic boys with ALD who have normal MRI of the brain, management consists of close monitoring, brain MRI surveillance, and adrenal testing (figure 1). (See 'Asymptomatic with normal MRI' above.)
•Leukodystrophy – The treatment of leukodystrophy varies by disease course (see 'Early leukodystrophy' above):
-For most boys with leukodystrophy who are early in their disease course and who have an appropriate matched donor, we suggest allogeneic hematopoietic cell transplantation (HCT) rather than supportive care alone (Grade 2C). HCT should not be undertaken in patients with advanced neurologic disease as it has not been shown to improve clinical outcomes in this setting. Similarly, HCT should not be undertaken in presymptomatic boys who lack MRI evidence of cerebral involvement. (See 'Allogeneic HCT' above.)
-For boys with early cerebral ALD who lack a matched human leukocyte antigen (HLA) donor, autologous HCT with ex vivo gene therapy (elivaldogene autotemcel, eli-cel) is an alternative treatment option that is offered at a few specialized centers in the United States. (See 'Autologous HCT with ex vivo gene therapy' above.)
-Adult patients with advanced neurologic disease are generally not considered candidates for HCT. (See 'Advanced leukodystrophy' above.)
•Myeloneuropathy – Benefit of HCT for myeloneuropathy in patients with ALD has not been demonstrated. Treatment of these patients is supportive and is similar to other types of myelopathy. Interventions are aimed at preventing and treating complications of myeloneuropathy (eg, spasticity, bladder dysfunction, sexual dysfunction, pressure ulcers). (See 'Myeloneuropathy' above and "Chronic complications of spinal cord injury and disease".)
•Adrenal insufficiency – For patients with adrenal insufficiency, with or without other manifestations of ALD, lifelong glucocorticoid replacement therapy is required. (See "Treatment of adrenal insufficiency in children" and "Treatment of adrenal insufficiency in adults".)
•Unproven therapies – For all patients with ALD, we suggest not routinely using dietary modifications (including Lorenzo's oil) or statin medications to lower very long-chain fatty acid (VLCFA) levels (Grade 2C). These interventions have not demonstrated clinical efficacy in limited observational studies and clinical trials. (See 'Ineffective and unproven therapies' above.)
●Prognosis – ALD is a progressive disorder. The prognosis depends on the disease manifestations. With symptomatic leukodystrophy, associated with growth and/or enhancement of lesions on brain MRI, rapid progression is common without treatment, leading to total disability over months to years and death within 10 years. Successful HCT for patients with early leukodystrophy is associated with prolonged survival. With myeloneuropathy, slower progression is typical, although many patients also develop leukodystrophy with more rapid progression to severe disability and death. (See 'Prognosis' above.)
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