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Adrenoleukodystrophy

Adrenoleukodystrophy (ALD), also known as X-linked adrenoleukodystrophy (X-ALD), is a rare, inherited peroxisomal disorder caused by pathogenic variants in the ABCD1 gene on the , resulting in the impaired transport and subsequent accumulation of very long-chain fatty acids (VLCFAs) in tissues such as the , , and adrenal glands. This buildup leads to demyelination of the , adrenal , and progressive neurological deterioration, with the most severe form, childhood cerebral ALD (cCALD), typically manifesting between ages 4 and 8 in affected males and potentially proving fatal within 5 to 10 years if untreated. The disorder exhibits significant phenotypic variability, with approximately 30-35% of affected males developing the rapidly progressive cCALD form, characterized by symptoms including behavioral changes, vision and , seizures, and motor deficits due to degeneration. In contrast, 40-45% of males present with adrenomyeloneuropathy (AMN), an adult-onset emerging in the 20s or 30s, featuring progressive stiffness, weakness in the legs, bladder dysfunction, and sensory disturbances from involvement. , often the earliest sign, affects up to 90% of neurologically symptomatic boys and 70% of those with AMN, manifesting as fatigue, weight loss, and low blood pressure due to deficient and aldosterone production. Females, who are typically heterozygous carriers, experience milder symptoms later in life, with 65-80% developing AMN-like features by age 65, though adrenal issues are less common. X-ALD follows an pattern, primarily affecting s with a prevalence of about 1 in 14,000 to 17,000 male births worldwide, while approximately 95% of cases are inherited from carrier mothers and 4-5% arise from mutations. Diagnosis is confirmed through elevated plasma VLCFA levels and for ABCD1 variants, with implemented in 46 U.S. states and the District of Columbia as of 2025, with all states expected to follow by year-end, and in several other countries to enable early intervention. Management includes (HSCT) or (such as elivaldogene autotemcel [Skysona], approved in 2022, with updated FDA safety warnings in 2025 regarding increased risk of hematologic malignancies) for presymptomatic or early cCALD cases to halt neurological progression, alongside lifelong corticosteroid replacement for and supportive multidisciplinary care for symptoms. Ongoing research emphasizes MRI surveillance for early detection of cerebral involvement and highlights the need for family screening to identify at-risk individuals.

Overview

Definition and classification

Adrenoleukodystrophy (ALD), also known as X-linked adrenoleukodystrophy (X-ALD), is a peroxisomal disorder characterized by pathogenic variants in the ABCD1 gene on the , which encodes a peroxisomal membrane transporter protein essential for the beta-oxidation of very long-chain fatty acids (VLCFAs, defined as fatty acids with 22 or more carbon atoms). These mutations impair the transport of VLCFA-CoA esters into peroxisomes, leading to their toxic accumulation in all tissues, including the , , , and testes. The resulting VLCFA buildup disrupts cellular membranes and induces , primarily affecting the and adrenal glands. The primary phenotypic classifications of X-ALD reflect its clinical heterogeneity and include cerebral ALD, adrenomyeloneuropathy (AMN), Addison-only ( without neurological involvement), and forms. Cerebral ALD is subdivided by age of onset into childhood (typically 3-10 years), adolescent (11-20 years), and adult (>20 years) variants, each involving progressive demyelination of cerebral . AMN predominantly manifests in adulthood as a slowly progressive , while the Addison-only presents isolated primary , often in childhood or early adulthood, and asymptomatic cases are identified through family screening or newborn testing before clinical onset. Historically, X-ALD was first described in the early as cases of diffuse sclerosis with adrenal involvement, with the term "adrenoleukodystrophy" coined in to unify these presentations; it was recognized as a distinct X-linked entity in the following the identification of VLCFA accumulation, distinguishing it from rare autosomal recessive peroxisomal disorders like neonatal ALD caused by PEX gene mutations. As a monogenic disorder driven by ABCD1 variants, X-ALD exhibits marked variable expressivity, with phenotypes ranging from severe, early-onset cerebral involvement to status, even among individuals with identical mutations or within the same family, underscoring the influence of uncharacterized genetic and environmental modifiers.

Inheritance and prevalence basics

Adrenoleukodystrophy (ALD), specifically the X-linked form (X-ALD), follows an pattern due to pathogenic variants in the ABCD1 gene located on the . Affected males, who have only one , inherit the variant from their mothers and typically exhibit severe symptoms, while females, with two s, are usually s but may develop milder neurological manifestations later in life due to . Approximately 95% of cases are inherited from a parent, with the remainder arising from mutations. In terms of transmission, a carrier mother has a 50% chance of passing the ABCD1 variant to each son, who would then be affected, and a 50% chance of passing it to each daughter, who would become a carrier; there is no male-to-male transmission because affected fathers pass their to sons. An affected male transmits the variant to all of his daughters (making them obligatory carriers) but none of his sons. This pattern underscores the importance of for families, as carrier testing in females can identify at-risk pregnancies. The worldwide prevalence of X-ALD is estimated at 1 in 14,000 to 1 in 17,000 live male births, with similar rates across populations. The carrier frequency among females is approximately 1 in 17,000. These figures highlight X-ALD as the most common peroxisomal disorder, though underdiagnosis may occur due to variable phenotypic expression. Rare de novo cases, accounting for about 5% of probands, can result from gonadal (germline) mosaicism in unaffected parents, particularly mothers, where the ABCD1 variant is present in some germ cells but not detectable in somatic tissues like blood leukocytes. This phenomenon explains sporadic occurrences in families without prior history and increases the recurrence risk slightly in such cases, estimated at less than 1%.

Clinical features

Cerebral adrenoleukodystrophy

Cerebral adrenoleukodystrophy (CALD) represents the most severe neurological of X-linked adrenoleukodystrophy, characterized by inflammatory demyelination in the that leads to rapid neurological decline if untreated. It primarily affects males and accounts for approximately 30-40% of cases in affected individuals, with onset typically in childhood but possible in or adulthood. The condition involves progressive destruction of in the , resulting in cognitive, behavioral, and motor impairments. CALD is classified into three main subtypes based on age of onset: childhood cerebral ALD (CCALD), which occurs between ages 4 and 8 years (peaking at 7 years) and represents about 30-35% of male cases; adolescent CALD, with onset between 10 and 15 years and comprising roughly 5% of cases; and CALD, beginning after age 20 years and affecting around 20% of males. Progression is fastest in CCALD, often leading to total within 6 months to 2 years, while adolescent and adult forms tend to advance more slowly. Initial symptoms in CCALD commonly include behavioral changes such as aggression or attention deficits resembling ADHD, school failure, and subtle motor clumsiness. These evolve into vision and , seizures, , and eventual progression to a without intervention. In adolescent and adult subtypes, early signs may involve similar cognitive and behavioral declines but with a more gradual onset of sensory and motor deficits. Magnetic resonance imaging (MRI) reveals a characteristic pattern of inflammatory demyelination in CALD, typically starting in the posterior periventricular of the parieto-occipital regions and progressing anteriorly to involve the frontal lobes and . Symmetric T2-weighted hyperintensities indicate demyelination, with contrast enhancement signaling active at the lesion edges. This posterior-to-anterior spread correlates with clinical progression and helps differentiate CALD from other phenotypes. Cerebral involvement in females is rare, occurring in less than 1% of cases due to X-chromosome inactivation patterns, and typically presents with later onset in adulthood compared to males. When it occurs, symptoms mirror those in males but follow a milder and slower progression, often including cognitive decline, instability, or focal neurological deficits without rapid deterioration to a .

Adrenomyeloneuropathy

Adrenomyeloneuropathy (AMN) represents the most common adult-onset phenotype of X-linked adrenoleukodystrophy (ALD), primarily affecting males with a slowly progressive and peripheral nerve disorder. It typically manifests in the second to fourth decade of life, with initial symptoms often emerging between ages 20 and 40. The hallmark features include progressive spastic paraparesis, characterized by leg stiffness and weakness that impairs , leading to a stiff walking pattern and eventual need for assistive devices such as wheelchairs in advanced stages. Sensory disturbances, particularly loss of vibratory sense in the lower limbs, accompany these motor deficits, while urinary urgency, incontinence, and bowel dysfunction arise from involvement of autonomic pathways in the . A key component of AMN is , which manifests as a sensorimotor with predominant axonal degeneration affecting long nerve fibers. This leads to distal weakness, , and , particularly in the legs, contributing to overall . Electrophysiological studies confirm mixed axonal loss and multifocal demyelination, though axonal predominates, distinguishing it from the more inflammatory cerebral forms of ALD. The accumulation of very long-chain fatty acids (VLCFAs) in neuronal tissues contributes to this axonal damage through and impaired energy metabolism. The progression of AMN is insidious and spans decades, with patients experiencing gradual worsening of mobility and control, often requiring multidisciplinary management including and urological interventions. Approximately 20%-63% of affected males develop cerebral involvement later in the disease course, which can accelerate decline and lead to cognitive or behavioral changes, though this risk varies with age and monitoring. In female carriers of ALD, AMN-like symptoms occur in a milder form, affecting 65%-80% by age 65, typically onsetting in the fourth or fifth decade. These manifestations include subtle spastic disturbances, mild leg weakness, sensory symptoms, and occasional issues, progressing more slowly than in males and rarely leading to severe disability.

Adrenal-only phenotype

The adrenal-only phenotype of X-linked adrenoleukodystrophy (X-ALD) refers to the presentation of isolated primary , also known as Addison disease, in the absence of neurological involvement. This form occurs in approximately 10% of affected males, where adrenal dysfunction manifests as the sole clinical feature, often preceding any cerebral or pathology by years or decades. In broader cohorts, up to 70-80% of males with X-ALD exhibit some degree of adrenal impairment prior to neurological symptoms, though only a subset remains truly isolated without progression. Symptoms typically emerge in childhood or , with a peak onset between ages 3 and 10 years, and include , , of due to elevated (ACTH), salt craving, and . In severe cases, an Addisonian crisis may occur, presenting with unexplained , weakness, or even , necessitating urgent medical intervention. These manifestations arise from and aldosterone deficiencies, leading to imbalances such as and , but without any evidence of demyelination on . Biochemically, this phenotype is characterized by low serum levels and markedly elevated ACTH, reflecting primary adrenocortical failure, alongside the diagnostic hallmark of X-ALD: elevated very long-chain fatty acids (VLCFAs) in . Unlike other X-ALD variants, shows no abnormalities, confirming the absence of cerebral involvement. involves lifelong and replacement therapy to stabilize hormone levels and prevent crises. In female carriers of X-ALD, isolated is rare, occurring in approximately 5% of cases and generally milder than in males, with symptoms limited to subtle endocrine disruptions rather than full-blown Addison disease. Most affected males with this eventually progress to adrenomyeloneuropathy or cerebral forms by , underscoring the need for ongoing monitoring.

Features in females

Female carriers of X-linked adrenoleukodystrophy (ALD), who are heterozygous for mutations in the ABCD1 gene, often remain in early life but can develop progressive neurological symptoms due to random X-chromosome inactivation, which may lead to skewed expression of the mutant allele in a significant proportion of cells. Studies indicate that more than 80% of female carriers develop resembling adrenomyeloneuropathy (AMN) by age 60, with symptom onset typically occurring in the fourth or fifth decade of life. This contrasts with the more severe, earlier-onset forms observed in affected males, highlighting the milder but still substantial burden in females. The most common manifestations in symptomatic female carriers include progressive spastic gait disturbance, affecting approximately 66% of cases, often accompanied by lower limb weakness and sensory disturbances such as numbness or in about 65%. neuropathic pain is reported in around 43% of affected women, contributing to reduced mobility and increased fall risk, while is evident in over 52%. Bladder and bowel dysfunction, including urinary urgency and incontinence, occur in up to 74% and 61% respectively, further impacting daily function. Cerebral involvement is rare, affecting less than 1% of female carriers and typically presenting with milder cognitive or behavioral changes compared to the aggressive childhood cerebral form in males. Adrenal insufficiency develops in approximately 5% of female carriers, usually with later onset than in males, and may manifest as , , or requiring hormone replacement. Recent post-2020 research underscores additional non-neurological burdens, with reported in 62% and issues such as or anxiety in 64% of symptomatic women, significantly diminishing and leading to barriers in healthcare access for nearly 90%. These findings emphasize the underrecognized progressive in female carriers, often managed supportively to alleviate symptoms and prevent complications.

Genetics

ABCD1 gene and protein function

The ABCD1 gene is located on the long arm of the at cytogenetic band , spanning approximately 19 kilobases and consisting of 10 exons. It encodes the adrenoleukodystrophy protein (ALDP), formally known as ATP-binding cassette subfamily D member 1 (ABCD1), a 745-amino-acid with a molecular weight of about 84 kDa. This gene belongs to the ATP-binding cassette ( superfamily, specifically the D subfamily, which is characterized by half-transporter architecture requiring homodimerization for full functionality. ABCD1 functions as a peroxisomal membrane half-transporter, mediating the ATP hydrolysis-dependent import of very long-chain fatty acyl-coenzyme A (VLCFA-CoA) esters from the cytosol into the peroxisomal lumen. Examples of transported substrates include CoA esters of saturated VLCFAs such as tetracosanoyl-CoA (C24:0-CoA) and hexacosanoyl-CoA (C26:0-CoA), which have chain lengths exceeding 22 carbons. Once inside the peroxisome, these VLCFA-CoA molecules are substrates for beta-oxidation, a process that iteratively shortens the fatty acid chains through sequential removal of two-carbon units, ultimately yielding shorter-chain fatty acids that can be further metabolized in mitochondria. This transport mechanism is essential for maintaining cellular lipid homeostasis, as peroxisomes are the primary site for VLCFA catabolism in humans. In normal cellular physiology, ABCD1's role prevents the toxic buildup of VLCFAs by ensuring their efficient degradation, thereby supporting integrity and energy production across tissues like the , adrenal glands, and testes. Structural studies reveal that ABCD1 forms a homodimer with a substrate- pocket that accommodates the hydrophobic VLCFA tail and the CoA headgroup, facilitating translocation across the peroxisomal via conformational changes driven by ATP and at the nucleotide-binding domains. Mutations in ABCD1 disrupt this half-transporter's function, leading to impaired VLCFA-CoA import and consequent VLCFA accumulation, though the precise biochemical consequences are addressed elsewhere.

Types of mutations

Adrenoleukodystrophy (ALD) is caused by pathogenic variants in the ABCD1 gene, with more than 1,200 unique variants reported across databases cataloging thousands of cases. The mutation spectrum is broad and heterogeneous, encompassing point mutations, small insertions/deletions, and larger structural changes, with no predominant hotspots identified despite some clustering in exons such as 1, 8, and 9. Among pathogenic variants, missense mutations are the most frequent, accounting for approximately 65% of cases, followed by frameshift variants at 15%, mutations at 9%, and splice-site alterations at 4%. These missense changes often result in substitutions that disrupt protein function, while and frameshift variants typically lead to premature termination and truncated proteins. Common recurrent variants include the frameshift p.Gln472Argfs83, observed in about 5% of reported cases, as well as mutations such as p.Arg518 (R518X) and p.Trp352* (W352X), though most variants remain private to individual families with evidence of familial clustering rather than population-wide hotspots. Genotype-phenotype correlations in ALD are limited, as the same ABCD1 variant can manifest as diverse phenotypes within families, such as childhood cerebral ALD (CCALD) in one affected male and adrenomyeloneuropathy (AMN) in another, suggesting the influence of modifier genes or environmental factors. For instance, certain missense mutations like p.Arg554His have been associated with both cerebral and adult-onset forms across kindreds. Molecular detection of ABCD1 variants achieves high sensitivity, with genomic sequencing identifying over 95% of pathogenic changes, while rare large deletions or duplications (comprising about 2-5% of cases) require additional gene-targeted methods like (MLPA). This comprehensive approach ensures robust variant identification for and family studies.

Pathophysiology

VLCFA accumulation mechanisms

Adrenoleukodystrophy (ALD), specifically X-linked ALD, arises from mutations in the ABCD1 gene, which encodes the peroxisomal membrane protein ALDP responsible for transporting very long-chain fatty acyl-CoAs (VLCFA-CoAs) into peroxisomes for beta-oxidation. Defects in ALDP impair this transport, preventing the degradation of VLCFAs—saturated fatty acids with chain lengths of 22 or more carbons—leading to their accumulation in various cellular compartments, including the and lysosomes. This failure in peroxisomal beta-oxidation is the primary biochemical disruption, as peroxisomes are the sole site for shortening VLCFAs, while shorter-chain fatty acids are oxidized in mitochondria. Among VLCFAs, hexacosanoic acid (C26:0) is particularly elevated, often 5- to 10-fold higher in plasma compared to controls, serving as a key biomarker. Diagnostic assessments commonly use ratios such as C26:0 to behenic acid (C22:0) to quantify this buildup, reflecting the impaired oxidation pathway. Secondary effects of VLCFA accumulation include disruptions in lipid metabolism; for instance, excess VLCFAs incorporate into complex lipids, impairing plasmalogen synthesis—a peroxisomal process essential for membrane structure—due to reduced availability of acyl-CoA substrates. Similarly, VLCFAs esterify with cholesterol, leading to abnormal cholesterol ester accumulation that alters membrane fluidity and function. Tissue specificity of VLCFA accumulation is pronounced in the white matter, , and testes (particularly Leydig cells), where levels of VLCFA-containing , such as with C26:0, can increase up to 17-fold in affected regions. In the , VLCFA-cholesterol esters rise dramatically to about 30% of total esters (versus 1-3% in controls), contributing to localized metabolic imbalances. This selective buildup underscores the vulnerability of these steroidogenic and myelinating tissues to peroxisomal dysfunction.

Neurological and adrenal damage

In X-linked adrenoleukodystrophy (X-ALD), the accumulation of very long-chain fatty acids (VLCFAs) leads to their incorporation into complex lipids within myelin sheaths, destabilizing these structures and impairing their integrity. This destabilization triggers a robust neuroinflammatory response, characterized by the activation of microglia, which release pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α). Microglial activation further exacerbates tissue damage by promoting the recruitment of T-lymphocytes and peripheral macrophages, amplifying the inflammatory cascade in affected brain regions. VLCFA accumulation also induces mitochondrial dysfunction and oxidative stress, exacerbating axonal damage and inflammation. The demyelination process in cerebral X-ALD follows a distinct pattern, beginning with dysfunction that manifests as responses, including elevated expression of heat shock proteins, prior to significant loss. This early impairment disrupts supportive functions for , contributing to progressive breakdown and axonal vulnerability. Concurrently, the blood-brain barrier undergoes breakdown, allowing on MRI and facilitating immune infiltration, which intensifies the inflammatory demyelination. In the adrenal glands, VLCFA accumulation exerts direct toxicity on cells of the and zona reticularis, leading to cellular , glandular , and subsequent deficiency. This selective damage spares the but results in primary , a common early manifestation in affected males. Due to its X-linked inheritance, X-ALD exhibits sex-specific pathology in s, where skewed X-chromosome inactivation can lead to patterns of ABCD1 expression in tissues, resulting in heterogeneous VLCFA accumulation and variable degrees of neurological or adrenal damage. Highly skewed inactivation correlates with increased risk of clinical manifestations in female carriers, observed in 32% of a small cohort of carriers (symptomatic and asymptomatic) in a 2002 study and 18.6% of female patients in a 2025 analysis.

Diagnosis

Biochemical testing

The primary biochemical test for diagnosing adrenoleukodystrophy (ALD) is the measurement of very long-chain fatty acids (VLCFAs) in , which detects the characteristic accumulation due to impaired peroxisomal beta-oxidation. This assay serves as the initial screening tool for at-risk individuals, including newborns, symptomatic patients, and family members, and is essential for confirming suspicion before proceeding to genetic analysis. The gold standard method is gas chromatography-mass spectrometry (GC-MS) analysis of for hexacosanoic acid (C26:0) and related VLCFAs, often including ratios such as C26:0/C22:0 and C24:0/C22:0 to enhance specificity. In ALD, C26:0 levels are markedly elevated, while pristanic acid remains within normal limits, distinguishing it from other peroxisomal disorders like Zellweger spectrum disorder where pristanic acid is also increased. reference ranges for plasma C26:0 typically indicate normal values up to 0.3 μg/mL (approximately 0.8 μmol/L), with levels exceeding 0.4 μg/mL (about 1.05 μmol/L) diagnostic in hemizygous males; in heterozygous females, levels above 0.2 μg/mL are suggestive but require cautious interpretation due to variable expression. The C26:0/C22:0 ratio further refines , with values greater than 0.02 considered abnormal in most labs. A more sensitive complementary biomarker is C26:0-lysophosphatidylcholine (C26:0-LPC), measured via liquid chromatography-tandem mass spectrometry (LC-MS/MS) in or dried blood spots. This detects elevations in nearly 100% of affected males and over 85% of carriers, outperforming traditional VLCFA testing, which shows normal levels in 10-20% of carriers due to . C26:0-LPC is the standard for in many programs and aids in early carrier detection. Complementary tests include VLCFA measurement in membranes, which can corroborate plasma findings in select cases, and functional assays in cultured fibroblasts, where elevated VLCFA accumulation confirms the defect, particularly for assessing variants of uncertain significance. cultures are grown under standard conditions and analyzed via GC-MS to quantify VLCFA levels, providing a cellular-level validation. A key limitation is that approximately 10-20% of female carriers show normal plasma VLCFA levels due to favorable X-chromosome inactivation skewing. For prenatal diagnosis in at-risk pregnancies, VLCFA or C26:0-LPC assays can be performed on cultured amniocytes obtained via or on chorionic villus samples, enabling early detection as early as the first when combined with . These biochemical approaches must be interpreted in clinical context, as nonfasting samples or certain dietary factors can influence results.

Neuroimaging

Magnetic resonance imaging (MRI) is the primary neuroimaging modality for detecting and characterizing cerebral adrenoleukodystrophy (CALD), revealing characteristic T2-weighted hyperintensities in the parieto-occipital white matter regions, often involving the splenium of the corpus callosum. These lesions typically progress from the occipital lobes anteriorly and superiorly, reflecting demyelination and associated inflammatory pathology. Gadolinium contrast enhancement at the advancing edge of these lesions indicates active inflammation due to blood-brain barrier disruption, serving as a marker of disease activity. The Loes score provides a semiquantitative of burden on brain MRI, ranging from 0 (normal) to 34, with each cerebral region scored as 0 for normal, 0.5 for unilateral involvement, or 1 for bilateral involvement or . A Loes score greater than 9 at is associated with poor neurologic outcomes in untreated CALD patients. This scoring system aids in monitoring disease progression and guiding therapeutic decisions, such as eligibility for . In adrenomyeloneuropathy (AMN), spinal cord MRI often demonstrates and T2 hyperintense signal changes, particularly in the thoracic , indicating degenerative involvement of long tracts. These findings correlate with clinical symptoms of spastic paraparesis and sensory deficits, though brain MRI may remain normal in pure AMN cases. Advanced techniques like diffusion tensor imaging (DTI) enhance early detection by identifying microstructural changes, such as reduced , prior to conventional MRI abnormalities in presymptomatic boys with ALD. DTI metrics also correlate with severity and neurocognitive outcomes in CALD. For adrenal involvement, computed tomography () can reveal bilateral adrenal or calcifications in patients with insufficiency, supporting clinical evaluation.

Genetic confirmation

Genetic confirmation of X-linked adrenoleukodystrophy (X-ALD) is achieved through molecular of the ABCD1 gene, which identifies pathogenic variants responsible for the . This testing is recommended following presumptive based on clinical or biochemical findings, providing definitive proof of the . In hemizygous males, detection of a single pathogenic variant confirms the , while in females, identification of a heterozygous variant establishes carrier status, though symptomatic females may require correlation with clinical features. The primary testing methods include next-generation sequencing (NGS) for detecting point mutations, small insertions/deletions, and other sequence variants, which account for approximately 97.5% of ABCD1 pathogenic variants. For the remaining cases involving larger deletions or duplications, is employed to assess copy number variations. Overall sensitivity exceeds 99% in hemizygous males when combining these approaches. In heterozygous females, challenges arise due to potential skewed X-chromosome inactivation, where allele-specific assays may be used to evaluate expression patterns and aid interpretation of variant pathogenicity. Cascade testing is essential for at-risk relatives of an with a known familial ABCD1 variant, enabling early identification of affected males and carrier females to inform clinical monitoring and . This process typically involves targeted sequencing of the specific variant in siblings, maternal relatives, and offspring. Prenatal diagnosis is available through (CVS) at 10-13 weeks gestation or at 15-18 weeks, allowing direct ABCD1 testing on fetal DNA once the familial variant is known. Postnatally, genetic confirmation can be performed on newborn blood spots or peripheral blood, particularly in contexts integrating with programs.

Management

Hematopoietic stem cell transplantation

(HSCT) is the established for treating early-stage childhood cerebral adrenoleukodystrophy (CCALD), offering a potential cure by halting neurological progression in presymptomatic or early symptomatic cases. It is indicated for boys with gadolinium-enhanced MRI lesions and a Loes score of 0.5 to 9, alongside a neurologic score (NFS) of 0 or 1, typically before age 8 to maximize efficacy; it is not recommended for advanced disease (Loes score >9 or NFS >1) or adrenomyeloneuropathy (AMN) phenotypes due to poor outcomes. The procedure involves myeloablative conditioning regimens, such as combined with or , to eradicate the patient's hematopoietic cells, followed by infusion of allogeneic stem cells from a (HLA)-matched donor, including related siblings (preferred), unrelated , or umbilical blood. This replaces defective with donor-derived cells expressing functional ABCD1 protein, thereby normalizing very long-chain fatty acid (VLCFA) metabolism in the and preventing further demyelination. Outcomes are most favorable when HSCT is performed early, with 5-year overall rates of 78% to 89% in patients with Loes scores below 10 and no or minimal symptoms, compared to 55% without ; major functional disability-free reaches 84% at 2 years for early gadolinium-positive cases. Neurological stabilization occurs in 70% to 90% of young patients (<8 years) treated promptly, with resolution of gadolinium enhancement in 93% within 4 months and minimal NFS progression (change ≤3) in the majority at 2 years post-transplant. However, risks include transplant-related mortality of 5% to 10% within the first year (primarily from infection or disease progression), graft failure in up to 17% (higher with cord blood), and acute graft-versus-host disease (GVHD) in 18% of cases, with chronic GVHD affecting 20% to 30%. Recent advances in the 2020s have expanded donor options, demonstrating comparable success with unrelated donors (event-free survival up to 71% post-2013) and reduced-intensity conditioning protocols like busulfan/fludarabine, which lower toxicity while achieving stable engraftment and >80% donor chimerism in most patients. These developments have improved accessibility for those without matched siblings, though long-term monitoring for secondary malignancies remains essential.

Gene therapy

Gene therapy for adrenoleukodystrophy (ALD) represents an autologous approach to address the underlying ABCD1 gene mutation, primarily targeting early cerebral ALD (CALD) in male patients. The therapy involves of the patient's own + hematopoietic stem cells (HSCs) with a lentiviral vector, such as Lenti-D, encoding a functional copy of the ABCD1 gene, which restores peroxisomal very long-chain (VLCFA) and aims to halt neurological progression by enabling microglia replacement in the brain. Following , the modified HSCs are reinfused after myeloablative conditioning, similar to (HSCT) but using the patient's cells to avoid donor-related risks. Elivaldogene autotemcel (eli-cel; trade name Skysona) is the primary gene therapy product developed for this purpose. The U.S. (FDA) granted accelerated approval to Skysona on September 16, 2022, for slowing neurologic dysfunction in boys aged 4-17 years with early, active CALD who lack a suitable HSCT donor; in August 2025, the FDA updated the labeling with warnings for hematologic malignancy risk. This approval was based on surrogate endpoints like enhancement on MRI and Loes score stabilization, with continued approval contingent on confirmatory trials. Clinical trial data from the phase 2/3 ALD-102 study (Starbeam) and phase 3 ALD-104 study demonstrated efficacy in halting disease progression. In ALD-102, 87% of 23 evaluable boys achieved major functional disability (MFD)-free survival at 24 months post-infusion, compared to rapid deterioration in natural history controls. Longer-term follow-up across trials showed 81% MFD-free survival at 4 years among 67 treated patients, indicating durable stabilization of neurological function and VLCFA normalization in some cases. Integration site analysis is ongoing to monitor clonal expansion, as 10 of 67 patients (15%) developed hematologic malignancies by July 2025, prompting FDA-mandated labeling changes. Current limitations include its restriction to early CALD in males, with no approval for symptomatic females, adrenomyeloneuropathy (AMN), or advanced disease phenotypes. Long-term and data remain under evaluation as of 2025, with phase 3 confirmatory results expected to inform full approval.

Dietary therapies

, a dietary developed for X-linked adrenoleukodystrophy (ALD), consists of a 4:1 mixture of glyceryl trioleate () and glyceryl trierucate (), derived from and oils, respectively. This formulation inhibits the elongase ELOVL1, which is responsible for the of very long-chain fatty acids (VLCFAs), thereby reducing their accumulation in and tissues. specifically competes with saturated fatty acids in the elongation pathway, further lowering VLCFA production. In presymptomatic boys with ALD, normalizes plasma VLCFA levels in the majority of cases, typically within 4 weeks of administration. A follow-up study of 89 patients showed that this normalization was associated with a reduced of developing MRI abnormalities indicative of cerebral involvement. However, clinical remains limited: while it may delay the onset of adrenomyeloneuropathy (AMN) in some individuals, it has not demonstrated proven benefits in preventing cerebral ALD progression or halting neurological deterioration in symptomatic patients. Common side effects include , which can lead to low platelet counts but is generally reversible upon discontinuation, and occasional lymphopenia. Other dietary interventions include low-VLCFA diets, which restrict intake of foods high in these fatty acids to further modulate levels, often showing reductions in plasma VLCFA concentrations when adhered to strictly. supplementation alone has been explored as an alternative, demonstrating the ability to lower hexacosanoate (C26:0) levels in both affected males and female carriers. Experimental approaches combining these diets with statins, such as , aim to enhance VLCFA reduction by lowering cholesterol synthesis, though evidence for clinical benefits is inconclusive and primarily biochemical. Current guidelines, informed by long-term observational data, recommend and similar dietary therapies as adjunctive measures for presymptomatic males with normal brain MRI, but not as standalone treatments, emphasizing the need for regular VLCFA monitoring via biochemical testing. These interventions do not address or advanced disease stages.

Pharmacological and supportive care

Pharmacological management for adrenoleukodystrophy (ALD), particularly in non-curative phenotypes such as adrenomyeloneuropathy (AMN), focuses on alleviating symptoms to improve rather than altering disease progression. , a common feature in AMN, is typically treated with spasmolytics like , which can be administered orally or intrathecally in severe cases to reduce muscle stiffness and improve mobility. , often affecting the lower limbs, is managed with anticonvulsants such as or , which help mitigate sensory disturbances and enhance daily functioning. Additionally, men with AMN experiencing may benefit from phosphodiesterase-5 inhibitors like , which have demonstrated in improving in this population. Efforts to target underlying inflammation and through pharmacological means have yielded mixed results. Clinical trials exploring agents, including nonsteroidal anti-inflammatory drugs like ibuprofen and antibiotics with properties such as , have generally failed to demonstrate significant benefits in slowing ALD progression or improving neurological outcomes. In contrast, antioxidants like N-acetylcysteine () have shown promise as adjunctive therapy, particularly in advanced cerebral ALD, by reducing oxidative damage and improving survival when combined with ; ongoing investigations explore its role in AMN to address contributing to axonal degeneration. Supportive care plays a crucial role in managing AMN symptoms and preventing complications. Physical and are essential to maintain muscle strength, prevent contractures, and support stability, often incorporating assistive devices like walkers or braces. dysfunction, prevalent in AMN due to involvement, requires urological evaluation and management strategies such as timed voiding, medications, or intermittent catheterization to avoid urinary tract infections and incontinence. Psychological support, including counseling and access to specialists, addresses the emotional burden of progressive , with groups providing additional resources for coping and family dynamics. As of 2025, no disease-modifying pharmacological treatments are approved specifically for AMN, though emerging therapies targeting and remyelination are under investigation. For instance, leriglitazone, a PPAR gamma agonist with and neuroprotective effects, has shown reductions in gait impairment and neurofilament light chain levels in phase 2/3 trials for early-symptomatic AMN patients, offering potential to slow progression. In July 2025, a Marketing Authorization Application for leriglitazone in CALD was submitted to and validated by the , with approval pending as of November 2025. These advancements complement dietary therapies like , which may serve as an adjunct but lack proven long-term benefits in symptomatic AMN.

Adrenal insufficiency management

Adrenal insufficiency affects approximately 70-80% of males with X-linked adrenoleukodystrophy over their lifetime, necessitating routine screening and lifelong management to prevent life-threatening adrenal crises. Screening begins shortly after , typically with early morning and (ACTH) levels measured every 3-6 months in children under 10 years, transitioning to annual assessments thereafter, alongside monitoring of electrolytes and to detect deficiency. In cases of borderline results, an (using cosyntropin) is recommended annually or as needed to confirm subclinical insufficiency, with particular attention to growth parameters in pediatric patients. , while effective for cerebral disease, does not halt the progression of adrenal dysfunction, requiring ongoing endocrine surveillance post-procedure. Glucocorticoid replacement forms the cornerstone of therapy, with administered at a daily dose of 8-12 mg/m² in children, divided into three doses to mimic physiologic rhythms and minimize side effects such as growth suppression. In adults, dosing typically ranges from 15-25 mg per day, adjusted based on clinical response, weight, and symptoms like or . replacement with (0.05-0.2 mg daily) is indicated only if there is evidence of aldosterone deficiency, such as elevated renin levels, , or , and is not routinely required in all ALD patients due to variable involvement of the . Patients and families should receive education on recognizing crisis symptoms (e.g., , ) and carrying medical alert identification. During periods of , such as acute illness, fever, or , stress dosing is essential to prevent , involving an increase to 2-3 times the baseline dose orally (e.g., 50-100 mg/m² per day divided every 6-8 hours), or intramuscular/intravenous administration if oral intake is impossible. Post-stress, doses are tapered back to maintenance levels over 2-3 days, with close monitoring of and electrolytes to avoid over-replacement complications like or . Long-term management emphasizes individualized adjustments by an endocrinologist, with periodic reassessment to optimize hormone levels and .

Prognosis

Outcomes by phenotype

Childhood cerebral adrenoleukodystrophy (CCALD) represents the most severe , typically manifesting between ages 4 and 10 years. Without intervention, the disease progresses rapidly, leading to profound neurological within 6 months to 2 years of symptom onset, with approximately 30-40% mortality within 5 years post-diagnosis due to respiratory complications or . (HSCT), when performed early in the disease course, significantly improves outcomes, achieving 5-year survival rates exceeding 80% and preserving major functional abilities in over 90% of cases at early stages. with elivaldogene autotemcel, approved in 2022, has shown approximately 80% major functional -free survival at 4 years in early cases, though with a noted 15% risk of hematologic malignancies as of 2025. Adrenomyeloneuropathy (AMN), the adult-onset phenotype, usually begins in the third or fourth decade of life with progressive spastic paraparesis, sensory disturbances, and bladder dysfunction. Median survival ranges from 50 to 60 years, though many individuals live into their 60s or beyond with supportive care, albeit with accumulating morbidity. advances gradually, with most patients requiring assistive devices for ambulation within 10 to 15 years of onset and eventual dependency in advanced stages, severely impacting mobility and . The Addison-only phenotype, characterized by isolated primary adrenal insufficiency without initial neurological involvement, affects approximately 10% of males, often presenting in childhood or adolescence. With and replacement therapy, individuals achieve a normal lifespan comparable to the general population. However, the majority (approximately 70-90%) will eventually progress to neurological manifestations, such as AMN or cerebral disease, over decades, necessitating ongoing monitoring. Symptomatic heterozygous females, who comprise carrier mothers and sisters, exhibit a milder due to random , with approximately 20-50% developing AMN-like symptoms such as progressive leg stiffness, weakness, and by age 60, increasing to about 65% by age 65. These manifestations typically onset after age 30 and progress slowly, leading to moderate that affects daily activities and but rarely results in severe or high mortality; overall survival approaches that of unaffected females.

Prognostic factors

The prognosis of X-linked adrenoleukodystrophy (ALD) is influenced by several key clinical and imaging factors, particularly in the cerebral form, where early can significantly alter outcomes. Age at onset plays a critical role, with earlier presentation in childhood cerebral ALD (typically 4-8 years) associated with more rapid progression and poorer compared to adolescent or adult-onset cases. In presymptomatic boys, the risk of cerebral involvement peaks between ages 3 and 12, underscoring the need for vigilant monitoring. Brain magnetic resonance imaging (MRI) findings are among the strongest predictors of disease trajectory. The Loes score, which quantifies the extent of demyelination on a scale from 0 to 34, is particularly prognostic; scores below 4 at the time of treatment initiation correlate with the best stabilization or halting of progression following interventions like hematopoietic stem cell transplantation. Gadolinium enhancement on MRI, indicating active inflammation at the lesion's leading edge, signals aggressive disease and is linked to faster neurological decline if untreated. Genetically, while over 1,000 pathogenic variants in the ABCD1 gene have been identified, there is no established strong between specific and clinical phenotypes, making prediction challenging based on alone. However, family history remains predictive, as the X-linked inheritance pattern allows for risk stratification in relatives of affected individuals. Early diagnosis through programs markedly improves outcomes by enabling presymptomatic detection and timely , reducing the incidence of advanced cerebral involvement. Sex differences confer a protective effect in females, who are heterozygous carriers and typically develop milder symptoms, such as adrenomyeloneuropathy in adulthood, rather than the severe cerebral form seen predominantly in hemizygous males. Recent advancements as of 2025 highlight as an emerging for monitoring progression. NfL levels, measurable via ultrasensitive assays, establish a in presymptomatic boys with ALD; a sustained increase of over 50% above indicates early cerebral disease activation, often preceding MRI changes, and correlates with inflammatory activity and therapeutic response. Higher pre-treatment NfL concentrations are associated with inferior post-hematopoietic transplantation outcomes, positioning it as a tool for risk stratification and reduced reliance on frequent imaging.

Epidemiology

Global prevalence

Adrenoleukodystrophy (ALD), an X-linked peroxisomal disorder, has a global birth prevalence estimated at approximately 1 in 17,000 newborns, encompassing both males and females. This figure aligns with data from programs in high-resource settings, where the incidence among male newborns specifically ranges from 1 in 14,000 to 1 in 17,000. In the United States, aggregate results from multiple state newborn screening initiatives indicate a slightly higher overall incidence of about 1 in 10,500 births, reflecting improved detection of cases without prior family history. Similarly, programs, such as those in , report prevalences in the range of 1 in 15,000 to 1 in 17,000. Among affected males, nearly all will develop symptoms by adulthood, with an estimated prevalence of approximately 1 in 15,000 individuals worldwide. However, underdiagnosis remains a significant issue in low-resource regions due to limited access to and diagnostic tools, leading to lower reported rates; for instance, literature reviews show fewer documented cases in large populations like compared to smaller cohorts in , despite comparable expected incidences. Prevalence rates appear stable across global populations, with no major ethnic variations reported, though rare founder effects may occur in isolated communities. This uniformity underscores the disorder's pan-ethnic distribution, primarily driven by mutations in the ABCD1 gene without strong geographic clustering.

Demographic patterns

Adrenoleukodystrophy (ALD) exhibits distinct patterns of expression influenced by , with males who are hemizygous for the ABCD1 mutation universally affected, manifesting clinical phenotypes by adulthood in nearly all cases. In contrast, female carriers, who are heterozygous, experience variable ; approximately 80-85% develop neurological symptoms, primarily and , with the proportion increasing age-dependently from about 20% in early adulthood to over 80% by age 60. This age-related progression in females underscores the progressive nature of the disease even in carriers, often leading to supportive care needs in later life. Age at onset varies significantly across ALD phenotypes, particularly in males. The cerebral form typically peaks between ages 4 and 10 years, presenting with rapid neurological deterioration if untreated. Adrenomyeloneuropathy (AMN), the most common adult phenotype, usually emerges in the 30s to 40s, with average onset around 28-35 years, characterized by progressive spastic paraparesis and . , a frequent early manifestation, often appears in childhood, affecting up to 80% of boys before neurological symptoms. These temporal patterns highlight the importance of phenotype-specific monitoring, as cerebral ALD requires early intervention to alter progression. The disease shows uniform prevalence across ethnic groups worldwide, with no significant variations attributable to or in underlying incidence. However, detection rates differ markedly due to screening availability; in the United States, where is implemented in most states, the estimated incidence is approximately 1 in 10,000 male births, reflecting higher ascertainment. In unscreened regions such as parts of , estimates suggest a lower reported rate of around 1 in 30,000, likely due to underdiagnosis rather than true prevalence differences. Recent studies as of 2025 have increasingly highlighted the burden on female carriers, with expanded cohorts revealing that symptoms like affect significantly, often diagnosed in the late 30s, prompting greater emphasis on carrier surveillance and support. This growing recognition stems from longitudinal data showing age-dependent symptom accumulation, influencing family planning and clinical guidelines.

Screening and prevention

Newborn screening programs

Newborn screening programs for X-linked adrenoleukodystrophy (X-ALD) utilize to detect elevated levels of C26:0-lysophosphatidylcholine (Lyso-C26:0), a derived from very-long-chain fatty acids, in dried blood spots collected from newborns typically between 24 and 48 hours after birth. This method offers high sensitivity for identifying affected individuals early, allowing for timely intervention to prevent or mitigate disease progression, such as or cerebral involvement.01535-5/fulltext) The assay is integrated into existing newborn screening panels as a first-tier test, often followed by a second-tier confirmation if initial results are elevated, to minimize false positives. Adoption of ALD newborn screening has advanced significantly, particularly in the United States, where it was added to the Recommended Uniform Screening Panel by the Advisory Committee on Heritable Disorders in Newborn and Children in 2016, endorsed by the American College of Medical Genetics and Genomics (ACMG). As of 2025, 46 states and the District of Columbia have implemented mandatory screening for all newborns, reflecting widespread recognition of its value in early detection. In Europe, implementation remains partial and varies by country; for example, the Netherlands initiated nationwide screening for male newborns in October 2023, while Italy has conducted a pilot program in the Lombardy region since 2021, screening over 138,000 newborns by mid-2025 with plans for broader expansion. Upon a positive screen, infants undergo confirmatory testing, including plasma very-long-chain (VLCFA) analysis and ABCD1 genetic sequencing, to verify the and determine sex-specific risks. Affected males and females are then referred for clinical evaluation, including adrenal function assessments, with immediate family counseling to discuss patterns and testing for relatives. These programs demonstrate high , identifying nearly all affected males (sensitivity approaching 100%) and approximately 80-85% of female s through biochemical markers, though genetic confirmation is essential for full accuracy. Moreover, the addition of ALD screening to standard panels is cost-effective, with an incremental cost of about $5-10 per test, enabling broad population coverage at minimal expense.

Carrier testing and counseling

Carrier testing for X-linked adrenoleukodystrophy (ALD) primarily involves molecular genetic of the to identify heterozygous pathogenic in females at risk due to family history. For families with a known familial , targeted sequencing or testing for the specific variant is recommended to confirm status efficiently. In cases of without prior family identification, full sequencing and deletion/duplication of ABCD1 is necessary to detect potential variants comprehensively. Biochemical testing using plasma very long-chain fatty acids (VLCFA) can support detection but has limited sensitivity in females, identifying approximately 80-85% of due to X-chromosome inactivation patterns that may normalize VLCFA levels in 15-20% of heterozygous individuals. via ABCD1 sequencing achieves near-complete detection rates, exceeding 97% for pathogenic variants, making it the preferred method over biochemical assays for accurate identification. Rare cases of "escapees," where non-inactivation of the mutant X-chromosome leads to atypical presentations, occur but affect fewer than 5% of and require additional evaluation. Genetic counseling is essential for ALD families, providing based on the X-linked pattern, where carrier females have a 50% chance of transmitting the ABCD1 variant to each child (sons affected, daughters carriers). Counselors discuss reproductive options, including prenatal genetic diagnosis via or , and (PGD) during in vitro fertilization to select unaffected embryos. Psychological support is emphasized for presymptomatic carriers, addressing emotional impacts such as anxiety over potential transmission or late-onset symptoms like adrenomyeloneuropathy. As of 2025 guidelines, testing is recommended for all female relatives of diagnosed individuals to facilitate early and risk stratification. Annual , including adrenal function tests and neurologic assessments, is advised for identified carriers starting in adulthood to detect any emerging symptoms promptly, though routine screening for cerebral involvement is not indicated in asymptomatic females.