副腎白質ジストロフィー

X-linked adrenoleukodystrophy (ALD) is an inherited peroxisomal disorder caused by pathogenic variants in the ABCD1 gene, encoding a peroxisomal membrane transporter required for the import of very-long-chain fatty acids (VLCFA) into peroxisomes for degradation. ABCD1 deficiency leads to VLCFA accumulation in plasma and tissues. The resulting disease has a highly variable clinical presentation. In males, this manifests as cerebral demyelination, progressive myelopathy, and adrenal insufficiency, alone or in combination. Women predominantly develop myelopathy, while cerebral disease and adrenal insufficiency are rare, occurring almost exclusively in cases of extreme X-inactivation skewing toward the mutant allele. The lipid-mediated mechanisms linking VLCFA accumulation to tissue-specific pathology remain incompletely understood. Here, we review evidence that VLCFA-containing complex lipids, rather than free VLCFAs alone, are central mediators of tissue-specific pathology in ALD and discuss the therapeutic implications of this lipid-centric perspective. VLCFAs are incorporated into a broad range of complex lipids, including phosphatidylcholines, lysophosphatidylcholines, cholesterol esters, triacylglycerols, sphingomyelins, ceramides, and plasmalogens. The degree of lipid dysregulation increases with acyl chain length and saturation. VLCFA-containing lipid species correlate with disease severity across all clinical phenotypes. In the brain, VLCFA-containing phosphatidylcholines accumulate before demyelination onset, cholesterol ester accumulation is associated with neuroinflammatory cascades, and plasmalogen depletion reflects early oxidative damage. In the spinal cord, VLCFA-containing myelin lipids are associated with non-inflammatory axonopathy, mitochondrial dysfunction, and microglial phagocytic activation. In the adrenal gland, VLCFA accumulation in cholesterol ester-rich lipid droplets impairs ACTH receptor signaling and sequesters cholesterol from steroidogenic pathways. Enzymatic regulators of VLCFA homeostasis, including ELOVL1, SCD1, and the omega-oxidation enzymes CYP4F2 and CYP4F3B, are potential therapeutic targets for substrate reduction. Plasma VLCFA-lipid profiles correlate with disease severity across all affected tissues, positioning lipidomic profiling as a potential clinical instrument for risk stratification and treatment monitoring. Secondary lipid mediators amplify primary VLCFA toxicity through distinct, cell-type-specific pathways. The near-exclusive occurrence of cerebral ALD and adrenal insufficiency in women with extreme X-inactivation skewing suggests that partial reduction of the VLCFA lipid burden, rather than complete normalization, may be sufficient to prevent severe disease manifestations. This has direct implications for substrate-reduction therapy development.

BACKGROUND: Leukodystrophies are inherited disorders that primarily affect the central nervous system white matter and often present with nonspecific symptoms, making early diagnosis difficult. Magnetic resonance imaging (MRI) is the key initial imaging test because it reveals characteristic myelin patterns that can guide biochemical and genetic workups. OBJECTIVE: To review clinically useful MRI and MR spectroscopy (MRS) patterns in major leukodystrophies and emphasize their diagnostic relevance using a practical, pattern-recognition approach. METHODS: Narrative review of the literature integrating conventional MRI, including T1/T2 fluid-attenuated inversion recovery (FLAIR), and diffusion-weighted imaging (DWI), as well as advanced techniques (MRS), with a pictorial, case-based approach. RESULTS: The pivotal imaging distinction is between hypomyelination-diffuse, persistent T2/FLAIR hyperintensity with relative temporal stability and absent enhancement-and demyelination, characterized by confluent, progressive lesions with disorder-specific topographic predilection. Recognizable signatures include U-fiber sparing and a tigroid pattern in metachromatic leukodystrophy (MLD); parieto-occipital predominance with trizonal enhancement and restricted diffusion in X-linked adrenoleukodystrophy (X-ALD); frontal predominance and the "tadpole sign" in Alexander's disease; optic pathway and thalamic involvement in Krabbe's disease; markedly elevated N-acetylaspartate (NAA) on MRS in Canavan's disease; and tract-selective leukoencephalopathy brainstem/spinal cord involvement with a lactate peak (LBSL). These imaging clues refine differential diagnosis, guide targeted genetic testing, and support longitudinal monitoring. CONCLUSION: The use of MRI-especially when complemented by DWI and MRS-remains central for early recognition and classification of leukodystrophies. A structured, pattern-based approach integrating clinical context with imaging topography can reduce diagnostic delay and support timely management.

OBJECTIVES: To determine whether boys with VUS detected through Newborn screening (NBS) for Adrenoleukodystrophy (ALD) develop adrenal insufficiency (aiALD) and cerebral ALD (cALD) at rates comparable to those with pathogenic variants, and to evaluate the relationship between C26:0-lysophosphatidylcholine (C26:0-LPC) levels and clinical outcomes. METHODS: We conducted a retrospective multicenter cohort study (2013-2025) across six US centers, including 201 males identified through NBS in 19 states. Variants were classified as pathogenic (n=65), likely pathogenic (n=45), or VUS (n=88). Primary outcomes were development of aiALD and cALD; secondary outcomes included C26:0-LPC levels. Statistical analyses included Kaplan-Meier, mixed-effects regression, and Cox models. RESULTS: 201 males with ABCD1 variants identified through NBS for ALD. Median age at last follow-up was 4.2 years (IQR 2.5-7.9). Overall, 26% developed aiALD (54% pathogenic, 16% likely pathogenic, 11% VUS), and 8% developed cALD (11%, 9%, and 4.5%, respectively). Pathogenic/likely pathogenic variants were associated with higher odds of aiALD than VUS (OR 5.8; 95% CI 2.16-15.58; p=0.001). At 150 months, 39% of individuals with pathogenic/likely pathogenic variants remained free of aiALD versus 85% with VUS. C26:0-LPC levels were higher in pathogenic variants and correlated with genotype (p=0.0006). Higher levels were associated with increased aiALD risk and earlier onset (HR 1.38 per 0.1 µmol/L; 95% CI 1.20-1.59; p<0.0001). CONCLUSIONS: Boys with VUS had lower rates of aiALD and lower C26:0-LPC levels than those with pathogenic variants, although some developed disease. C26:0-LPC correlates with genotype and risk, supporting its role in variant classification and risk-stratified surveillance. WHAT’S KNOWN ON THIS SUBJECT: Newborn screening for X-linked adrenoleukodystrophy has increased identification of variants of uncertain significance, accounting for up to 50% of screen-positive cases in some states. These are often associated with borderline biomarker levels, and their natural history remains poorly understood. WHAT THIS STUDY ADDS: Screen-positive individuals with VUS had substantially lower rates of disease onset than those with pathogenic variants. Newborn biomarker levels also correlated with variant pathogenicity and disease onset, which may aid future variant classification and risk stratification.

OBJECTIVE: To compare adult females with X-linked adrenoleukodystrophy to age-matched controls and to evaluate the influence of this pathology on clinical presentation and responsiveness to exercise. METHODS: 14 females with X-linked adrenoleukodystrophy and 12 age-matched controls participated in a pre-post design with a 12-week exercise intervention. Outcome measures include neurological exam; quantitative strength, sensation, and walking measures; pain and quality of life questionnaires, and 3 T imaging for white matter integrity of brain and cervical spinal cord. RESULTS: At pre-test, females with X-linked adrenoleukodystrophy were significantly worse than controls in hip strength (flexion p = 0.02, extension p = 0.008), sensation (p < 0.0001), walk speed (Timed 25 ft walk p = 0.006, Timed up and go p = 0.02, walk velocity p = 0.13), pain (p = 0.007), and quality of life (p = 0.01). Significant positive changes are found in post-training for strength (flexion p = 0.03, extension p = 0.006) and walking (Timed 25-ft walk p = 0.01, walk velocity p = 0.008). Strength is the most significant factor affecting change in walk velocity in the regression model including group, disability, and imaging. Pain is the only factor that relates to quality of life, however, post training, improved strength moderates this relationship. Age significantly contributes to weakness in X-linked adrenoleukodystrophy but not to vibratory loss. White matter integrity contributes to models of vibratory loss and predicting walking benefits from exercise. INTERPRETATION: This data identifies meaningful outcomes for clinical trials and treatment guidelines for the health of females with X-linked adrenoleukodystrophy. Sensory loss quantification is an important marker of this pathology regardless of age-related changes. Pain significantly impacts quality of life. Importantly, we show that females with X-ALD responded to exercise with improved strength and walking as much as controls, despite starting from a more impaired state.