Adrenoleukodystrophy

Etiology

Adrenoleukodystrophy is usually X-linked (X-ALD) and caused by over 2700 known mutations in the ABCD1 gene mutations.[3] The ABCD1 gene plays a significant role in the VLCFA transport system into peroxisomes, where VLCFAs can undergo further metabolism. Mutations in the ABCD1 gene product interfere with this process, leading to the abnormal accumulation of VLCFAs in various body organs and interfering with their normal physiological functions.

A similar peroxisomal syndrome, Zellweger spectrum disorder, is caused by mutations in the PTS1 receptor, PXR, or any of the many identified PEX genes. The PEX genes are involved in the formation and function of peroxisomes. One of the Zellweger spectrum disorders is neonatal adrenoleukodystrophy, which has an earlier and more severe presentation than other forms of ALD.[2][4]

Four main subtypes of adrenoleukodystrophy are described based on the organs affected and the age at presentation—neonatal, childhood cerebral, adrenomyeloneuropathy, and adrenal insufficiency.

Epidemiology

Adrenoleukodystrophy is the most common genetic disorder affecting peroxisomes, with an estimated prevalence of 1 in 14,700.[3] The disease incidence is higher in patients of Latino or African descent.[5] Neonatal adrenoleukodystrophy has a prevalence of 1 in 50,000.[6]

Prevalence

Adrenoleukodystrophy affects approximately 1 in 20,000 to 1 in 50,000 individuals globally.

Sex Distribution

Adrenoleukodystrophy primarily affects males due to its X-linked recessive inheritance. Females are typically carriers and may have mild or no symptoms.

Age of Onset

• Childhood cerebral adrenoleukodystrophy: Presents between ages 4 and 10, with rapid progression.
• Adolescent and adult cerebral adrenoleukodystrophy: Milder form that appears during adolescence or adulthood, with slower progression.
• Adrenomyeloneuropathy: Manifests in adulthood (between ages 20 and 40 in men and by age 65 in women) with gradual motor and sensory deficits.[7]

Geographic and Ethnic Distribution

Adrenoleukodystrophy is found worldwide and affects all ethnic groups. Prevalence varies based on genetic factors and diagnostic capabilities.

Carrier Frequency

Approximately 1 in 17,000 females are carriers of adrenoleukodystrophy.

Risk Factors and Genetic Considerations

The primary risk factor is an inherited mutation in the ABCD1 gene. A family history of adrenoleukodystrophy also increases the risk.

Public Health Implications

Early diagnosis through newborn screening is critical. Genetic counseling for families is essential. Increased awareness and research are needed to improve diagnostics, treatment, and support.

Pathophysiology

Adrenoleukodystrophy is a rare genetic disorder that affects the nervous system and adrenal glands. Except for neonatal adrenoleukodystrophy, it is an X-linked recessive disorder, primarily affecting males, while females can be carriers. The pathophysiology is characterized by the accumulation of VLCFAs in tissues throughout the body, including the brain, spinal cord, and adrenal cortex.[7] Although adrenoleukodystrophy is linked to mutations in the ABCD1 and PEX genes, these mutations do not fully account for the clinical syndromes, suggesting that other modifier genes, epigenetic factors, and environmental influences likely contribute as well.[8]

Key Aspects of Adrenoleukodystrophy Pathophysiology

Genetic mutation: The disorder is caused by mutations in the ABCD1 gene, which is located on the X chromosome. This gene encodes the adrenoleukodystrophy protein (ALDP), which is involved in transporting VLCFAs into peroxisomes for degradation.

VLCFA accumulation: Due to defective ALDP, VLCFAs cannot be properly transported into peroxisomes, leading to their accumulation in the body. Elevated VLCFA levels are toxic to cells, particularly affecting myelin, the protective sheath around nerve fibers in the central nervous system.

Demyelination: The accumulation of VLCFAs leads to progressive demyelination, where the myelin sheath is damaged and destroyed. This disruption severely impairs the conduction of nerve impulses, resulting in neurological symptoms.

Inflammatory response: The breakdown of myelin triggers an inflammatory response in the brain, which exacerbates the damage. The immune system's attack on the myelin leads to further neurological decline.

Adrenal insufficiency: VLCFAs also accumulate in the adrenal cortex, impairing its ability to produce adrenal hormones such as cortisol and aldosterone. This results in adrenal insufficiency, leading to symptoms such as fatigue, weight loss, and skin changes.

Histopathology

On gross examination, affected adrenal glands appear small and atrophied. Histological findings show nodular swelling primarily affecting the zona fasciculata and zona reticularis, with visible cellular vacuoles and clefts. The medulla is typically spared and appears normal.[9]

Central nervous system (CNS) pathological findings in adrenoleukodystrophy include symmetrical demyelination of the white matter, typically affecting the corpus callosum and occipitoparietal region. In severe cases, the spinal cord may also be involved. At the cellular level, swelling and vacuolization result from infiltrates of active inflammatory cells, such as macrophages and astrocytes. These changes lead to the loss of myelin sheaths, oligodendrocytes, and neuronal axons. Histological examination ultimately reveals dystrophic mineralization.[10]

Microscopic Examination

Luxol fast blue staining: This technique identifies myelin by staining it blue. Areas of demyelination will appear as pale or unstained regions.

Periodic acid-Schiff staining: This stain highlights macrophages with accumulated myelin debris, which appear as magenta deposits.

Immunohistochemistry: This technique uses specific markers (such as myelin basic protein) and inflammatory cells (such as CD68 for macrophages) to identify and characterize the cellular components involved in the pathological process.

Toxicokinetics

Absorption

Small amounts of VLCFA are absorbed from the diet, but they are primarily synthesized endogenously through the ELOVL1 enzyme.[3]

Distribution

VLCFAs accumulate in the brain, adrenal glands, and peripheral nerves due to defective transport into peroxisomes.

Metabolism

The defect in the ABCD1 gene impairs the peroxisomal beta-oxidation of VLCFAs, leading to their buildup.

Toxic Effects

Accumulated VLCFAs lead to demyelination, inflammation, and adrenal insufficiency. Increased oxidative stress also contributes to pathology.[3]

Excretion

Inefficient degradation and excretion result in their persistent VLCFA accumulation in tissues.

Understanding these toxicokinetic processes is crucial for developing therapeutic strategies aimed at improving clinical symptoms.[7]

History and Physical

Clinical manifestations of adrenoleukodystrophy vary significantly based on disease severity and age at presentation. The condition is broadly categorized into neonatal adrenoleukodystrophy and X-ALD. Neonatal adrenoleukodystrophy may present immediately after birth, but some infants may exhibit only mild symptoms, potentially delaying diagnosis in these cases.

Typical signs and symptoms of neonatal adrenoleukodystrophy include:[2][7]

• Seizures, hypotonia, and hearing dysfunction
• Vision loss, cataracts, and optic nerve dysplasia
• Jaundice and hepatomegaly
• Failure to thrive and facial dysmorphism (such as hypertelorism and flat midface) [11]

X-ALD is classified into the following 3 main phenotypes based on the age at presentation and the organs affected:

• Childhood cerebral adrenoleukodystrophy
• Addison disease
• Adrenomyeloneuropathy

Childhood cerebral adrenoleukodystrophy typically presents between ages 3 and 10. The hallmark of this form is developmental regression, and it is characterized by progressive sensory and severe neurological deficits, which often lead to significant disability, coma, and eventually death. Some adults may also develop symptoms similar to those seen in childhood cerebral adrenoleukodystrophy. 

Addison disease is characterized by adrenal gland dysfunction in X-ALD. This phenotype results from reduced production of aldosterone and cortisol, leading to manifestations such as hyponatremia, fatigue, hypotension, dehydration, hypoglycemia, and generalized weakness. Hyperpigmentation of the skin may also occur. Males with adrenoleukodystrophy have an 80% lifetime risk of developing adrenal insufficiency.[3]

Adrenomyeloneuropathy is a milder spectrum of X-ALD. The typical age at presentation is usually in the third decade of life for men and post-menopausal for women, with initial symptoms often involving spinal cord dysfunction. Approximately 65% of women with this form will exhibit symptoms of adrenoleukodystrophy by age 65.[3] Most men who survive until adulthood have the adrenomyeloneuropathy form of adrenoleukodystrophy. This form is characterized by a chronic progressive axonopathy affecting the sensory and motor spinal cord tracts, leading to progressive spastic paraparesis, peripheral neuropathy, bowel and bladder sphincter dysfunction, and sexual dysfunction, sometimes accompanied by adrenal insufficiency. Involvement of the cerebellum can result in walking difficulties, ataxia, and unbalanced gait.[12]

Female carriers of X-ALD may also develop subtler symptoms, such as unsteady gait, neuropathy, and mild paresis. Involvement of the adrenal glands and cerebrum is rare.[13]

Evaluation

The evaluation of adrenoleukodystrophy begins with considering the typical clinical presentation, characteristics, symptoms, signs, and suggestive family history. Several states have introduced newborn screening tests to identify infants with X-ALD. Including X-ALD in newborn screening programs helps identify affected newborns early, allowing for intervention before symptoms develop. Currently, approximately 30 states have implemented newborn screening programs for X-ALD.[7][14]

Laboratory workup may show abnormal liver function and a reduced response to adrenocorticotropic hormone administration. More specific indicators of adrenoleukodystrophy include elevated concentrations of VLCFAs in plasma, skin fibroblasts, and amniocytes.[3] Although increased VLCFA levels are strongly indicative of adrenoleukodystrophy, the degree of elevation does not necessarily correlate with disease type or severity.[15] Additional findings may include decreased plasmalogen levels in red blood cells and increased concentrations of pipecolic and phytanic acids in both plasma and fibroblasts.[16]

Magnetic resonance imaging (MRI) of the brain is crucial for the evaluation of adrenoleukodystrophy. Typical MRI findings include a white matter demyelination pattern, microgyria, and germinolytic cysts in the caudothalamic groove. Further genetic testing to identify the specific mutation causing the disorder is recommended to confirm the diagnosis.[17]

Treatment / Management

Adrenoleukodystrophy has no effective cure. Supportive care, including optimizing nutrition, occupational therapy, and respiratory support, can help alleviate some of the severe consequences of the disorder but typically does not significantly impact survival or long-term outcomes. Corticosteroid and mineralocorticoid replacement therapy is recommended for patients with impaired adrenal gland function. Some studies report that allogeneic hematopoietic stem cell transplantation (HSCT) can halt cerebral demyelination if performed before advanced brain disease develops, highlighting the importance of early screening for at-risk babies.[3][18] Gene therapy trials using autologous stem cell transplants have shown short-term improvements without the significant risks of HSCT.[7][19](A1)

Adrenoleukodystrophy gained recognition through the movie "Lorenzo's Oil." However, this mixture of oleic and erucic triglycerides has not been proven effective in randomized controlled trials and is not approved by the US Food and Drug Administration (FDA). Bezafibrate and statin therapy have also been studied but have not yet been proven effective. Crossing the blood-brain barrier is a pharmacodynamic challenge.[3]

A multicenter, open-label phase I trial using lentiviral vectors carrying the ABCD1 gene is currently underway in China. So far, significant adverse events have not been noted.[19] Recent trials exploring docosahexaenoic acid use to induce peroxisome proliferation have yielded inconclusive results.[20][21] (A1)

Physical therapy, management of urologic complications, and vocational counseling are adjunctive treatments that help improve patients' overall functional status. Given the multiple organs affected and the diverse needs of patients with adrenoleukodystrophy, an interprofessional team approach is recommended. This healthcare team should include, at a minimum, endocrinologists, neurologists, geneticists, and psychologists.

Differential Diagnosis

The differential diagnosis of neonatal adrenoleukodystrophy is comprehensive and includes several other genetic syndromes that present with neurological signs and symptoms in the neonatal period. These conditions include Angelman syndrome, Prader-Willi syndrome, Zellweger spectrum disorders (such as Zellweger syndrome, infantile Refsum disease, and rhizomelic chondrodysplasia punctata type 1), hypoxic-ischemic encephalopathy, metabolic disorders, and myotonic dystrophy.

For X-linked adrenoleukodystrophy (X-ALD), differential diagnoses include conditions characterized by demyelination, such as acute disseminated encephalomyelitis and multiple sclerosis.

Pertinent Studies and Ongoing Trials

The 2 below-mentioned ongoing clinical trials are actively recruiting participants to evaluate potential therapeutic interventions for adrenoleukodystrophy.

• NCT03727555: This clinical trial investigates the use of the lentiviral vector TYF-ABCD1 to correct the defective ABCD1 gene responsible for adrenoleukodystrophy symptoms.
• NCT03852498: This trial aims to assess the effects of autologous CD34+ HSCT on adrenoleukodystrophy.

Prognosis

The prognosis for neonatal adrenoleukodystrophy and most forms of X-ALD is generally poor. However, patients with adrenomyeloneuropathy can survive past age 65, although often with significant morbidity.[12] Treatment is usually limited to symptomatic supportive management. Replacement therapy is effective for patients with Addison disease, while HSCT may benefit asymptomatic patients identified through newborn screening or incidental imaging, as well as those with mild symptoms. 

Complications

Patients with adrenomyeloneuropathy have significantly increased other comorbid conditions that have not been fully characterized yet. These include increased levels of pulmonary disease, liver disease, cerebrovascular disease, and cancer.[12]