Clinical manifestations

Presentation and course

The spectrum of clinical phenotypes in adrenoleukodystrophy ranges from being asymptomatic; having isolated primary adrenal insufficiency; childhood, adolescent, or adult cerebral adrenoleukodystrophy; and adult-onset myeloneuropathy in males. Female carriers can be asymptomatic but go on later to develop adult-onset myeloneuropathy.

Classically, the disease is thought of as three distinct clinical presentations: cerebral, myeloneuropathy, and isolated adrenal insufficiency. Patients with cerebral disease have clinical and radiological evidence of cerebral hemispheric involvement with onset and prognosis dependent on the age of presentation – childhood, adolescent, or adult. On the other hand, patients with myeloneuropathy have primary involvement of the spinal cord and peripheral nerves.

Cerebral adrenoleukodystrophy is the most rapidly progressive form, characterized by severe inflammatory demyelination. This form is generally seen in childhood between 3 and 18 years of age with 7 years as the mean age of onset (41). The first symptoms are frequently learning and behavioral problems with decline in school performance, but some can present with seizures (91). Patients are often misdiagnosed as being hyperactive with attention deficit disorders, causing delays in diagnosis. The disease onset may also be associated with a trigger, such as minor head trauma (07). With the progression of the disease, patients start to develop signs of dementia, impaired auditory discrimination and vision, ataxia, seizure, and signs of corticospinal tract involvement (73). Once inflammation is noted, the illness advances rapidly and leads to a vegetative state within 2 years and death at variable intervals thereafter.

Cerebral adrenoleukodystrophy though rare can also be seen in adolescents and adults. It occurs with similar characteristic findings as seen in the childhood cerebral form (C-ALD) but with slower progression and more prominent psychiatric disturbances (20). In patients with later onset, progressive neuroinflammation may not rapidly develop or even progress once inflammation has developed (15). Diagnosis of adrenoleukodystrophy may be delayed in these patients if there is no family history of adrenoleukodystrophy or symptoms of adrenal insufficiency.

Myeloneuropathy is the most common adult form. As its name implies, it affects mainly the spinal cord and peripheral nerves (22). Peripheral neuropathy can be the first symptom, but all patients eventually develop progressive spastic paraparesis, impaired vibration sense, pain in the legs, sensory ataxia, sexual dysfunction, and sphincter disturbances. The illness tends to progress slowly over decades, and some patients are now in their seventies. It is important to note that patients diagnosed with myeloneuropathy can develop cerebral disease (82). These findings underscore that the distinction between disease affecting the cerebral and spinal cord is not absolute.

Rarely, patients with the cerebral form can remain stable for years with spontaneous halt in the progression of demyelination, and these patients are classified as having arrested cerebral adrenoleukodystrophy. However, after years of stability, rapid neurologic progression can occur (15). Hence, close follow-up and monitoring for lesion progression is recommended.

Adrenal insufficiency is the most common initial presenting symptom in patients with adrenoleukodystrophy years before neurologic symptoms. Although primary adrenal insufficiency is commonly the first clinical manifestation, the diagnosis may be missed because of nonspecific clinical symptoms such as fatigue, anorexia, skin hyperpigmentation, weight loss, and gastrointestinal upsets (28). Dubey and colleagues found increased plasma ACTH levels in 69% and reduced ACTH stimulation test at baseline in 43% of asymptomatic boys with X-linked adrenoleukodystrophy, even though there was no clinical evidence of adrenal insufficiency with normal baseline cortisol levels (09). More than 90% of patients with C-ALD and 70% of patients with myeloneuropathy have Addison disease or impaired adrenal reserve (09). Therefore, it is important to consider X-linked adrenoleukodystrophy in all male patients with adrenal insufficiency. All these symptoms respond readily to hormone replacement therapy.

As adrenoleukodystrophy is a X-linked disease, female carriers were initially presumed to be asymptomatic. However, it is now known that more than 80% of female carriers may develop neurologic impairment by the age of 60 (14; 24). The frequency of symptomatic women increases sharply with age, from 18% in women less than 40 years of age to 88% in women over 60 years of age. The clinical manifestations resemble that of the myeloneuropathy phenotype seen in males who are affected but typically with later onset (mean 35 years) and with milder symptoms. Neuropathic pain can be observed in 90% of female carriers who are older than 60 years. In contrast, neuropathic pain is generally not seen in men with myeloneuropathy (27). Adrenal insufficiency and cerebral disease are found in less than 1% of female carriers (13; 24). According to 2022 consensus guidelines, all female patients with the ABCD1 pathogenic variant should be classified as “asymptomatic/presymptomatic” or “symptomatic women with adrenoleukodystrophy” and should not use heterozygous or carrier status while reporting (16).

With the onset of newborn screening, there is also a growing cohort of patients identified to be at risk for disease based on biochemical or genetic results but who are asymptomatic and need follow-up to assess for disease onset.

Prognosis and complications

The prognosis of adrenoleukodystrophy varies a great deal with the phenotype, and a clear phenotype-genotype correlation is lacking, with no clear biomarkers predicting prognosis.

In patients with childhood cerebral adrenoleukodystrophy, the rate of progression usually is rapid and often leads to an apparent vegetative state within 2 years after symptoms onset. However, duration of life depends on supportive care such as the treatment of spasticity, bed sores, and other supportive therapies. Though most patients have rapid progression of symptoms after the onset of demyelination, some can show a halt in demyelination. Additionally, adolescent and adults who develop the cerebral form tend to have a less rapid course than children who develop cerebral disease. Although hematopoietic stem cell transplantation can arrest the neurologic findings if done early with improvement in 5-year survival rates, hematopoietic stem cell transplantation does not prevent or treat adrenoleukodystrophy associated adrenal insufficiency or myelopathy (83).

Though the prognosis for patients with myeloneuropathy is more favorable, approximately 40% of the patients with myeloneuropathy can still develop some degree of cerebral involvement with rapid progression of symptoms (82). Spinal cord cross sectional areas have been associated with clinical outcomes allowing for a marker for follow-up in patients with myeloneuropathy (81). Of note, other complications seen in patients with myeloneuropathy are decubitus ulcers, bowel perforation secondary to constipation, or urinary infections – all of which also need to be considered.

Most patients with adrenal insufficiency progress to have symptoms concerning for myelopathy by their fourth decade. Most female carriers also develop symptoms of myelopathy by their sixth decade (14).

Biological basis

Genetics. Adrenoleukodystrophy is a X-linked genetic disorder due to mutations in the ABCD1 gene. The ABCD1 gene is mapped to Xq28 (49) and encodes the peroxisomal transmembrane protein, ALDP, which is important in transporting very long-chain fatty acids-CoA esters into the peroxisomes (88). ALDP deficiency causes VLCFA beta-oxidation damage and accumulation of very long-chain fatty acids-CoA esters in the cells. Currently, more than 800 variants in the ABCD1 gene have been described and 49% of these variants are missense mutations with decreased or loss of ABCD1 protein expression. A mutational database website is now available at Mutation database for X-linked adrenoleukodystrophy. Unfortunately, there is no currently known correlation between the nature of the mutation and the phenotype (60; 87).

Etiology and pathogenesis

ABCD1 mutations lead to ALDP deficiency causing very long-chain fatty acids beta-oxidation damage and accumulation of very long-chain fatty acids-CoA esters in cells (33). In patients with the cerebral form, the initiation of cerebral demyelination is postulated to be directly related to the very long chain fatty acids accumulation or a resultant inflammatory cascade that leads to axonopathy (02). Postmortem tissues have demonstrated the correlation between the anatomical location of inflammation with very long-chain fatty acids levels along with the expression of the inflammatory cytokines. These findings suggest that very long-chain fatty acids activate resident microglia and astrocytes and result in the loss of oligodendroglia and myelin (61). Schmidt and colleagues reported that 25% of adult X-linked adrenoleukodystrophy patients have antibodies to myelin oligodendrocyte glycoproteins compared to that of 10% in controls (71). Additionally, elevations of various cytokines and matrix metalloproteinases in the CSF along with elevated CSF protein being associated with disease severity as seen on MRI all indicate the role inflammation plays in cerebral adrenoleukodystrophy (44; 77).

In vivo studies suggested that very long-chain fatty acids accumulation-related oxidative stress and damage along with microglial activation contribute to the pathogenesis of the X-linked adrenoleukodystrophy (19). The microglial damage precedes active demyelinating lesions and can be seen before white matter is disrupted (03). Microglial dysfunction leading to excessive neuronal and synaptic phagocytosis has been recognized in the spinal cord of patients and a mouse model of the disease (21).

ABCD1-related changes to the brain endothelium are thought to lead to blood-brain barrier dysfunction (56). The role of inciting factors like minor head trauma has also been proposed (68). A summary of the effort to identify genetic modifiers in X-linked adrenoleukodystrophy has been published (87). Importantly, as there is a lack of genotype-phenotype correlation, biomarkers can play an important role in risk stratification. Biomarkers that can predict deterioration are currently under investigation. For example, superoxide dismutase activity shows a decrease prior to and at the time of cerebral diagnosis over a period of 13 to 42 months (78).

Epidemiology

Adrenoleukodystrophy is a X-linked genetically determined disorder. The estimated incidence of X-linked adrenoleukodystrophy in the United States is 1 per 21,000 in affected males and 1 per 16,800 in females (04). X-linked adrenoleukodystrophy has been observed in all ethnic groups, without evidence of differential rates (37). With the addition of adrenoleukodystrophy to the newborn screen, our understanding of the incidence and prevalence is anticipated to change over time. Since adrenoleukodystrophy has been added to the newborn screen in Minnesota, the overall birth prevalence has been estimated to be five times more than previous reports (86). These findings suggest that the spectrum of X-linked adrenoleukodystrophy may be broader than previously described and that milder cases may previously have been underrepresented.

Prevention

The most important preventative technique is the identification of carriers and affected males who are asymptomatic or only mildly symptomatic. The most widely used screening method is the measurement of very long-chain fatty acid levels in plasma, which has both a high specificity and sensitivity and should be confirmed with genetic confirmation (55; 54). When a new patient is diagnosed, it is important to screen, identify, and counsel at-risk family members. Prenatal mutation analysis to diagnose X-linked adrenoleukodystrophy can be performed by amniocentesis at 15 to 18 weeks of pregnancy (38). Additionally, preimplantation genetic diagnosis can be successful (30).

Newborn screening and follow-up

In 2016, adrenoleukodystrophy was added to the U.S. Recommended Uniform Screening Panel for newborn screening. Screening is generally performed with a 3-tier algorithm: first tier with tandem mass spectrometry analysis (MS/MS) of C26:0-lysophosphatidylcholine (LPS), second with high performance liquid chromatography and MS/MS screening on the sample used for the first-tier testing, and third with ABCD1 gene sequencing on the same samples. All patients with reported mutations undergo confirmatory very long-chain fatty acid analysis in an independent laboratory and parental testing is suggested for all affected patients.

Because there is currently no definite genotype-phenotype correlation, once the patient is diagnosed with suspicious variants in the gene, they should be screened regularly for both adrenal insufficiency and development of cerebral adrenoleukodystrophy. It is recommended that all patients be screened for adrenal insufficiency every 3 to 4 months in the first 2 years of life and every 4 to 6 months thereafter (69). Additionally, a consensus meeting suggested that individuals with adrenoleukodystrophy have their first noncontrasted MRI between 12 to 18 months followed by repeat noncontrasted MRI between 12 to 30 months and 12 months after the first. However, as the risk for the development of cerebral adrenoleukodystrophy sharply increases after the age of 3, it is recommended that individuals get contrasted MRIs every 6 months until they turn 12 years of age. MRIs thereafter should be performed every year. During this time, if a lesion is identified, an individual should undergo contrasted MRIs every 3 months to ensure he/she does not develop inflammatory demyelination with referral to a transplant center urgently if he/she does (45).

It is important to note that not all cases of X-linked adrenoleukodystrophy will require treatment but all cases of X-linked adrenoleukodystrophy require monitoring for a period of years to determine if treatment is indicated (34).

The benefit of early diagnosis from newborn screening is clearly that it helps with early identification and early initiation of treatment options for the adrenal and the cerebral forms of adrenoleukodystrophy. The unique challenges that have surfaced include the identification of children with genetic variants of uncertain significance and the identification of female carriers.

Differential diagnosis

The differential diagnosis of adrenoleukodystrophy must be considered separately for each of the major phenotypes.

Childhood cerebral adrenoleukodystrophy. As the common early symptoms of childhood cerebral adrenoleukodystrophy are decline in school performance, hyperactivity, and learning issues, the main differential diagnoses are hyperactivity or attention deficit disorders. Clues to the diagnosis of cerebral adrenoleukodystrophy are evidence of cognitive issues, difficulty in auditory discrimination, and deterioration of handwriting. In later stages, the disease must be differentiated from encephalitis, seizure disorders, brain tumors, and other neurodegenerative disorders. Radiologically, other leukodystrophies will also need to be distinguished from childhood cerebral adrenoleukodystrophy, with the typical findings on imaging guiding diagnosis (70; 84). Typically, hyperintense lesions usually originate from the parieto-occipital region then progress frontotemporally on T2-weighted images in patients with cerebral adrenoleukodystrophy. MRI in conjunction with plasma very long-chain fatty acid levels and genetic testing will lead to a definitive diagnosis.

Myeloneuropathy. Because myeloneuropathy manifests primarily with myelopathy, other causes of spinal cord dysfunction must be distinguished including chronic progressive multiple sclerosis, familial spastic paraparesis, cervical spondylosis, and spinal cord tumors. Patients with myeloneuropathy do not exhibit the exacerbations and remissions that are common in multiple sclerosis. The abnormal oligoclonal bands that are present in multiple sclerosis are usually not present in adrenoleukodystrophy patients with myeloneuropathy. When Addison disease is combined with a progressive myelopathy, myeloneuropathy is by far the most likely diagnosis. The characteristic high plasma very long-chain fatty acid level is the most reliable diagnostic tool (55; 54).

Addison disease. The “Addison-only” adrenoleukodystrophy phenotype cannot be distinguished from other causes of Addison disease by history and physical examination. The plasma very long-chain fatty acid assay (55; 54) provides the only reliable method of identification. The plasma very long-chain fatty acid and ACTH levels are increased in patients with adrenoleukodystrophy and Addison disease due to other causes. Serum adrenal antibody levels are not increased in adrenoleukodystrophy-associated Addison disease. Therefore, in patients presenting with Addison disease, it is important to screen patients for adrenoleukodystrophy with very long-chain fatty acids (74; 29).

Addison disease combined with neurologic deficits. Other disorders cause adrenal insufficiency combined with neurologic disturbances: (1) brain damage due to hypoglycemic episodes in Addisonian crises; (2) central pontine myelinolysis--this disorder may occur when serum sodium levels are replenished rapidly in a patient in Addisonian crisis (59); (3) global developmental delay and Addison disease often co-occur in the X-linked genetic disorder glycerol kinase deficiency (90). Adrenal insufficiency, global developmental delay, achalasia, and deficient tear production co-occur in a syndrome described by Allgrove and colleagues (01). Apart from the clinical findings, definitive distinction depends on the demonstration of increased levels of very long-chain fatty acids in plasma in adrenoleukodystrophy. These levels are normal in all of the other conditions.

Neurologic dysfunction in women who are heterozygous for adrenoleukodystrophy. Slowly progressive paraparesis, sensory and sphincter disturbances are the most common neurologic manifestations in women who are heterozygous for adrenoleukodystrophy. This syndrome is difficult to distinguish from multiple sclerosis or other progressive spinal cord disorders (18). Most commonly the diagnosis is made in a woman who is a relative of a male adrenoleukodystrophy patient. Very long-chain fatty acid levels in plasma or fibroblasts are increased in nearly all female X-linked adrenoleukodystrophy carriers who develop signs and symptoms of myelopathy (63%) or peripheral neuropathy (57%), as well as fecal incontinence (28%) (14). Clinical presentations that primarily manifest as neuropathy will need to be distinguished from other causes of polyneuropathy.

Confusing conditions

The condition referred to as “neonatal adrenoleukodystrophy” represents a possible source of confusion and must be differentiated sharply (32). Neonatal adrenoleukodystrophy is a disorder that has an autosomal recessive mode of inheritance with pathology arising from defects in importing a variety of proteins into the peroxisome (40). Its clinical manifestations are wholly different from the X-linked form of adrenoleukodystrophy described in this chapter. Neonatal adrenoleukodystrophy is now considered to be member of a clinical continuum, with Zellweger syndrome the most severe, neonatal adrenoleukodystrophy of intermediate severity, and infantile Refsum disease the least severe.

Diagnostic workup

The main diagnostic procedure is the demonstration of increased plasma levels of very long-chain fatty acids (C26:0, C26:0 to C22:0 ratio, and C24:0 to C22:0 ratio) (55; 54). The levels are increased in all male adrenoleukodystrophy patients and in approximately 80% of carriers. Methodological advances have further improved the specificity of the very long-chain fatty acid assay and reduced the time and sample size required to carry out the assay (75; 79). False positives are rarely reported, and the known causes are liver insufficiency, ketogenic diet, and diabetic ketoacidosis. Plasma very long-chain fatty acids levels are increased also in other peroxisomal disorders, such as the Zellweger syndrome or neonatal adrenoleukodystrophy (52), and in children with seizure disorders who are on a ketogenic diet (76). However, all of these are readily distinguished based on the history and clinical presentation.

The combination of typical clinical findings and markedly elevated very long-chain fatty acids level are sufficient for preliminary diagnosis of X-linked adrenoleukodystrophy in most affected males. The diagnosis should be confirmed by genetic testing. Genetic testing is especially important in patients with borderline very long-chain fatty acid levels or atypical features and female patients with symptoms or family history of adrenoleukodystrophy due to the less sensitive results of very long-chain fatty acid testing. Confirmatory genetic test options range from a single-gene test to a multigene panel to exome or genome sequencing depending on the clinical presentation and very long-chain fatty acids results. In patients with clinical and biochemical diagnosis, single-gene testing should be adequate. However, patients with borderline findings and complicated presentations, multigene panel, or exome or genome sequencing should be considered.

Adrenal function should always be evaluated in the patients with X-linked adrenoleukodystrophy diagnosis. The Endocrine Society’s Clinical Practice Guideline suggests standard cosyntropin stimulation testing to diagnose the primary adrenal insufficiency. If stimulation testing is not feasible, morning cortisol and ACTH level measurements are recommended for evaluation. Regelmann and colleagues reported a detailed suggested algorithm for surveillance of adrenal function (69).

Once a diagnosis is made based on genetic biochemical screening, there are currently no reliable biomarkers to help with the prediction of the likely phenotype in the patient. Increased plasma neurofilament light has been suggested as a possible biomarker indicating cerebral adrenoleukodystrophy onset in children with X-ALD (85). Further evaluation is required to assess the clinical utility of these cutoffs in assessing the risk prognosis of cerebral adrenoleukodystrophy onset.

Brain MRI studies are of great diagnostic value for the childhood, adolescent, and adult cerebral forms of adrenoleukodystrophy. All those with confirmed genetic variants should have neuroimaging as part of their baseline evaluation. The cerebral white matter involvement typically begins from the splenium of the corpus callosum and progresses to the periventricular and occipital regions. However, in approximately 15% of patients, the initial demyelinating lesions present in the genu of the corpus callosum and expand into the frontal lobes (80).

The posterior predominant T2 hyperintensity forms the most common MRI finding in the whole cohort and in children and adolescent age groups. The cerebellar variant is more common in adults, the corticospinal tract is often involved, and a brain MRI may occasionally show subtle abnormalities in the internal capsule and even brainstem pyramidal lesions (12; 57; 05). Psychiatric and working memory impairment are more common in patients with frontal lesions, which warrants considering lesion location as a risk factor for development of neurocognitive and psychiatric morbidities (23). Rare temporal lesions have also been described.

Loes and colleagues have developed a formula based on the patient’s age, the severity of the Loes MRI score (43), the pattern of MRI brain lesions, and the presence or absence of enhancement that allows considerable accuracy in the rate of progression over the next 12 months and candidacy for bone marrow transplantation as an intervention (53; 42). Diffusion tensor brain imaging (31; 72) and Dual-Echo Fast Fluid-Attenuated Inversion Recovery MRI (48) are also important tools to select patients who are candidates for bone marrow transplantation and other interventions by aiding in distinguishing between zones of early and active demyelination from those in which the process is no longer active. Although, diffusion tensor imaging can detect subtle abnormalities that are not evident on a conventional MRI, the Loes score is superior to diffusion tensor imaging in predicting outcomes after bone marrow transplantation (47).

Additionally, proton MR spectroscopy (MRS) imaging based on the N-acetylaspartate to choline ratio can be valuable in predicting both impending demyelination or lesion progression in areas that still appeared normal on conventional MRI scans (11). There is also a positive association between posttransplant clinical outcomes and N-acetylaspartate levels seen on MRS imaging (89). High N-acetlyaspartate concentration in affected white matter areas before transplantation was demonstrated to be beneficial in terms of posttransplant outcomes. The use of these techniques may permit detection of cerebral abnormalities at a time when conventional MRI is still normal and are of value for identifying patients who have the greatest chance of benefiting from bone marrow transplantation. Fatemi and colleagues studied brain MRI in 76 women heterozygous for X-ALD and found abnormalities attributable to X-ALD in only two (17). Brain MRI was normal in 65 who had a myeloneuropathy-like syndrome. MR spectroscopy studies were performed in eight and revealed a statistically significant reduction in N-acetyl aspartate levels in the corticospinal tract and parieto-occipital regions. These studies indicate that brain involvement demonstrable by MRI is rare, even in those women who have myeloneuropathy, but the preliminary MR spectroscopy studies suggest that there are subtle axonal abnormalities even in those women with normal MRI. These axonal changes may be indicative of the distal axonopathy that represents the principal neuropathological change in myeloneuropathy (66).

Management

Treatment of adrenal insufficiency. Therapy for individuals with adrenal insufficiency associated with adrenoleukodystrophy is the one form of therapy that is known to be completely effective, making it imperative that patients be referred to an endocrinologist once diagnosed. Patients with impaired adrenal reserve need careful follow-up and early initiation of adrenal hormone therapy. This should make it possible to prevent overt Addison disease and the morbidity and mortality associated with it. Although it can overcome virtually all of the handicaps related to the adrenal insufficiency, it does not appear to alter the course of the neurologic disease. The glucocorticoid dose requirement is usually the same as for other forms of primary adrenal insufficiency. To mimic the diurnal rhythm of physiological cortisol secretion, 25 mg of cortisone acetate or 20 mg of hydrocortisone is administered in the early morning with a smaller second dose, 12.5 or 10 mg, respectively, given in the late afternoon. Patients are instructed to augment glucocorticoid coverage during stress, provided with a parenteral methylprednisolone dose for potential use if vomiting prevents oral dosing, and are strongly encouraged to wear Medic-Alert identification declaring their dependency on adrenal steroid therapy. Bornstein and colleagues detailed further management guidance for adrenal insufficiency in patients with adrenoleukodystrophy (06).

Allogenic hematopoietic stem cell transplantation (HSCT). Allogenic hematopoietic stem cell transplantation has been demonstrated to be an effective treatment in arresting progression of neurologic sequela especially when performed early (50; 67). It is currently regarded as the treatment of choice in early cerebral adrenoleukodystrophy. Stem cells can be harvested from bone marrow or umbilical cord blood.

It has been shown that patients with a Loes score of 0.5 to 9 with a neurologic function scale of less than 1 – used to define individuals thought to be in earlier stages of disease progression - have more favorable outcomes after hematopoietic stem cell transplantation when compared to individuals who are more affected (50; 67). The degree of enhancement also predicts neurologic outcomes after hematopoietic stem cell transplantation (51). However, it has been shown that even individuals transplanted with a Loes score between 2.5 to 4.5 have progression of disease as evidenced by detailed neurocognitive testing when compared to individuals with a Loes score of less than 2, highlighting the importance of early diagnosis and intervention (64; 65).

Despite the importance of early intervention with hematopoietic stem cell transplantation, it is important to note the morbidities and mortalities associated with hematopoietic stem cell transplantation. It has been estimated that the 5-year survival is 78% in patients treated with hematopoietic stem cell transplantation compared to 55% in that of the untreated group (67). Although hematopoietic stem cell transplantation has favorable and effective outcomes, it may cause some fatal complications including infections, graft-versus-host disease, and graft rejection or failure (62; 50). It is also noted that hematopoietic stem cell transplantation is ineffective for the manifestations of adrenal insufficiency and may not impact the adult-onset myeloneuropathy development (63; 83).

Ex-vivo gene therapy. Gene therapy with autologous hematopoietic stem cells transfected with elivaldogene autotemcel (eli-cel) received accelerated approval from the U.S. FDA in September 2022. It is currently approved for boys aged 4 to 17 with early active cerebral adrenoleukodystrophy.

The earliest results of the now approved gene therapy with autologous hematopoietic stem cells transduced with elivaldogene autotemcel lentiviral was a single group, open-label study of 17 boys with progressive inflammatory childhood-onset cerebral adrenoleukodystrophy, without an HLA-matched donor through ex vivo gene therapy (10). The study found that 88% of the boys remained alive at 24 months post-transplantation, without any significant functional limitations except for death in two patients: one from disease progression and one who withdrew from complications of subsequent allogeneic HSCT.

A study on white matter restoration in cerebral adrenoleukodystrophy with HSCT gene therapy showed a resolution of contrast enhancement in patients treated with gene therapy within 1 month of infusion, much shorter than the 60 to 100 days seen in allo-HSCT treated patients (39). However, in half of the patients, a recurrence of weak T1-weighted hyperintensity between 6 months and 2 years and an inverse correlation between gene dosage and lesion growth suggested that corrected cells contribute to a long-term remodeling of brain microvascular function.

Other interventions, including Lorenzo oil and statins, have not demonstrated efficacy in clinical trials.

Emerging studies. The use of 4-phenylbutyrate (FDA-approved drug) conjugated to hydroxyl polyamidoamine (PAMAM) dendrimers for a long-lasting and intracellular approach to upregulate Abcd2 and its downstream pathways showed a positive outcome in mouse models. Additionally, combining antioxidant/4-PBA therapy on the dendrimer platform, as previously shown by the conjugation of N-acetylcysteine and dendrimer, reverses oxidative stress and the proinflammatory cytokine in adrenomyelopneuropathy and cerebral adrenoleukodystrophy patient macrophages. This may lead to the enrollment of younger adrenomyelopneuropathy patients who are early in the disease stage to monitor results (58).

Randomized, double-blind, placebo-controlled, phase 2–3 trials were conducted at 10 hospitals across the world in men aged 18 to 65 years with adrenomyeloneuropathy without gadolinium enhancing lesions suggestive of progressive cerebral adrenoleukodystrophy who were assigned leriglitazone 150 mg for preventing disease progression (36). Although the primary endpoint (6-minute walk test at week 96) of the study was not met, the drug was shown to be well tolerated among patients, with no adverse events beyond that expected for the drug class. Interestingly, leukodystrophy was noted in none of the treatment group compared to 5% in the placebo group. Further investigation into the use of leriglitazone in slowing the progression of cerebral adrenoleukodystrophy is currently underway.

Surveillance for patients detected pre-symptomatically through newborn screening. Because there is no current definite genotype-phenotype correlation, patients should be regularly screened for both adrenal insufficiency and development of cerebral adrenoleukodystrophy once they are diagnosed with suspicious variants in the gene.

It is recommended that all males identified with adrenoleukodystrophy be screened for adrenal insufficiency every 3 to 4 months in the first 2 years of life and every 4 to 6 months thereafter (69). Testing will be abnormal in 90% of boys with neurologic disease and in more than 80% of men with myeloneuropathy (28).

Additionally, a consensus meeting suggested that individuals with adrenoleukodystrophy have their first noncontrasted MRI between 12 to 18 months followed by repeat noncontrasted MRI between 12 to 30 months and 12 months after the first (45). However, as the risk for the development of cerebral adrenoleukodystrophy sharply increases after the age of 3, it is recommended that individuals get contrasted MRIs every 6 months until they turn 12 years of age. MRIs should be performed every year thereafter. If a lesion is identified during this time, the individual should undergo contrasted MRIs every 3 months to ensure they do not develop inflammatory demyelination, with urgent referral to a transplant center if they do.

In a mixed retrospective/prospective cohort study of 71 boys diagnosed with presymptomatic childhood cerebral adrenoleukodystrophy, lesions appeared at a median age of 6.4 years and as early as 2 years (46). Half of the patients displayed lesion enhancement, and the other half developed enhancement on 6-month surveillance. The time from enhancement to treatment was 3.8 months. The results showed that capturing presymptomatic childhood cerebral adrenoleukodystrophy did not correlate with younger age as well as a lack of significant correlation between diagnostic age, Loes Score at diagnosis, and time-to-detection of lesional enhancement.

Advanced C-ALD supportive care. As there are limitations in altering the course of disease progression once significant neurologic abnormalities develop, a major part of management involves supportive care – general support, counseling, advice with respect to schooling and employment, ensuring access to rehabilitative and supportive services, and management of food intake, sphincter disturbances, impotence, spasticity, and seizures. Baclofen in gradually increasing dosages (5 mg twice a day to 25 mg every 6 hours) has been the most effective therapy for spasticity. Intrathecal administration of baclofen has shown benefit and tolerance by several patients with myeloneuropathy (26) and has also been reported to benefit a boy with the childhood cerebral form of X-ALD (08). The United Leukodystrophy Foundation, Inc. (224 North Second Street, Suite 2, DeKalb, IL 60115 | (800) 728-5483 | (815) 748-3211 | F: (815) 748-0844; http://ulf.org) is a major source of information and support for many families.

Special considerations

Anesthesia

Although there are many comorbidities such as adrenal insufficiency, cognitive dysfunction, dysphagia, gastroesophageal reflux, aspiration, spasticity, progressive myelopathy, hypotonia, and seizure, with the presence of the skilled pediatric anesthesia care, there are no major complications and mortality in the patients with X-linked adrenoleukodystrophy needing anesthesia (35).