X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal metabolic disorder caused by mutations in the ABCD1 gene, leading to accumulation of very long-chain fatty acids (VLCFAs, C22:0 to C26:0) in plasma and tissues including the brain, spinal cord, and adrenal [cortex](/brain-regions/cortex). It is one of the most common peroxisomal disorders, with an incidence of approximately 1 in 17,000 live births. [@moser2000][@dubey2021]
X-ALD affects multiple organ systems, particularly the nervous system and adrenal glands. The disease spectrum includes four main phenotypes:
| Phenotype | Onset Age | Prevalence | Key Features | |-----------|-----------|------------|---------------| | Childhood cerebral ALD (cALD) | 3-10 years | ~35% of males | Rapid demyelination, cognitive decline, adrenal insufficiency | | Adrenomyelopathy (AMN) | 20-40 years | ~40% of males | Progressive spinal cord disease, bladder dysfunction, gait disturbance | | Addison's disease | Any age | ~50% of males | Primary adrenal insufficiency, often precedes neurological symptoms | | Adult cerebral ALD | >18 years | ~5% of males | Progressive demyelination, behavioral changes, dementia |
The ABCD1 gene on chromosome Xq28 encodes the peroxisomal ATP-binding cassette transporter D1 (ALDP), which is essential for importing very long-chain fatty acyl-CoA synthetase into peroxisomes for beta-oxidation. Loss of ALDP function blocks peroxisomal VLCFA metabolism. [@moser2000][@kemp2016]
X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal metabolic disorder caused by mutations in the ABCD1 gene, leading to accumulation of very long-chain fatty acids (VLCFAs, C22:0 to C26:0) in plasma and tissues including the brain, spinal cord, and adrenal [cortex](/brain-regions/cortex). It is one of the most common peroxisomal disorders, with an incidence of approximately 1 in 17,000 live births. [@moser2000][@dubey2021]
X-ALD affects multiple organ systems, particularly the nervous system and adrenal glands. The disease spectrum includes four main phenotypes:
| Phenotype | Onset Age | Prevalence | Key Features | |-----------|-----------|------------|---------------| | Childhood cerebral ALD (cALD) | 3-10 years | ~35% of males | Rapid demyelination, cognitive decline, adrenal insufficiency | | Adrenomyelopathy (AMN) | 20-40 years | ~40% of males | Progressive spinal cord disease, bladder dysfunction, gait disturbance | | Addison's disease | Any age | ~50% of males | Primary adrenal insufficiency, often precedes neurological symptoms | | Adult cerebral ALD | >18 years | ~5% of males | Progressive demyelination, behavioral changes, dementia |
The ABCD1 gene on chromosome Xq28 encodes the peroxisomal ATP-binding cassette transporter D1 (ALDP), which is essential for importing very long-chain fatty acyl-CoA synthetase into peroxisomes for beta-oxidation. Loss of ALDP function blocks peroxisomal VLCFA metabolism. [@moser2000][@kemp2016]
Genetics
ABCD1 Gene
The ABCD1 gene (ATP-binding cassette subfamily D member 1) spans approximately 20 kb on chromosome Xq28. It encodes a 745-amino-acid peroxisomal membrane protein belonging to the ATP-binding cassette (ABC) transporter family. ALDP forms homodimers that transport VLCFA-CoA synthetase from the cytosol into the peroxisomal matrix. [@kemp2016]
Mutation Spectrum
Over 900 pathogenic variants have been identified in ABCD1, distributed throughout the gene with no clear mutational hot spot: [@kemp2016]
Missense mutations: ~60% of cases — affect protein folding, trafficking, or function
Nonsense mutations: ~15% — premature stop codons, complete loss of function
ABCD1 sequencing: Confirms diagnosis and identifies specific variant
Deletion/duplication analysis: For cases with no point mutation identified
Newborn screening: Implemented in many US states and countries using C26:0-lyso-PC from dried blood spots [@wodski2020]
Imaging
MRI brain: Detects cerebral demyelination in cALD (confluent white matter changes, contrast enhancement at advancing edge)
MRI spine: Shows spinal cord atrophy in AMN
Management
Disease-Modifying Treatments
Hematopoietic stem cell transplantation (HSCT): For early cALD — can halt progression if performed before extensive demyelination [@cartier2015]
Gene therapy (Skysona/Lenti-D): Autologous HSCT with lentiviral ABCD1 gene correction — FDA-approved for cALD in children not eligible for HSCT [@cartier2015]
HSCT from unrelated donors: Alternative when no matched sibling donor
Supportive Care
Adrenal steroid replacement: Essential for all males with adrenal insufficiency